Lipids

NATURE OF LIPIDSNATURE OF LIPIDS

Lipids have a hydrophobic nature Lipids have a hydrophobic nature because of the predominance of because of the predominance of hydrocarbon chains (—CHhydrocarbon chains (—CH22—CH—CH22 —CH—CH22—) in their structure. —) in their structure.

They areThey are insoluble or only poorly insoluble or only poorly soluble in water, but readily soluble in water, but readily soluble in nonpolar solvents such soluble in nonpolar solvents such as ether and benzene.as ether and benzene.

Some common classifications of Some common classifications of lipids and their general biologic lipids and their general biologic functionsfunctions

Lipid Primary Functions

Fatty acids Energy sources, biosynthetic precursors

Triacylglycerols Storage, transport

Phosphoglycerides Membrane components

Ketone bodies Energy sources

Sphingolipids Membrane components

Eicosanoids Modulators of physiologic activity

Cholesterol Membrane component

Steroid hormones Modulators of physiologic activity

Common Common NameName

Systematic NameSystematic Name No. No. Carbon Carbon AtomsAtoms

No. No. Double Double BondsBonds

MelMel. . Point Point (°C)(°C)

LauricLauric DodecanoicDodecanoic 1212 00 43.543.5

MyristicMyristic TetradecanoicTetradecanoic 1414 00 54.454.4

PalmiticPalmitic HexadecanoicHexadecanoic 1616 00 62.862.8

StearicStearic OctadecanoicOctadecanoic 1818 00 69.669.6

PalmitoleicPalmitoleic cis-cis-99-Hexadecenoic-Hexadecenoic 1616 11 1.01.0

OleicOleic cis-cis-99-Octadecenoic-Octadecenoic 1818 11 13.013.0

LinoleicLinoleic all cis-all cis-99,,1212-Octadecadienoic-Octadecadienoic 1818 22 -11.0-11.0

LinolenicLinolenic all cis-all cis-99,,1212,,1515-Octadecatrienoic-Octadecatrienoic 1818 33 -11.2-11.2

ArachidonicArachidonic all cis-all cis-55,,88,,1111,,1414-Eicosatetraenoic-Eicosatetraenoic 2020 44 -49.5-49.5

Saturated fatty acids Saturated fatty acids do not do not have double bonds in the have double bonds in the chainchain

– Nomenclature. The systematic Nomenclature. The systematic namename gives the number of carbons, gives the number of carbons, with the suffix with the suffix -anoic -anoic appended. appended. Palmitic acid, for example, has 16 Palmitic acid, for example, has 16 carbons and has the systematic carbons and has the systematic name hexadecanoic acid.name hexadecanoic acid.

– Structure. The general formulaStructure. The general formula of saturated fatty acids is CHof saturated fatty acids is CH33——(CH(CH22)n-COOH, where )n-COOH, where n n is the number is the number of methylene groups between the of methylene groups between the methyl and carboxyl carbons.methyl and carboxyl carbons.

Unsaturated fatty acids Unsaturated fatty acids have have one or more double bondsone or more double bonds In naturally occurring fatty acids, these bonds In naturally occurring fatty acids, these bonds

are always in a are always in a ciscis as opposed to a as opposed to a trans trans configuration (i.e., the single hydrogens bonded configuration (i.e., the single hydrogens bonded to each carbon are oriented in the same to each carbon are oriented in the same direction). direction).

The most commonly used system for designating The most commonly used system for designating the position of double bonds in an unsaturated the position of double bonds in an unsaturated fatty acid is the delta (fatty acid is the delta () numbering system. ) numbering system.

– Numbering system.Numbering system. The terminal carboxyl carbon is The terminal carboxyl carbon is designated C-1, and the double bond is given the designated C-1, and the double bond is given the number of the carbon on the carboxyl side of the number of the carbon on the carboxyl side of the double bond. For example, palmitoleic acid, which has double bond. For example, palmitoleic acid, which has 16 carbons and a double bond between C-9 and C-10, is 16 carbons and a double bond between C-9 and C-10, is designated 16:1:designated 16:1:9, or 16:1:9. 9, or 16:1:9.

– The The systematic namesystematic name gives the number of carbon gives the number of carbon atoms, number of double bonds (unless it has only atoms, number of double bonds (unless it has only one), and bears the suffix one), and bears the suffix -enoic-enoic. Thus, linoleic acid, . Thus, linoleic acid, with 18 carbons and two with 18 carbons and two ciscis double bonds, is double bonds, is ciscis--9,9,12-octadecadienoic acid.12-octadecadienoic acid.

Source of fatty acidsSource of fatty acids

1. Nonessential fatty acids. 1. Nonessential fatty acids. Nonessential fatty acids can be Nonessential fatty acids can be synthesized from products of glucose synthesized from products of glucose oxidation and do not, therefore, have oxidation and do not, therefore, have to be included in the diet.to be included in the diet.

2. Essential fatty acids. 2. Essential fatty acids. Fatty acids Fatty acids of the linoleic (18:2:of the linoleic (18:2:9,129,12) and linolenic ) and linolenic (18:3:(18:3:9,12,159,12,15) families must be obtained ) families must be obtained from the diet.from the diet.

Physical propertiesPhysical properties

Fatty acids are detergent-like because of Fatty acids are detergent-like because of their their amphipathic natureamphipathic nature. . They have They have non-polar (CHnon-polar (CH33) and polar (—COOH) ends. ) and polar (—COOH) ends. In biphasic systems, they orient with the In biphasic systems, they orient with the polar end associated with water and the polar end associated with water and the nonpolar end associated with the nonpolar end associated with the hydrophobic phase.hydrophobic phase.

The melting point of fatty acids is related The melting point of fatty acids is related to chain length and degree of to chain length and degree of unsaturation. The longer the chain length, unsaturation. The longer the chain length, the higher the melting point; the greater the higher the melting point; the greater the number of double bonds, the lower the the number of double bonds, the lower the melting point.melting point.

Triacylglycerols Triacylglycerols (triglycerides)(triglycerides)

Structure.Structure. Triacylglycerols are Triacylglycerols are triesters of glycerol and three triesters of glycerol and three fatty acids.fatty acids.

FunctionFunction Fatty acids are converted to triacylglycerols for Fatty acids are converted to triacylglycerols for

transport between tissues and for storage of transport between tissues and for storage of metabolic fuel.metabolic fuel.– The main stores of metabolic fuel in humans are the fat The main stores of metabolic fuel in humans are the fat

deposits in fat cells deposits in fat cells (adipocytes).(adipocytes). These serve long-term These serve long-term needs for metabolic fuel.needs for metabolic fuel. Triacylglycerols have two major advantages over other forms Triacylglycerols have two major advantages over other forms

of metabolic fuel. of metabolic fuel. – Triacylglycerols provide a concentrated form of fuel because their Triacylglycerols provide a concentrated form of fuel because their

complete combustion to carbon dioxide (COcomplete combustion to carbon dioxide (CO22) and water releases ) and water releases 9 kcal/g as opposed to 4 kcal/g for carbohydrate.9 kcal/g as opposed to 4 kcal/g for carbohydrate.

– Because they are water insoluble, triacylglycerols present no Because they are water insoluble, triacylglycerols present no osmotic problems to the cell when stored in large amounts.osmotic problems to the cell when stored in large amounts.

LipolysisLipolysis involves the involves the hydrolysis of hydrolysis of triacylglycerols to free glycerol and free fatty triacylglycerols to free glycerol and free fatty acidsacids (also known as (also known as nonesterified fatty acids)nonesterified fatty acids) with both products leaving the adipocyte. The with both products leaving the adipocyte. The appearance of fatty acids in the blood during fasting appearance of fatty acids in the blood during fasting is due to the mobilization of fat stores by this is due to the mobilization of fat stores by this process.process.– Utilization of fatty acidsUtilization of fatty acids. . Fatty acids are used by most Fatty acids are used by most

tissues, except the brain, as a metabolic fuel.tissues, except the brain, as a metabolic fuel.– Utilization of glycerolUtilization of glycerol. . Glycerol is used by the liver as a Glycerol is used by the liver as a

substrate for gluconeogenesis.substrate for gluconeogenesis.

Ketone bodiesKetone bodies

Ketone bodies, Ketone bodies, which are formed from fatty which are formed from fatty acids and carbohydrates, include acetone, acids and carbohydrates, include acetone, acetoacetate, and acetoacetate, and -hydroxybutyrate.-hydroxybutyrate.

– Ketone bodies are synthesized in liver mitochondria Ketone bodies are synthesized in liver mitochondria and released into the blood for use as metabolic fuel and released into the blood for use as metabolic fuel by other tissues. by other tissues. The liver does not use ketone The liver does not use ketone bodiesbodies..

– Levels of synthesis are high when the rate of fatty Levels of synthesis are high when the rate of fatty acid oxidation is high and carbohydrate utilization is acid oxidation is high and carbohydrate utilization is low. This occurs during fasting, starvation, untreated low. This occurs during fasting, starvation, untreated diabetes, and prolonged alcohol abuse.diabetes, and prolonged alcohol abuse.

C O

CH3

CH3

C O

CH3

CH2

CHO

O

CH OH

CH3

CH2

CHO

O

KetoacidosisKetoacidosis

Ketoacidosis Ketoacidosis is an imbalance of blood pH is an imbalance of blood pH caused by the excessive accumulation of caused by the excessive accumulation of acetoacetate or acetoacetate or -hydroxybutyrate, which are -hydroxybutyrate, which are weak acids.weak acids. – KetosisKetosis refers to refers to ketonuriaketonuria (high urine levels of (high urine levels of

ketone bodies) and ketone bodies) and ketonemiaketonemia (high blood levels (high blood levels of ketone bodies).of ketone bodies).

– During starvation, ketone bodies are the only During starvation, ketone bodies are the only source of fuel, so they are consumed by the body, source of fuel, so they are consumed by the body, and there is no excess to accumulate. In contrast, and there is no excess to accumulate. In contrast, in untreated diabetes, blood levels of ketone in untreated diabetes, blood levels of ketone bodies may become high enough to produce life-bodies may become high enough to produce life-threatening ketoacidosisthreatening ketoacidosis

PHOSPHOLIPIDSPHOSPHOLIPIDS

are the major lipid constituents of are the major lipid constituents of cellular membranes. cellular membranes.

They comprise approximately They comprise approximately 40% of the lipids in the 40% of the lipids in the erythrocyte membrane and more erythrocyte membrane and more than 95% of the lipids in the inner than 95% of the lipids in the inner mitochondrial membrane. mitochondrial membrane.

PhosphoglyceridesPhosphoglycerides

are triesters of glycerol-3-are triesters of glycerol-3-phosphate in which two phosphate in which two esters have been formed esters have been formed between the two hydroxyl between the two hydroxyl groups and fatty acid side groups and fatty acid side chains (Rchains (R11 and R and R22), and a third ), and a third ester has been formed ester has been formed between the phosphate group between the phosphate group and a hydroxyl-containing and a hydroxyl-containing compound, X.compound, X.

CH2

CH

CH2

O

O

O

P

C

C

O

O

O

R1

R2

O

O-

X

Classification of Classification of phosphoglyceridesphosphoglycerides

Phosphoglycerides include the Phosphoglycerides include the following compounds:following compounds:– PhosphatidylcholinePhosphatidylcholine (lecithin)(lecithin)– PhosphatidylethanolaminePhosphatidylethanolamine (a cephalin)(a cephalin)– PhosphatidylserinePhosphatidylserine (a cephalin)(a cephalin)– PhosphatidylinositolPhosphatidylinositol– Cardiolipin,Cardiolipin, which comprises which comprises

approximately 20% of the lipids of the approximately 20% of the lipids of the inner mitochondrial membraneinner mitochondrial membrane

Characteristics of Characteristics of phosphoglyceridesphosphoglycerides Phosphoglycerides are the most polar Phosphoglycerides are the most polar

lipids and are lipids and are amphipathicamphipathic, , possessing possessing both hydrophilic and both hydrophilic and hydrophobic groupshydrophobic groups. . They inhabit They inhabit transition regions between aqueous and transition regions between aqueous and nonaqueous phases.nonaqueous phases.

Phosphoglycerides are Phosphoglycerides are amphoteric, amphoteric, bearingbearing both negatively and both negatively and positively charged groups.positively charged groups.

SPHINGOLIPIDSSPHINGOLIPIDS are present in are present in nearly all human tissues. The nearly all human tissues. The greatest concentration of greatest concentration of sphingolipids is found in the sphingolipids is found in the central nervous system (CNS), central nervous system (CNS), particularly in white matterparticularly in white matter

SPHINGOLIPIDSSPHINGOLIPIDS

Function.Function. Sphingomyelin is the major Sphingomyelin is the major phospholipid component of membranes in phospholipid component of membranes in neural tissues.neural tissues.

Structure.Structure. Sphingomyelin, which is Sphingomyelin, which is derived from the amino alcohol, derived from the amino alcohol, sphingosine, is the only sphingolipid that sphingosine, is the only sphingolipid that contains phosphate and has no sugar contains phosphate and has no sugar moiety. It is formed from moiety. It is formed from ceramideceramide, , which is the which is the core structurecore structure of naturally of naturally occurring sphingolipids, including the occurring sphingolipids, including the glycosphingolipids.glycosphingolipids.

Glycosphingolipids Glycosphingolipids are are sphingolipids that sphingolipids that contain carbohydrate contain carbohydrate moietiesmoieties CerebrosidesCerebrosides are ceramide monohexosides, the are ceramide monohexosides, the

most important being most important being galactocerebroside and galactocerebroside and glucocerebroside.glucocerebroside. Cerebrosides are found in neural Cerebrosides are found in neural tissue membranes, particularly the myelin sheath.tissue membranes, particularly the myelin sheath.

SulfatidesSulfatides are Cerebrosides that contain sulfated are Cerebrosides that contain sulfated sugars. sugars. -Sulfogalactocerebroside-Sulfogalactocerebroside accounts for accounts for approximately 15% of the lipids in white matter of approximately 15% of the lipids in white matter of the brain.the brain.

GlobosidesGlobosides are ceramide oligosaccharides that are ceramide oligosaccharides that contain two or more sugar molecules, most often contain two or more sugar molecules, most often galactose, glucose, or N-acetylgalactosamine, galactose, glucose, or N-acetylgalactosamine, attached to ceramide. They are found in serum, the attached to ceramide. They are found in serum, the spleen, the liver, and erythrocytes. For example, spleen, the liver, and erythrocytes. For example, lactosylceramidelactosylceramide is found in erythrocyte is found in erythrocyte membranesmembranes

GangliosidesGangliosides

Nature Nature Gangliosides are glycosphingolipids that contain one or Gangliosides are glycosphingolipids that contain one or

more neuraminic acid residues, usually as the N-acetyl more neuraminic acid residues, usually as the N-acetyl derivative [i.e., derivative [i.e., N-acetylneuraminic acidN-acetylneuraminic acid (NANA)], which (NANA)], which is is sialic acid. sialic acid. They are found in high concentration in They are found in high concentration in ganglion cells of the CNS and in lower concentration in the ganglion cells of the CNS and in lower concentration in the membranes of most cells.membranes of most cells.

NomenclatureNomenclature The letter G is used to denote a ganglioside, with M, D, T, or The letter G is used to denote a ganglioside, with M, D, T, or

Q to indicate, respectively, mono-, di-, tri-, or quatrosialic Q to indicate, respectively, mono-, di-, tri-, or quatrosialic acid contents. Numerical subscripts are based on their acid contents. Numerical subscripts are based on their chromatographic migration. For example:chromatographic migration. For example:– GM1 = Gal-(N-AcGal)-Gal-Glc-CerGM1 = Gal-(N-AcGal)-Gal-Glc-Cer– GM2 = (N-AcGal)-Gal-Glc-CerGM2 = (N-AcGal)-Gal-Glc-Cer– GM3 = Gal-Glc-CerGM3 = Gal-Glc-Cer

where where Cer Cer = ceramide, = ceramide, Glc = Glc = glucose, glucose, Gal = Gal = galactose, and galactose, and N-AcGal N-AcGal = N-acetylgalactosamine.= N-acetylgalactosamine.

For example, the GM2 ganglioside is:For example, the GM2 ganglioside is:

(N-AcGal)-Gal-Glc-Cer

NANA

SphingolipidosesSphingolipidoses are inherited genetic disorders are inherited genetic disorders referred to as referred to as lipid storage diseases, lipid storage diseases, in which there is a in which there is a deficiency of an enzyme that is involved in the normal deficiency of an enzyme that is involved in the normal catabolism of a particular sphingolipidcatabolism of a particular sphingolipid. . This results in This results in the intracellular accumulation of that lipid to harmful the intracellular accumulation of that lipid to harmful levels.levels.

Disease Lipid Accumulated Enzyme Deficiency

Primary Organ Affected

Niemann-Pick Sphingomyelin Sphingomyelinase Brain, liver, spleen

Gaucher's Glucocerebroside -Glucosidase Brain, liver, spleen

Krabbe's Galactocerebroside -Galactosidase Brain

Metachromatic leukodystrophy

-Sulfogalactocerebroside Sulfatide sulfatase Brain

Fabry's Ceramide trihexoside -Galactosidase Kidneys

Tay-Sachs Ganglioside GM2 Hexosaminidase A Brain

STEROIDSSTEROIDS

STEROIDSSTEROIDS are lipids that contain are lipids that contain four fused carbon rings that form the four fused carbon rings that form the cyclopentanoperhydrophenanthrene cyclopentanoperhydrophenanthrene steroid nucleus.steroid nucleus.

CholesterolCholesterol is the major is the major sterolsterol in the human body. in the human body. Sterols are a class of steroids characterized by a Sterols are a class of steroids characterized by a hydroxyl group at carbon 3, and an aliphatic chain hydroxyl group at carbon 3, and an aliphatic chain of at least eight carbons at C-17of at least eight carbons at C-17

Cholesterol is a Cholesterol is a structural componentstructural component of of cell membranes and plasma lipoproteins.cell membranes and plasma lipoproteins.

ItIt is the is the precursorprecursor from which steroid from which steroid hormones and bile acids are synthesized.hormones and bile acids are synthesized.

Vitamin DThe binding of vitamin D to receptor turns on the gene responsiblefor the synthesis of a Ca2+ binding protein

Absence in diet, or insufficient sunlight, leads to rickets

Typically vitamins areincluded in various foodssuch as bread and milk.

Vitamin D2 is added to milk and butter

Purification of Lipids from Biological Samples

Purification of Lipids from Biological Samples

Lipid metabolism. OVERVIEW

Digestion of lipidsDigestion of lipids

Triacylglycerol Triacylglycerol is the major is the major dietary lipid of nutritional dietary lipid of nutritional valuevalue EmulsificationEmulsification

– Digestion of lipids begins in the duodenum, when the Digestion of lipids begins in the duodenum, when the entrance of the entrance of the acid chyme acid chyme from the stomach from the stomach stimulates secretion of enteric hormones by the stimulates secretion of enteric hormones by the duodenal mucosa.duodenal mucosa.

– Bile salts and phosphatidylcholine Bile salts and phosphatidylcholine act as detergents act as detergents in the duodenum due to their amphipathic structures. in the duodenum due to their amphipathic structures. They aid in formation of mixed micelles (which have a They aid in formation of mixed micelles (which have a large surface area) from fat globules (which have a small large surface area) from fat globules (which have a small surface area).surface area).

– The micellar associations of lipids are the substrates for The micellar associations of lipids are the substrates for hydrolyzing enzymes.hydrolyzing enzymes.

Hydrolysis of triacylglycerols is effected by Hydrolysis of triacylglycerols is effected by three enzymes.three enzymes.– Pancreatic lipase Pancreatic lipase cleaves triacylglycerols to 2-cleaves triacylglycerols to 2-

monoacylglycerol and two fatty acids.monoacylglycerol and two fatty acids.– Cholesterol esterase Cholesterol esterase hydrolyzes cholesterol esters to hydrolyzes cholesterol esters to

cholesterol plus a fatty acid. cholesterol plus a fatty acid. – Phospholipase Phospholipase A2 hydrolyzes phospholipid.A2 hydrolyzes phospholipid.

CHYLOMICRON FORMATIONCHYLOMICRON FORMATIONFree fatty acids and monoacylglycerols are Free fatty acids and monoacylglycerols are absorbed by intestinal epithelial cells. absorbed by intestinal epithelial cells. Triacylglycerols are resynthesized and packaged Triacylglycerols are resynthesized and packaged with other lipids and apoprotein B-48 to form with other lipids and apoprotein B-48 to form chylomicrons, which are then released into the chylomicrons, which are then released into the lymph system.lymph system.

Schematic Model of Low-Density Lipoprotein. The LDL particle is approximately 22 nm (220 Å) in diameter

Sites of lipoprotein formation Sites of lipoprotein formation and transportand transport

The liver is the formation site of:The liver is the formation site of:– Very low-density lipoproteinsVery low-density lipoproteins (VLDL),(VLDL), which transport which transport

triacylglycerols from the liver to other tissues triacylglycerols from the liver to other tissues – High-density lipoproteinsHigh-density lipoproteins (HDL),(HDL), which transport excess which transport excess

cholesterol from other tissues to the liver and are sometimes referred cholesterol from other tissues to the liver and are sometimes referred to as "good" cholesterolto as "good" cholesterol

The intestineThe intestine is the site of is the site of chylomicron formationchylomicron formation. . Chylomicrons are triacylglycerols that are given a coat composed Chylomicrons are triacylglycerols that are given a coat composed of protein, phospholipids, and cholesterol esters.of protein, phospholipids, and cholesterol esters.– Chylomicrons are transported in membrane-bound vesicles to Chylomicrons are transported in membrane-bound vesicles to

membranes of mucosal cells, where they are released by exocytosis membranes of mucosal cells, where they are released by exocytosis into the extracellular space. Once chylomicrons are in the plasma, into the extracellular space. Once chylomicrons are in the plasma, most of the lipids contained in the chylomicrons are removed by most of the lipids contained in the chylomicrons are removed by lipoprotein lipase, forming lipoprotein lipase, forming chylomicron remnants,chylomicron remnants,

– Chylomicron remnants deliver dietary fat to the liver. The Chylomicron remnants deliver dietary fat to the liver. The chylomicron remnants that remain after delipidation are enriched in chylomicron remnants that remain after delipidation are enriched in cholesterol and cholesterol ester. They are cleared by the liver, cholesterol and cholesterol ester. They are cleared by the liver, where most of the cholesterol is used for bile acid synthesis.where most of the cholesterol is used for bile acid synthesis.

The plasmaThe plasma is the formation site of:is the formation site of:– Intermediate-density lipoproteinsIntermediate-density lipoproteins (IDL),(IDL), which are the initial which are the initial

product of VLDL degradationproduct of VLDL degradation– Low-density lipoproteinsLow-density lipoproteins (LDL),(LDL), which transport cholesterol esters which transport cholesterol esters – Chylomicron remnantsChylomicron remnants

Properties of Major Plasma Properties of Major Plasma LipoproteinsLipoproteins

HDL LDL IDL VLDL Chylomicron

Density (g/ml) 1.06-1.2 1.02-1.06 1.01-1.02 0.95-1.01 <0.95

Diameter (nm) 5-20 20-25 25-30 30-90 90-1 000

% Lipid 50-55 75-80 80-85 90-95 98

% Total lipid as:

Cholesterol (free) 3-4 7-10 8 5-10 1-3

Cholesterol ester 12 35-40 22 10-12 3-5

Phospholipid 20-25 15-20 22 15-20 7-9

Triacylglycerol 3 7-10 30 50-65 84-89

% Protein content 45-50 20-25 15-20 5-10 2

% Total protein as apoprotein (Apo):

ApoA-1,A-2,A-4 90-95 0 0 0-3 0-3

ApoB-48,B-100 0-2 95-100 50-60 40-50 20-22

ApoC-1,C-2,C-3 4-6 0-5 20 35-40 60-65

ApoD 0-2 0 0 0 1

ApoE 0-5 0 15-20 5-10 5

Receptor-Mediated EndocytosisReceptor-Mediated Endocytosis

The process of receptor-mediated endocytosis is The process of receptor-mediated endocytosis is illustrated for the cholesterol-carrying complex, low-illustrated for the cholesterol-carrying complex, low-density lipoprotein (LDL): density lipoprotein (LDL):

(1) LDL binds to a specific receptor, the LDL receptor;(1) LDL binds to a specific receptor, the LDL receptor; (2) this complex invaginates to form an internal (2) this complex invaginates to form an internal

vesicle; vesicle; (3) after separation from its receptor, the LDL-(3) after separation from its receptor, the LDL-

containing vesicle fuses with a lysosome, leading to containing vesicle fuses with a lysosome, leading to degradation of the LDL and release of the cholesteroldegradation of the LDL and release of the cholesterol

(A) Electron micrograph showing LDL (A) Electron micrograph showing LDL (conjugated to ferritin for visualization, (conjugated to ferritin for visualization, dark spots) bound to a coated-pit region on dark spots) bound to a coated-pit region on the surface of a cultured human fibroblast the surface of a cultured human fibroblast cell.cell.

(B) Micrograph showing this region (B) Micrograph showing this region invaginating and fusing to form an invaginating and fusing to form an endocytic vesicleendocytic vesicle

Endocytosis of LDL Bound to Its Endocytosis of LDL Bound to Its ReceptorReceptor

Disorders of Disorders of lipoprotein metabolismlipoprotein metabolism

HyperlipidemiasHyperlipidemias represent an represent an abnormally high level of plasma abnormally high level of plasma lipoproteins. lipoproteins.

The most serious consequence of The most serious consequence of hyperlipidemias is increased risk of hyperlipidemias is increased risk of atherosclerosis,atherosclerosis, an arterial an arterial disease that causes heart attacks disease that causes heart attacks and stroke.and stroke.

Types of HyperlipidemiasTypes of Hyperlipidemias

Type Generic Classification Increased Lipoprotein

Increased Lipid

I Lipoprotein lipase deficiency Chylomicrons Triacylglycerols

IIa Hypercholesterolemia (LDL receptor deficiency)

LDL Cholesterol

IIb Combined hyperlipidemia LDL, VLDL Triacylglycerols, cholesterol

III Dysbetalipoproteinemia -VLDL Triacylglycerols, cholesterol

IV Hypertriglyceridemia VLDL Triacylglycerols

V Mixed hyperlipidemia VLDL, chylomicrons

Triacylglycerols

AN ATHEROSCLEROTIC AN ATHEROSCLEROTIC PLAQUEPLAQUE

A plaque (marked A plaque (marked by an arrow) blocks by an arrow) blocks most of the lumen most of the lumen of this blood vessel. of this blood vessel. The plaque is rich The plaque is rich in cholesterol.in cholesterol.

HypolipidemiasHypolipidemias are caused by a deficiency are caused by a deficiency of one or more of the plasma lipoproteinsof one or more of the plasma lipoproteins

HypobetalipoproteinemiaHypobetalipoproteinemia (abetalipoproteinemia) (abetalipoproteinemia) is a genetic disorder characterized by neurologic is a genetic disorder characterized by neurologic symptoms, including ataxia and mental retardation. symptoms, including ataxia and mental retardation.

– Plasma triacylglycerol and cholesterol levels are decreased.Plasma triacylglycerol and cholesterol levels are decreased.– There is a complete absence of (3-lipoproteins (no There is a complete absence of (3-lipoproteins (no

chylomicrons or VLDLs).chylomicrons or VLDLs).– Absorption of fat is greatly reduced.Absorption of fat is greatly reduced.

HDL deficiency (Tangier disease)HDL deficiency (Tangier disease) is is characterized by recurrent polyneuropathy, characterized by recurrent polyneuropathy, lymphadenopathy, tonsillar hyperplasia, and lymphadenopathy, tonsillar hyperplasia, and hepatosplenomegaly (from storage of cholesterol in hepatosplenomegaly (from storage of cholesterol in reticuloendothelial cells).reticuloendothelial cells).

– Plasma cholesterol levels are low; triacylglycerols are Plasma cholesterol levels are low; triacylglycerols are normal or increasednormal or increased

– There is a marked decrease in plasma HDLsThere is a marked decrease in plasma HDLs

FATTY ACIDS FATTY ACIDS BIOSYNTHESISBIOSYNTHESIS

GENERAL FEATURES OF FATTY GENERAL FEATURES OF FATTY ACIDS BIOSYNTHESISACIDS BIOSYNTHESIS Fatty acids may be synthesized from dietary Fatty acids may be synthesized from dietary

glucose via pyruvate.glucose via pyruvate. Fatty acids are the preferred fuel source for the Fatty acids are the preferred fuel source for the

heart and the primary form in which excess fuel is heart and the primary form in which excess fuel is stored in adipose tissue.stored in adipose tissue.

The major site of fatty acid synthesis is the The major site of fatty acid synthesis is the liver.liver. The enzymes that synthesize fatty acids are The enzymes that synthesize fatty acids are

localized in the localized in the cytosol,cytosol, and they are completely and they are completely different from the mitochondrial enzymes that different from the mitochondrial enzymes that catalyze fatty acid degradation.catalyze fatty acid degradation.

The major synthetic pathway involves The major synthetic pathway involves polymerization of two-carbon units derived from polymerization of two-carbon units derived from acetyl coenzyme Aacetyl coenzyme A (acetyl CoA)(acetyl CoA) to form a to form a sixteen-carbon saturated fatty acid, palmitic acid.sixteen-carbon saturated fatty acid, palmitic acid.

Reduced nicotinamide adenine dinucleotide Reduced nicotinamide adenine dinucleotide phosphate (NADPH) and adenosine triphosphate phosphate (NADPH) and adenosine triphosphate (ATP) are required for fatty acid synthesis.(ATP) are required for fatty acid synthesis.

Sources of acetyl CoA and NADPHSources of acetyl CoA and NADPH CytosolCytosol

– Acetyl CoA is derived from the oxidation Acetyl CoA is derived from the oxidation of glucose via glycolysis and pyruvate of glucose via glycolysis and pyruvate dehydrogenase. dehydrogenase.

– NADPH is generated by the pentose NADPH is generated by the pentose phosphate pathway.phosphate pathway.

Acetyl CoA carboxylaseAcetyl CoA carboxylase

This enzyme catalyzes the ATP-dependent This enzyme catalyzes the ATP-dependent carboxylation of acetyl CoA to malonyl CoA. carboxylation of acetyl CoA to malonyl CoA.

This is the This is the key regulatory sitekey regulatory site for fatty acid for fatty acid synthesis.synthesis.

– ActivatorsActivators are citrate and insulin.are citrate and insulin.– InhibitorsInhibitors are palmitoyl CoA and glucagon.are palmitoyl CoA and glucagon.

BiotinBiotin is a required cofactor. Acetyl CoA carboxylase is a required cofactor. Acetyl CoA carboxylase is one of the enzymes that is inactive in the condition is one of the enzymes that is inactive in the condition known as known as multiple carboxylasemultiple carboxylase deficiencydeficiency, which is , which is due to an inability to utilize biotin.due to an inability to utilize biotin.

Animal Fatty Acid Animal Fatty Acid SynthaseSynthase

Schematic Representation of Animal Fatty Acid Schematic Representation of Animal Fatty Acid SynthaseSynthase

Each of the identical chains in the dimer contains three domains. Each of the identical chains in the dimer contains three domains. Domain 1 (blue) contains acetyl transferase (AT), malonyl transferase (MT), and Domain 1 (blue) contains acetyl transferase (AT), malonyl transferase (MT), and

condensing enzyme (CE). condensing enzyme (CE). Domain 2 (yellow) contains acyl carrier protein (ACP), β-ketoacyl reductase (KR), Domain 2 (yellow) contains acyl carrier protein (ACP), β-ketoacyl reductase (KR),

dehydratase (DH), and enoyl reductase (ER). Domain 3 (red) contains thioesterase dehydratase (DH), and enoyl reductase (ER). Domain 3 (red) contains thioesterase (TE). (TE).

The flexible phosphopantetheinyl group (green) carries the fatty acyl chain from one The flexible phosphopantetheinyl group (green) carries the fatty acyl chain from one catalytic site on a chain to another, as well as between chains in the dimercatalytic site on a chain to another, as well as between chains in the dimer

The fatty acid synthase enzyme The fatty acid synthase enzyme complexcomplex catalyzes several reactions catalyzes several reactions that convert acetyl CoA and malonyl that convert acetyl CoA and malonyl CoA to butyryl CoACoA to butyryl CoA

The acetyl transacylaseThe acetyl transacylase component catalyzes component catalyzes the conversion ofthe conversion of

acetyl CoA + acyl carrier protein (ACP) → acetyl-ACP + acetyl CoA + acyl carrier protein (ACP) → acetyl-ACP + CoACoA

– ACP possesses a ACP possesses a phosphopantetheine prosthetic phosphopantetheine prosthetic group, group, which is derived from the vitamin pantothenic which is derived from the vitamin pantothenic acid and is identical to that portion of the CoA molecule.acid and is identical to that portion of the CoA molecule.

– The acyl groups of the substrate molecules are The acyl groups of the substrate molecules are covalently bound to ACP via a thioester linkage with the covalently bound to ACP via a thioester linkage with the terminal sulfhydryl group.terminal sulfhydryl group.

The malonyl transacylaseThe malonyl transacylase component component catalyzes the conversion of catalyzes the conversion of malonyl CoA + ACP → malonyl-ACP + CoAmalonyl CoA + ACP → malonyl-ACP + CoA

PhosphopantetheinePhosphopantetheine

Both acyl carrier protein and CoA include Both acyl carrier protein and CoA include phosphopantetheine as their reactive units. ACP, a phosphopantetheine as their reactive units. ACP, a single polypeptide chain of 77 residues, can be single polypeptide chain of 77 residues, can be regarded as a giant prosthetic group, a “macro regarded as a giant prosthetic group, a “macro CoA.”CoA.”

The 3-ketoacyl synthaseThe 3-ketoacyl synthase component component catalyzes the conversion of catalyzes the conversion of

malonyl-ACP + acetyl-ACP → acetoacetyl-ACP + ACP + COmalonyl-ACP + acetyl-ACP → acetoacetyl-ACP + ACP + CO22

The 3-ketoacyl reductaseThe 3-ketoacyl reductase component component catalyzes the NADPH-dependent conversion of catalyzes the NADPH-dependent conversion of

acetoacetyl-ACP → 3-hydroxybutyryl-ACPacetoacetyl-ACP → 3-hydroxybutyryl-ACP The 3-hydroxybutyryl-ACP dehydrataseThe 3-hydroxybutyryl-ACP dehydratase

component catalyzes the conversion of component catalyzes the conversion of

3-hydroxybutyryl-ACP → crotonyl-ACP3-hydroxybutyryl-ACP → crotonyl-ACP.. The enoyl-ACP reductaseThe enoyl-ACP reductase component component

catalyzes the NADPH-dependent conversion of catalyzes the NADPH-dependent conversion of

crotonyl-ACP → butyryl-ACPcrotonyl-ACP → butyryl-ACP

Formation of palmitic acidFormation of palmitic acid Reaction.Reaction. Butyryl-ACP (a four-carbon unit) reacts Butyryl-ACP (a four-carbon unit) reacts

with another malonyl group via the reactions with another malonyl group via the reactions described above to form a six-carbon unit, and the described above to form a six-carbon unit, and the reactions of the fatty acid synthase complex reactions of the fatty acid synthase complex continue. continue.

Reaction repeats.Reaction repeats. After After seven turns seven turns of this cycle, of this cycle, palmitic-ACP (a 16-carbon unit) is synthesized. palmitic-ACP (a 16-carbon unit) is synthesized.

Release.Release. Palmitic acid is released from ACP and the Palmitic acid is released from ACP and the fatty acid synthase complex fatty acid synthase complex by palmitoyl by palmitoyl deacylasedeacylase (thioesterase).(thioesterase).

Stoichiometry of the synthesis of Stoichiometry of the synthesis of palmitatepalmitate

8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H++ + H + H22O O → →

→→ Palmitate + 7 ADP + 7PPalmitate + 7 ADP + 7Pii + 8 CoASH + 14 + 8 CoASH + 14 NADPNADP++

Elongation of fatty acidsElongation of fatty acids. .

Fatty acids longer than 16 carbons can be Fatty acids longer than 16 carbons can be formed via one of two elongation systems formed via one of two elongation systems adding 2-carbon unitsadding 2-carbon units

The endoplasmic reticulum systemThe endoplasmic reticulum system is the most is the most active. It adds malonyl CoA onto palmitate in a active. It adds malonyl CoA onto palmitate in a manner similar to the action of fatty acid synthase, manner similar to the action of fatty acid synthase, except that CoASH is used rather than the ACP. except that CoASH is used rather than the ACP. Stearic acid (an 18-carbon unit) is the product.Stearic acid (an 18-carbon unit) is the product.

A mitochondrial elongation system A mitochondrial elongation system uses acetyl uses acetyl CoA units, rather than malonyl CoA units, to CoA units, rather than malonyl CoA units, to elongate fatty acids for the synthesis of structural elongate fatty acids for the synthesis of structural lipids in this organelle.lipids in this organelle.

Desaturation of fatty acidsDesaturation of fatty acids

The two most common monounsaturated The two most common monounsaturated fatty acids in mammals are palmitoleic acid fatty acids in mammals are palmitoleic acid (16:1:(16:1:99) and oleic acid (18:1:) and oleic acid (18:1:99).).

In the endoplasmic reticulum, double bonds In the endoplasmic reticulum, double bonds are introduced between carbons 9 and 10 by are introduced between carbons 9 and 10 by fatty acid oxygenasefatty acid oxygenase, , which requires which requires molecular oxygen (Omolecular oxygen (O22) and NADPH) and NADPH

FATTY ACID FATTY ACID OXIDATIONOXIDATION

Fatty acids are an important energy Fatty acids are an important energy source. source.

Oxidation of fatty acids generates Oxidation of fatty acids generates the high-energy compounds reduced the high-energy compounds reduced NAD (NADH) and reduced flavin NAD (NADH) and reduced flavin adenine dinucleotide (FADHadenine dinucleotide (FADH22) and ) and yields acetyl CoA, which is the yields acetyl CoA, which is the substrate for the citric acid cyclesubstrate for the citric acid cycle

-Oxidation of fatty acids-Oxidation of fatty acids

-Oxidation of fatty acids is the -Oxidation of fatty acids is the principal pathway. principal pathway.

It occurs in the mitochondrial It occurs in the mitochondrial matrix and involves oxidation of matrix and involves oxidation of the the -carbon to form a -carbon to form a -keto acid-keto acid

Activation of free fatty Activation of free fatty acidsacids

Free fatty acids are taken up from the Free fatty acids are taken up from the circulation by cells and are activated by circulation by cells and are activated by formation of acyl CoA derivatives. formation of acyl CoA derivatives.

– An endoplasmic reticulum acyl CoA An endoplasmic reticulum acyl CoA synthetasesynthetase (thiokinase) activates long-chain fatty (thiokinase) activates long-chain fatty acids of 12 or more carbons.acids of 12 or more carbons.

Fatty acid + ATP + CoASH → acylCoA + PPFatty acid + ATP + CoASH → acylCoA + PPii + AMP + AMP– Inner mitochondrial acyl CoA synthetasesInner mitochondrial acyl CoA synthetases

activate medium-chain (4-10 carbons) and short-activate medium-chain (4-10 carbons) and short-chain (acetate and propionate) fatty acids. These chain (acetate and propionate) fatty acids. These fatty acids enter the mitochondria freely from the fatty acids enter the mitochondria freely from the cytoplasm, whereas the long-chain fatty acids cytoplasm, whereas the long-chain fatty acids cannot.cannot.

Role of carnitineRole of carnitine

Long-chain fatty acyl CoAs cannot Long-chain fatty acyl CoAs cannot freely diffuse across the inner freely diffuse across the inner mitochondrial membrane. mitochondrial membrane.

Carnitine in the inner Carnitine in the inner mitochondrial membrane mediates mitochondrial membrane mediates transfer of fatty acyl groups from transfer of fatty acyl groups from the cytosol to the mitochondrial the cytosol to the mitochondrial matrix where they are oxidized. matrix where they are oxidized.

Transfer reactionTransfer reaction

Sources of carnitineSources of carnitine– DietaryDietary sources include red meat and dairy sources include red meat and dairy

products.products.– Synthesis.Synthesis. Carnitine (Carnitine (-hydroxy--hydroxy---

trimethylammonium butyrate) may be synthesized in trimethylammonium butyrate) may be synthesized in the body from the amino acid lysine. the body from the amino acid lysine.

Carnitine deficiencyCarnitine deficiency in humans may be in humans may be classified as:classified as:

– Systemic,Systemic, in which levels are reduced in all tissuesin which levels are reduced in all tissues– Myopathic,Myopathic, in which levels are reduced only in in which levels are reduced only in

muscle, including the heartmuscle, including the heart

Transfer reactionTransfer reaction

CPT - carnitine palmitoyl transferase

On the outer surface of On the outer surface of the inner mitochondrial the inner mitochondrial membrane, the enzyme membrane, the enzyme carnitine palmitoyl carnitine palmitoyl transferase I (CPT transferase I (CPT I)I) catalyzes the transfer of catalyzes the transfer of the acyl group from CoA the acyl group from CoA to carnitine. The fatty to carnitine. The fatty acyl group is acyl group is translocated across the translocated across the membrane to the inner membrane to the inner surface, where the surface, where the enzyme enzyme carnitine carnitine palmitoyl transferase palmitoyl transferase II (CPT II)II (CPT II) catalyzes the catalyzes the transfer of the acyl transfer of the acyl group to CoA drawn group to CoA drawn from the matrix CoA from the matrix CoA poolpool

Reaction Sequence for the Reaction Sequence for the Degradation of Fatty Acids. Degradation of Fatty Acids. Fatty acids are degraded Fatty acids are degraded by the repetition of a four-by the repetition of a four-reaction sequence reaction sequence consisting of oxidation, consisting of oxidation, hydration, oxidation, and hydration, oxidation, and thiolysisthiolysis

Pathway of Pathway of -oxidation-oxidation In the mitochondrial matrix, long-chain fatty acyl CoAs are In the mitochondrial matrix, long-chain fatty acyl CoAs are

subjected to a subjected to a repeated four-step processrepeated four-step process that successively that successively removes two-carbon units from the chain until the last two-carbon removes two-carbon units from the chain until the last two-carbon fragment remains.fragment remains.

Acyl CoA Acyl CoA → → enoyl CoAenoyl CoA– This This dehydrogenationdehydrogenation reaction is catalyzed by a family of reaction is catalyzed by a family of acyl CoA acyl CoA

dehy-drogenasesdehy-drogenases with varying specificity for different length acyl with varying specificity for different length acyl CoA chains.CoA chains.

– The prosthetic group of this enzyme, flavin adenine dinucleotide The prosthetic group of this enzyme, flavin adenine dinucleotide (FAD), is reduced to FADH(FAD), is reduced to FADH22 during this reaction. during this reaction.

– Genetic defectsGenetic defects in acyl CoA dehydrogenases (e.g., medium-chain in acyl CoA dehydrogenases (e.g., medium-chain acyl CoA dehydrogenase deficiency) impair acyl CoA dehydrogenase deficiency) impair -oxidation. -oxidation.

Enoyl CoA → 3-hydroxyacyl CoAEnoyl CoA → 3-hydroxyacyl CoA– This This hydrationhydration reaction is catalyzed by reaction is catalyzed by enoyl CoA hydrataseenoyl CoA hydratase. .

3-Hydroxyacyl CoA → 3-ketoacyl CoA3-Hydroxyacyl CoA → 3-ketoacyl CoA– This This dehydrogenationdehydrogenation reaction is catalyzed by 3-hydroxyacyl reaction is catalyzed by 3-hydroxyacyl CoA CoA

dehydrogenasedehydrogenase..– NAD+ is reduced to NADH during this reaction.NAD+ is reduced to NADH during this reaction.

3-Ketoacyl CoA + CoASH → acetyl CoA + tetradecanoyl CoA3-Ketoacyl CoA + CoASH → acetyl CoA + tetradecanoyl CoA– This This thiolytic cleavagethiolytic cleavage reaction is catalyzed by reaction is catalyzed by thiolasethiolase ((--

ketothiolase)ketothiolase)

First Three Rounds in the Degradation of Palmitate. Two-carbon units are sequentially removed from the carboxyl end of the fatty acid

Stoichiometry of Stoichiometry of --oxidationoxidation

-Oxidation of palmitate (16 carbons)-Oxidation of palmitate (16 carbons)

PalmitoylCoA + 7CoASH + 7FAD + 7NADPalmitoylCoA + 7CoASH + 7FAD + 7NAD++ + 7 H + 7 H22O →O →

→ → 8 acetylCoA + 7FADH8 acetylCoA + 7FADH22 + 7NADH + 7H + 7NADH + 7H++ ((11))– total of 7 moles of FADH2 yields 14 moles of ATP by total of 7 moles of FADH2 yields 14 moles of ATP by

electron transport and oxidative phosphorylation. A total electron transport and oxidative phosphorylation. A total of 7 moles of NADH yields 21 moles of ATP by electron of 7 moles of NADH yields 21 moles of ATP by electron transport and oxidative phosphorylation. Therefore,transport and oxidative phosphorylation. Therefore,

PalmitoylCoA + 7CoASH + 7OPalmitoylCoA + 7CoASH + 7O22 + 35ADP + 35P + 35ADP + 35Pii → →

→ → 8 acetylCoA + 35ATP + 42H8 acetylCoA + 35ATP + 42H22OO ((22)) Because it costs 2 moles of ATP to activate the Because it costs 2 moles of ATP to activate the

free palmitate, free palmitate, 33 moles of ATP are formed per 33 moles of ATP are formed per mole of palmitate via mole of palmitate via -oxidation-oxidation..

Total Total oxidationoxidation

The acetyl CoA derived from The acetyl CoA derived from -oxidation of fatty acyl CoAs -oxidation of fatty acyl CoAs may be oxidized to carbon dioxide (COmay be oxidized to carbon dioxide (CO22) and water (H) and water (H22O) O) by the citric acid cycle.by the citric acid cycle.

8 Acetyl CoA + 16 O8 Acetyl CoA + 16 O22 + 96 ADP + 96 P + 96 ADP + 96 Pii → →

→ → 8 CoASH + 96 ATP + 16 CO8 CoASH + 96 ATP + 16 CO22 + 104 H + 104 H22OO (3)(3)

The combined yield of ATP is obtained by addition of The combined yield of ATP is obtained by addition of equations (2) and (3)equations (2) and (3)

Palmitoyl CoA + 23 OPalmitoyl CoA + 23 O22 + 131 ADP + 131 P + 131 ADP + 131 Pii → →

→ → 8 CoASH + 131 ATP + 16 CO8 CoASH + 131 ATP + 16 CO22 + 146 H + 146 H22OO((44))

After subtraction of 2 moles of ATP for activation of the After subtraction of 2 moles of ATP for activation of the fatty acyl CoA, fatty acyl CoA, 129 moles of ATP are formed by total 129 moles of ATP are formed by total oxidation of palmitateoxidation of palmitate..

Respiratory quotient Respiratory quotient (RQ)(RQ) Respiratory quotient (RQ)Respiratory quotient (RQ) is is

defined as moles of COdefined as moles of CO22 produced, produced, divided by moles of oxygen divided by moles of oxygen consumed during complete oxidation consumed during complete oxidation of a metabolic fuel to COof a metabolic fuel to CO22 and H and H22O. O. – For palmitate, the RQ is given by:For palmitate, the RQ is given by:

(16 moles CO(16 moles CO22 produced)/(23 moles O produced)/(23 moles O22 consumed) = consumed) = 0.70.7

– In contrast, the complete oxidation of In contrast, the complete oxidation of glucose yields an RQ of glucose yields an RQ of 1.01.0

Oxidation of fatty acids Oxidation of fatty acids with an odd number of with an odd number of carbon atomscarbon atoms

Fatty acids that have an odd number Fatty acids that have an odd number of carbon atoms are a minor species in of carbon atoms are a minor species in human tissues.human tissues.

They undergo They undergo -oxidation as acyl CoA -oxidation as acyl CoA derivatives until a three-carbon fragment, derivatives until a three-carbon fragment, propionyl CoA, is formed.propionyl CoA, is formed.

Propionyl CoA is carboxylated to methylmalonyl Propionyl CoA is carboxylated to methylmalonyl CoA by biotin-dependent CoA by biotin-dependent propionyl CoA propionyl CoA carboxylasecarboxylase..

Methylmalonyl CoA is converted to succinyl CoA Methylmalonyl CoA is converted to succinyl CoA by by methylmalonyl CoA mutasemethylmalonyl CoA mutase..

Succinyl CoA can be metabolized via the citric Succinyl CoA can be metabolized via the citric acid cycle, of which it is an intermediate.acid cycle, of which it is an intermediate.

Conversion of Propionyl CoA Conversion of Propionyl CoA Into Succinyl CoAInto Succinyl CoA

Propionyl CoA, generated from fatty acids Propionyl CoA, generated from fatty acids with an odd number of carbons as well as with an odd number of carbons as well as some amino acids, is converted into the some amino acids, is converted into the citric acid cycle intermediate succinyl CoA.citric acid cycle intermediate succinyl CoA.

Oxidation of Oxidation of unsaturated fatty unsaturated fatty acidsacids In the human body, 50% of the fatty acids are In the human body, 50% of the fatty acids are

unsaturated. Many unsaturated fatty acids are unsaturated. Many unsaturated fatty acids are degraded by the degraded by the -oxidation pathway with the -oxidation pathway with the help of two additional enzymes.help of two additional enzymes.

Double bonds in naturally occurring fatty acids Double bonds in naturally occurring fatty acids are are cis. cis. The The -oxidation pathway can only -oxidation pathway can only process process trans trans double bonds using enoyl CoA double bonds using enoyl CoA hydratase.hydratase.

The The cis cis double bond is removed by the double bond is removed by the sequential reactions catalyzed by 2,4-dienoyl sequential reactions catalyzed by 2,4-dienoyl CoA reductase and enoyl CoA isomerase to CoA reductase and enoyl CoA isomerase to yield a yield a 2-trans enoyl CoA.2-trans enoyl CoA.

Oxidation of unsaturated fatty acidsOxidation of unsaturated fatty acids

In the human body, 50% of the fatty acids are unsaturated. In the human body, 50% of the fatty acids are unsaturated. Many unsaturated fatty acids are degraded by the Many unsaturated fatty acids are degraded by the --oxidation pathway with the help of two additional enzymes.oxidation pathway with the help of two additional enzymes.– Double bonds in naturally occurring fatty acids are Double bonds in naturally occurring fatty acids are cis. cis. The The --

oxidation pathway can only process oxidation pathway can only process trans trans double bonds using double bonds using enoyl CoA hydratase.enoyl CoA hydratase.

– The The cis cis double bond is removed by the sequential reactions double bond is removed by the sequential reactions catalyzed by 2,4-dienoyl CoA reductase and enoyl CoA catalyzed by 2,4-dienoyl CoA reductase and enoyl CoA isomerase to yield a isomerase to yield a 2-trans enoyl CoA.2-trans enoyl CoA.

-Oxidation of fatty -Oxidation of fatty acidsacids

This This pathwaypathway involves the oxidation of long-chain involves the oxidation of long-chain fatty acids to 2-hydroxy fatty acids, which are fatty acids to 2-hydroxy fatty acids, which are constituents of brain lipids, followed by oxidation to a constituents of brain lipids, followed by oxidation to a fatty acid with one less carbon. Removal of one fatty acid with one less carbon. Removal of one carbon from the carboxyl end of a fatty acid has been carbon from the carboxyl end of a fatty acid has been demonstrated in microsomal fractions from demonstrated in microsomal fractions from brain brain tissue.tissue.

Refsum's diseaseRefsum's disease (phytanic acid storage disease) is (phytanic acid storage disease) is caused by a defect of caused by a defect of -oxidation.-oxidation.– Phytanic acidPhytanic acid (derived from animal fat and cow's milk and (derived from animal fat and cow's milk and

probably originally from chlorophyll) accumulates in affected probably originally from chlorophyll) accumulates in affected individuals. Phytanic acid cannot alternatively be oxidized by individuals. Phytanic acid cannot alternatively be oxidized by -oxidation because the beta position is blocked by a methyl -oxidation because the beta position is blocked by a methyl group.group.

SymptomsSymptoms include retinitis pigmentosa, failing night include retinitis pigmentosa, failing night vision, peripheral neuropathy, and cerebellar ataxia.vision, peripheral neuropathy, and cerebellar ataxia.

-Oxidation-Oxidation

-Oxidation-Oxidation involves oxidation involves oxidation of the terminal methyl group to of the terminal methyl group to form an form an -hydroxy fatty acid. -hydroxy fatty acid.

This is a minor pathway observed This is a minor pathway observed with liver microsomal with liver microsomal preparationspreparations

BIOSYNTHESIS OF BIOSYNTHESIS OF TRIACYLGLYCEROLS (TRIGLYCERIDES)TRIACYLGLYCEROLS (TRIGLYCERIDES)

Fatty acids are converted to Fatty acids are converted to triacylglycerols for transport to triacylglycerols for transport to tissues and storage.tissues and storage.

FormationFormation involves the acylation involves the acylation of the three hydroxyl groups of of the three hydroxyl groups of glycerolglycerol

Activation of the fatty acidActivation of the fatty acid

1. 1. Formation of the CoA ester of Formation of the CoA ester of the fatty acid is catalyzed in the the fatty acid is catalyzed in the cytosolcytosol by an ATP-dependent by an ATP-dependent acyl CoA synthetaseacyl CoA synthetase..

Fatty acid + ATP + CoASH → Acyl Fatty acid + ATP + CoASH → Acyl CoA + AMP + PPCoA + AMP + PPii

Acylation of glycerolAcylation of glycerol

First acylation.First acylation. There are two routes for the acylation of There are two routes for the acylation of the first hydroxyl of glycerol.the first hydroxyl of glycerol.

One route uses One route uses dihydroxyacetone phosphate (DHAPdihydroxyacetone phosphate (DHAP), ), derived from derived from glycolysis, as the acceptor of an acyl moiety from a fatty acyl CoA.glycolysis, as the acceptor of an acyl moiety from a fatty acyl CoA.– This is followed by reduction, with This is followed by reduction, with NADPH NADPH as the electron acceptor, to form as the electron acceptor, to form

lysophosphatidate.lysophosphatidate.– The fatty acid preferentially introduced to form lysophosphatidate is The fatty acid preferentially introduced to form lysophosphatidate is

saturated.saturated. The second route gives the same product and shows the same The second route gives the same product and shows the same

preference for a saturated fatty acid, but the order is reversed, and preference for a saturated fatty acid, but the order is reversed, and reduction of DHAP to glycerol-3-phosphate occurs before acylation of the reduction of DHAP to glycerol-3-phosphate occurs before acylation of the C-1 hydroxyl. C-1 hydroxyl.

Second acylationSecond acylation. . An unsaturated fatty acyl CoA An unsaturated fatty acyl CoA thioester is introduced to the 2-hydroxyl of thioester is introduced to the 2-hydroxyl of lysophosphatidate. An exception occurs in the human lysophosphatidate. An exception occurs in the human mammary gland, where a saturated fatty acyl CoA is used.mammary gland, where a saturated fatty acyl CoA is used.

Third acylationThird acylation. . The phosphate group on C-3 is removed The phosphate group on C-3 is removed by a phosphatase and either a saturated or unsaturated by a phosphatase and either a saturated or unsaturated fatty acid is incorporated at that position.fatty acid is incorporated at that position.

Storage of triacylglycerols Storage of triacylglycerols in adipose tissue cellsin adipose tissue cells

(adipocytes)(adipocytes) The esterification of fatty acids in adipocytes The esterification of fatty acids in adipocytes

to form triacylglycerols depends on to form triacylglycerols depends on carbohydrate metabolism for the formation carbohydrate metabolism for the formation of DHAP.of DHAP.

Adipocytes lack a glycerol kinase and cannot Adipocytes lack a glycerol kinase and cannot phosphorylate glycerol to glycerol-3-phosphorylate glycerol to glycerol-3-phosphate. The only source of glycerol-3-phosphate. The only source of glycerol-3-phosphate for triacylglycerol synthesis is phosphate for triacylglycerol synthesis is from DHAP formed during glycolysis.from DHAP formed during glycolysis.

The entry of glucose into adipocytes is insulin The entry of glucose into adipocytes is insulin dependent. Thus, insulin is an essential dependent. Thus, insulin is an essential requirement for triacylglycerol synthesis in requirement for triacylglycerol synthesis in adipocytes.adipocytes.

Lipolysis of triacylglycerolsLipolysis of triacylglycerols Hormonal control of lipolysis in adipocytesHormonal control of lipolysis in adipocytes

– Hormone-sensitive lipaseHormone-sensitive lipase is activated by covalent is activated by covalent phosphorylation of the lipase by a cyclic adenosine phosphorylation of the lipase by a cyclic adenosine monophosphate (cAMP)-dependent protein kinase monophosphate (cAMP)-dependent protein kinase

– Epinephrine Epinephrine circulating in the blood in response to circulating in the blood in response to stress, or stress, or norepinephrinenorepinephrine released by neural released by neural connections to adipose tissue, activates the cell connections to adipose tissue, activates the cell membrane ade-nylate cyclase to produce cAMP. Thus, membrane ade-nylate cyclase to produce cAMP. Thus, under conditions of stress or when neural signals under conditions of stress or when neural signals indicate low levels of metabolic fuel, the hormone-indicate low levels of metabolic fuel, the hormone-sensitive lipase is activated.sensitive lipase is activated.

– InsulinInsulin inhibits lipolysis by two mechanisms.inhibits lipolysis by two mechanisms. It reduces cAMP levels, probably by inhibiting adenylate cyclase It reduces cAMP levels, probably by inhibiting adenylate cyclase

activity.activity. It increases glucose entry into the adipocytes, so that the It increases glucose entry into the adipocytes, so that the

formation of DHAP and glycerol-3-phosphate is increased. The formation of DHAP and glycerol-3-phosphate is increased. The availability of these products of glycolysis increases the rate of availability of these products of glycolysis increases the rate of re-esterification of free fatty acids to triacylglycerols, thus re-esterification of free fatty acids to triacylglycerols, thus reducing the rate of release of the fatty acids from adipocytes. reducing the rate of release of the fatty acids from adipocytes.

– ProstaglandinsProstaglandins inhibit lipolysis by reducing cAMP inhibit lipolysis by reducing cAMP levels.levels.

Enzymatic steps of Enzymatic steps of lipolysislipolysis

Three different lipases are required to release Three different lipases are required to release the three fatty acids from the triacylglycerols.the three fatty acids from the triacylglycerols.

– Hormone-sensitive triacylglycerol lipaseHormone-sensitive triacylglycerol lipase converts triacylglycerol to diacyl-glycerol plus a converts triacylglycerol to diacyl-glycerol plus a fatty acid.fatty acid.

– Diacylglycerol lipaseDiacylglycerol lipase converts diacylglycerol to converts diacylglycerol to monoacylglycerol plus a fatty acid.monoacylglycerol plus a fatty acid.

– Monoacylglycerol lipaseMonoacylglycerol lipase converts converts monoacylglycerol to glycerol plus a fatty acid.monoacylglycerol to glycerol plus a fatty acid.

The rate-limiting step of lipolysis in The rate-limiting step of lipolysis in adipocytesadipocytes is the reaction catalyzed by the is the reaction catalyzed by the hormone-sensitive triacylglycerol lipase. hormone-sensitive triacylglycerol lipase. Diacyl- and monoacylglycerol lipases are Diacyl- and monoacylglycerol lipases are present in excess, so that once triacylglycerol present in excess, so that once triacylglycerol lipase is activated, lipolysis of triacylglycerols lipase is activated, lipolysis of triacylglycerols goes to completion.goes to completion.

Lipolysis in other Lipolysis in other tissuestissues Triacylglycerols are stored mainly in Triacylglycerols are stored mainly in

adipocytes. However, other tissues, adipocytes. However, other tissues, including muscle and liver, store including muscle and liver, store small amounts of triacylglycerols as small amounts of triacylglycerols as intracellular lipid droplets for their intracellular lipid droplets for their own use. These fat stores appear to own use. These fat stores appear to be mobilized by hormonal controls be mobilized by hormonal controls similar to those found in adipocytes.similar to those found in adipocytes.

KETONE BODY KETONE BODY METABOLISMMETABOLISMKetone bodies (i.e., acetoacetate, Ketone bodies (i.e., acetoacetate, --hydroxybutyrate, acetone) are the preferred hydroxybutyrate, acetone) are the preferred energy substrates of the heart, skeletal energy substrates of the heart, skeletal muscle, and kidney during the fasting state. If muscle, and kidney during the fasting state. If blood levels of blood levels of -hydroxybutyrate and -hydroxybutyrate and acetoacetate increase sufficiently, as they do acetoacetate increase sufficiently, as they do during starvation, they also become the during starvation, they also become the primary energy substrate for the brain.primary energy substrate for the brain.

Biosynthesis of ketone Biosynthesis of ketone bodiesbodies Thiolase catalyzes the formation of two acetyl CoA Thiolase catalyzes the formation of two acetyl CoA

molecules from acetoacetyl CoA.molecules from acetoacetyl CoA. 3-Hydroxy-3-methylglutaryl CoA (HMG CoA) 3-Hydroxy-3-methylglutaryl CoA (HMG CoA)

synthase catalyzes the addition of another acetyl synthase catalyzes the addition of another acetyl CoA to acetoacetyl CoA to form HMG CoA.CoA to acetoacetyl CoA to form HMG CoA.

HMG CoA lyase catalyzes the cleavage of HMG CoA HMG CoA lyase catalyzes the cleavage of HMG CoA to to acetoacetateacetoacetate and acetyl CoA.and acetyl CoA.

-Hydroxybutyrate dehydrogenase catalyzes the -Hydroxybutyrate dehydrogenase catalyzes the formation of formation of -hydroxybutyrate -hydroxybutyrate from from acetoacetate when the NADH/NAD+ ratio is high, acetoacetate when the NADH/NAD+ ratio is high, as it is in the liver during fasting.as it is in the liver during fasting.

AcetoneAcetone is formed spontaneously from a small is formed spontaneously from a small fraction of the circulating acetoacetate and is fraction of the circulating acetoacetate and is exhaled by the lungs. In patients with untreated exhaled by the lungs. In patients with untreated diabetes, the odor of acetone is apparent on the diabetes, the odor of acetone is apparent on the patient's breath.patient's breath.

The Ketone bodies-acetoacetate, d-3-hydroxybutyrate, and The Ketone bodies-acetoacetate, d-3-hydroxybutyrate, and acetone from acetyl CoA—are formed primarily in the liver. acetone from acetyl CoA—are formed primarily in the liver. Enzymes catalyzing these reactions are (1) 3-ketothiolase, (2) Enzymes catalyzing these reactions are (1) 3-ketothiolase, (2) hydroxymethylglutaryl CoA synthase, (3) hydroxymethylglutaryl hydroxymethylglutaryl CoA synthase, (3) hydroxymethylglutaryl CoA cleavage enzyme, and (4) d-3-hydroxybutyrate CoA cleavage enzyme, and (4) d-3-hydroxybutyrate dehydrogenase. Acetoacetate spontaneously decarboxylates to dehydrogenase. Acetoacetate spontaneously decarboxylates to form acetone.form acetone.

Formation of Ketone BodiesFormation of Ketone Bodies

Ketone body oxidationKetone body oxidation A 3-keto acid CoA transferaseA 3-keto acid CoA transferase catalyzes the catalyzes the

formation of the CoA thioester of acetoacetate. This is formation of the CoA thioester of acetoacetate. This is a a nonhepatic enzymenonhepatic enzyme that prevents ketone bodies that prevents ketone bodies from being used as an energy source by the liver.from being used as an energy source by the liver.

ThiolaseThiolase catalyzes the cleavage of acetoacetyl CoA to catalyzes the cleavage of acetoacetyl CoA to two acetyl CoA molecules with the use of CoA, two acetyl CoA molecules with the use of CoA, providing two-carbon fragments for oxidation by the providing two-carbon fragments for oxidation by the citric acid cycle.citric acid cycle.

Energy yield from oxidation of ketone bodiesEnergy yield from oxidation of ketone bodies– Each mole of acetyl CoA that is formed yields 12 moles of ATP Each mole of acetyl CoA that is formed yields 12 moles of ATP

via the citric acid cycle, electron transport, and oxidative via the citric acid cycle, electron transport, and oxidative phosphorylation.phosphorylation.

– Conversion of Conversion of -hydroxybutyrate to acetoacetate yields an -hydroxybutyrate to acetoacetate yields an NADH molecule, which in turn yields three more ATP molecules NADH molecule, which in turn yields three more ATP molecules by electron transport and oxidative phosphorylation.by electron transport and oxidative phosphorylation.

– The activation reaction requires the equivalent of 1 mole of The activation reaction requires the equivalent of 1 mole of ATP.ATP.

– Therefore, Therefore, oxidation of acetoacetate yields 23 moles of oxidation of acetoacetate yields 23 moles of ATP; oxidation of ATP; oxidation of -hydroxybutyrate yields 26 moles of -hydroxybutyrate yields 26 moles of ATPATP

CH

OH

CH3

CH2

COOH

3-hydroxybutirate

NAD+

NADH+H+hydroxybutirate-dehydrohenase

CH3C

O

CH2C

O

OH

Acetoacetate

Succenyl-Cî À

Succinate

SuccinylCî À-acetoacetate-Cî À-transferase

CH3

C

O

CH2

C

O

SCoA

Acetoacetyl-Cî À

HSCoAThiolase

CH3 C

O

SCoA

CH3 C

O

SCoA

+

2 Acetyl-Cî À

Citric cycle

Keton body oxidation

STEROIDSSTEROIDS

are lipids that contain four fused are lipids that contain four fused carbon rings that form the carbon rings that form the cyclopentanoperhydrophenanthrcyclopentanoperhydrophenanthrene steroid nucleus.ene steroid nucleus.

CholesteroCholesterol l is the major is the major sterolsterol in the human in the human body. Sterols are a class of steroids characterized body. Sterols are a class of steroids characterized by a hydroxyl group at carbon 3, and an aliphatic by a hydroxyl group at carbon 3, and an aliphatic chain of at least eight carbons at C-17.chain of at least eight carbons at C-17.

Cholesterol is a Cholesterol is a structural componentstructural component of cell of cell membranes and plasma lipoproteins.membranes and plasma lipoproteins.

It It is the is the precursorprecursor from which steroid hormones from which steroid hormones and bile acids are synthesized.and bile acids are synthesized.

Steroid hormonesSteroid hormones produced in humans are produced in humans are formed and secreted by the formed and secreted by the adrenal cortex, the adrenal cortex, the testis, the ovarytestis, the ovary, , and the and the placentaplacenta..

Primary bile acidsPrimary bile acids. . Cholic and chenodeoxycholic Cholic and chenodeoxycholic acids are formed in the liver from cholesterolacids are formed in the liver from cholesterol

Biosynthesis of Biosynthesis of cholesterolcholesterol

The The liver is the major siteliver is the major site of of cholesterol biosynthesis, although other cholesterol biosynthesis, although other tissues also are active in this regard tissues also are active in this regard (e.g., the intestines, adrenal glands, (e.g., the intestines, adrenal glands, gonads, skin, neural tissue, and aorta). gonads, skin, neural tissue, and aorta).

All 27 carbon atoms of cholesterol are All 27 carbon atoms of cholesterol are derived from the acetate moiety of derived from the acetate moiety of acetyl CoA, and the enzymes reside in acetyl CoA, and the enzymes reside in the cytosolic and microsomal fractions.the cytosolic and microsomal fractions.

3-Hydroxy-3-methylglutaryl CoA 3-Hydroxy-3-methylglutaryl CoA (HMG CoA)(HMG CoA) is formed in the cytosol is formed in the cytosol from acetyl CoA in two steps by from acetyl CoA in two steps by thiolase thiolase and HMG CoA synthaseand HMG CoA synthase..

HMG CoA is converted to HMG CoA is converted to mevalonate by mevalonate by HMG CoA reductaseHMG CoA reductase, an NADPH-dependent , an NADPH-dependent enzyme. This is the enzyme. This is the key regulatory sitekey regulatory site of of cholesterol biosynthesischolesterol biosynthesis

This is regarded as the This is regarded as the rate-limiting step rate-limiting step in cholesterol biosynthesis.in cholesterol biosynthesis. Although Although later steps may be affected by a prolonged later steps may be affected by a prolonged stimulus (e.g., long-term feeding of stimulus (e.g., long-term feeding of cholesterol), their rates never become lower cholesterol), their rates never become lower than that of HMG CoA reductase.than that of HMG CoA reductase.

The feeding of cholesterol reduces the The feeding of cholesterol reduces the hepatic biosynthesis of cholesterol by hepatic biosynthesis of cholesterol by reducing the activity of HMG CoA reductase. reducing the activity of HMG CoA reductase. Importantly, intestinal cholesterol Importantly, intestinal cholesterol biosynthesis does not respond to the feeding biosynthesis does not respond to the feeding of high-cholesterol diets.of high-cholesterol diets.

HMG CoA reductase activity also is reduced HMG CoA reductase activity also is reduced by fasting, which limits the availability of by fasting, which limits the availability of acetyl CoA and NADPH for cholesterol acetyl CoA and NADPH for cholesterol biosynthesis.biosynthesis.

HMG CoA reductase undergoes reversible HMG CoA reductase undergoes reversible phosphorylation-dephosphorylation; the phosphorylation-dephosphorylation; the phosphorylated enzyme is less active than phosphorylated enzyme is less active than the dephosphorylated form.the dephosphorylated form.

Hormonal effects on Hormonal effects on cholesterol cholesterol biosynthesisbiosynthesis

InsulinInsulin stimulates HMG CoA stimulates HMG CoA reductase activity.reductase activity.

GlucagonGlucagon antagonizes the effect antagonizes the effect of insulin.of insulin.

Thyroid hormoneThyroid hormone stimulates stimulates HMG CoA reductase. HMG CoA reductase.

The drug lovastatin, The drug lovastatin, which is used to treat which is used to treat hypercholesterolemia, hypercholesterolemia, blocks endogenous blocks endogenous cholesterol synthesis cholesterol synthesis by inhibiting HMG CoA by inhibiting HMG CoA reductasereductase

Mevalonate is activated with high-energy Mevalonate is activated with high-energy phosphate bonds and then decarboxylated to phosphate bonds and then decarboxylated to form the five-carbon isoprenoid isomers, form the five-carbon isoprenoid isomers, 3,3-3,3-dimethylallyl pyrophosphate and dimethylallyl pyrophosphate and isopentenyl pyrophosphateisopentenyl pyrophosphate. . An isomerase An isomerase governs an equilibrium between these governs an equilibrium between these isomers.isomers.

A molecule of 3,3-dimethylallyl A molecule of 3,3-dimethylallyl pyrophosphate condenses with a molecule of pyrophosphate condenses with a molecule of isopentenyl pyrophosphate to form the 10-isopentenyl pyrophosphate to form the 10-carbon compound carbon compound geranyl pyrophosphategeranyl pyrophosphate..

Another molecule of isopentenyl Another molecule of isopentenyl pyrophosphate reacts with geranyl pyrophosphate reacts with geranyl pyrophosphate to form the 15-carbon pyrophosphate to form the 15-carbon compound compound farnesyl pyrophosphatefarnesyl pyrophosphate, , which which is also a precursor for ubiquinoneis also a precursor for ubiquinone..

Squalene synthaseSqualene synthase catalyzes the catalyzes the NADPH-dependent conversion of NADPH-dependent conversion of two molecules of farnesyl two molecules of farnesyl pyrophosphate to pyrophosphate to squalenesqualene..

Squalene is converted to Squalene is converted to squalene squalene 2,3-epoxide2,3-epoxide by an NADPH-by an NADPH-dependent monooxygenase.dependent monooxygenase.

A cyclaseA cyclase catalyzes the cyclization catalyzes the cyclization of squalene to form lanosterol, of squalene to form lanosterol, which also is a precursor for the which also is a precursor for the synthesis of vitamin D.synthesis of vitamin D.

Lanosterol is converted to Lanosterol is converted to cholesterolcholesterol by by a series of reactions that result in the a series of reactions that result in the removal of three methyl groups and removal of three methyl groups and rearrangement of double bondsrearrangement of double bonds

Esterification of Esterification of cholesterolcholesterol

The bulk of the cholesterol in tissues and The bulk of the cholesterol in tissues and approximately 65% of plasma cholesterol is esterified approximately 65% of plasma cholesterol is esterified with long-chain fatty acids at C-3.with long-chain fatty acids at C-3.

The synthesis of cellular cholesterol ester requires ATP The synthesis of cellular cholesterol ester requires ATP to form fatty acyl CoA derivatives, which are then to form fatty acyl CoA derivatives, which are then transferred to the 3-transferred to the 3--hydroxyl group of cholesterol.-hydroxyl group of cholesterol.

Cholesterol associated with plasma lipoproteins can be Cholesterol associated with plasma lipoproteins can be esterified by esterified by lecithin:cholesterol acyltransferaselecithin:cholesterol acyltransferase..

Phosphatidylcholine + Cholesterol → Phosphatidylcholine + Cholesterol → Lysophosphatidylcholine + Cholesterol fatty acyl esterLysophosphatidylcholine + Cholesterol fatty acyl ester

Bile acidsBile acids Bile acids are Bile acids are synthesized synthesized from from

cholesterol cholesterol in the liver and stored in in the liver and stored in the gallbladder.the gallbladder.

Enterohepatic circulationEnterohepatic circulation– After release of bile acids from storage in the After release of bile acids from storage in the

gallbladder to the intestine, the two primary gallbladder to the intestine, the two primary bile acids—cholic and chenodeoxycholic—are bile acids—cholic and chenodeoxycholic—are converted in part to the secondary bile acids—converted in part to the secondary bile acids—deoxycholate and lithocholate—by intestinal deoxycholate and lithocholate—by intestinal bacteria.bacteria.

– In the intestine, both primary and secondary In the intestine, both primary and secondary bile acids are deconjugated, reab-sorbed by the bile acids are deconjugated, reab-sorbed by the intestinal mucosa, and returned to the liver intestinal mucosa, and returned to the liver bound to serum albumin via the portal vein.bound to serum albumin via the portal vein.

– The liver takes up the bile acids, reconjugates The liver takes up the bile acids, reconjugates them with taurine or glycine, and secretes them them with taurine or glycine, and secretes them in the bile.in the bile.

Secretion of bile into the intestine is Secretion of bile into the intestine is the the main route for the excretion of main route for the excretion of cholesterolcholesterol because the steroid because the steroid nucleus cannot be oxidized to carbon nucleus cannot be oxidized to carbon dioxide and water by human tissues.dioxide and water by human tissues.

Solubility of cholesterol in bileSolubility of cholesterol in bile– Bile contains a considerable amount of Bile contains a considerable amount of

cholesterol, which would be insoluble cholesterol, which would be insoluble except for its association with bile salts and except for its association with bile salts and phospholipids (chiefly phosphatidylcholine).phospholipids (chiefly phosphatidylcholine).

– Despite the presence of these solubilizing Despite the presence of these solubilizing agents, an increased concentration of agents, an increased concentration of cholesterol in the bile can lead to the cholesterol in the bile can lead to the formation of formation of gallstones gallstones in the gallbladder in the gallbladder or duct. These are formed if cholesterol is or duct. These are formed if cholesterol is precipitated out of solution around a core precipitated out of solution around a core of protein and bilirubin, which is a condition of protein and bilirubin, which is a condition known as known as cholelithiasis.cholelithiasis.