CHOLESTEROL SYNTHESIS, TRANSPORT, AND EXCRETION

AT THE END OF THIS LECTURE YOU ARE EXPECTED TO:Give the biological importance of cholesterolIdentify the characteristics of cholesterol structureName the essential steps towards the synthesis of cholesterolDiscuss how cholesterol synthesis is regulated

AT THE END OF THIS LECTURE YOU ARE EXPECTED TO:Identify factors that influence cholesterol balance in the bodyDiscuss how cholesterol is transported to different body tissues Discuss how cholesterol is excreted from the bodyDefine some clinical conditions related to abnormal cholesterol metabolism

BIOLOGIC IMPORTANCE OF CHOLESTEROLStructural component of all cell membranesModulates membrane fluidityAt temperatures below melting temperature, it increases membrane fluidity

BIOLOGIC IMPORTANCE OF CHOLESTEROLCholesterol is a precursor of bile acids, steroid hormones, and Vitamin DCholesterol is a component of plasma lipoproteins sent to the peripheral tissuesWhen produced in excess, cholesterol causes atherosclerotic plaque formation and leads to an increased risk for coronary artery disease

CHOLESTEROL STRUCTUREHighly hydrophobicHas 4 fused hydrophobic rings (steroid nucleus) with 8-carbon branched hydrocarbon chain attached to C-17 of the D ringRing A has a hydroxyl group at C3Ring B has a double bond between C5 and C6Steroids with 8 to 10 carbon atoms in the side chain at C17 and a hydroxyl group at C3 are called sterolsCholesterol is the major sterol in animal tissues

CHOLESTERYL ESTERS (CE)Most plasma cholesterol is in an esterified form with a fatty acid attached at C3This makes the structure even more hydrophobic than free cholesterolNot normally found in membranesMust be transported in association with a protein (lipoprotein), or be solubilized by phospholipids and bile salts in bile

SYNTHESIS OF CHOLESTEROL

OVERVIEWCholesterol is synthesized by virtually all tissues, but is largely contributed by the liver, intestine, adrenal cortex, and reproductive tissuesAll C atoms are from acetateNADPH provides reducing equivalentsSynthesis occurs in the cytoplasm, with enzymes in both cytosol and ER membrane

SYNTHESIS OF 3-HYDROXY-3-METHYGLUTARYL CoA (HMG CoA)Similar to the pathway that produces ketone bodiesIn the liver, the cytosolic HMG CoA synthase participates in cholesterol synthesis, while the mitochondrial enzyme synthesizes ketone bodies

SYNTHESIS OF MEVALONIC ACID (MEVALONATE)Rate-limiting step in cholesterol synthesisIrreversibleOccurs in the cytosolHMG CoA reductase is an intrinsic membrane protein of the ER with the catalytic domain projecting into the cytosolThis step is inhibited by statins (Simvastatin, Atorvasatin, etc.)

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CHOLESTEROL SYNTHESISMevalonate (6C) is converted to Mevalonate 5 phosphate in 2 steps requiring ATP2. IPP (5C) is synthesized by decarboxylation. It is the precursor of the isoprenoids3. IPP is isomerized to DPP4. IPP and DPP condense to form the 10-carbon GPP5. A second molecule of IPP condenses with GPP to form a 15-C FPP

CHOLESTEROL SYNTHESIS6. Two molecules of FPP combine, releasing pyrophosphate, and are reduced to form Squalene (30C)7. Squalene is converted to lanosterol in a series of steps. Squalene hydroxylation triggers cyclization to lanosterol8. A multistep process converts lanosterol to cholesterol. This involves:a. Shortening of C chain from 30 to 27b. Removal of 2 methyl groups at C4c. Migration of double bond form C8 to C5d. Reduction of the double bond between C24 and C25

Many of the reactions involved in converting lanosterol to cholesterol and other steroids are catalyzed by members of the cytochrome P450 enzyme superfamily

Farnesyl pyrophosphate, an intermediate on the pathway for cholesterol synthesis, also serves also as precursor for synthesis of various non-steroidal isoprenoids.

FARNESYL PYROPHOSPHATE/DIPHOSPHATE GIVES RISE TO:DOLICHOL for the synthesis of N-glycosidesUBIQUINONE or coenzyme Q for the Electron Transport Chain

REGULATION OF CHOLESTEROL SYNTHESISMajor control point is the reaction catalyzed by HMG CoA reductase, which is inhibited by mevalonate, cholesterol, and statin drugsIt is only hepatic synthesis that is inhibited by dietary cholesterolInsulin or thyroid hormone increases HMG CoA reductase activity, while glucagon or glucocorticoids decrease it

FACTORS THAT INFLUENCE CHOLESTEROL BALANCE IN TISSUES

CELL CHOLESTEROL INCREASE IS DUE TO:Uptake of cholesterol-containing lipoproteins by receptorsUptake of free cholesterol from cholesterol-rich lipoproteins to the cell membraneCholesterol synthesisHydrolysis of cholesteryl esters by the enzyme cholesteryl ester hydrolase

CELL CHOLESTEROL DECREASE IS DUE TO:Efflux of cholesterol from the cell membrane to HDL promoted by LCAT (lecithin:cholesterol acyltransferase). LCAT is also known as PCATEsterification of cholesterol by ACAT (Acyl-CoA:cholesterol acyltransferase)Utilization of cholesterol for synthesis of other steroids, such as hormones, or bile acids in the liver

ROLE OF CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) IN PLASMA LIPID TRANSPORTCETP facilitates the transfer of CE from HDL to VLDL, IDL, and LDL in exchange for TAG. This allows LCAT conversion of free cholesterol to CE, facilitating reverse cholesterol transport

METABOLISM OF LDL AND THE ROLE OF THE LDL RECEPTORVLDL is produced from the liver and is composed mostly of TAGVLDL transfers TAG from liver to tissues. When TAG synthesis exceeds VLDL synthesis, it results in fatty liverVLDL is the precursor of LDLLDL contains less TAG than VLDLLDL has a high concentration of cholesterol and cholesteryl esters

METABOLISM OF LDL AND THE ROLE OF THE LDL RECEPTORThe primary function of LDL is to provide cholesterol to the peripheral tissues, or return cholesterol to the liverLDL binds to cell surface receptors that recognize apolipoprotein B-100

DEGRADATION OF CHOLESTEROL

The ring structure of cholesterol cannot be metabolized to carbon dioxide and water in humansThe intact sterol nucleus is eliminated by conversion to bile acids and bile saltsBile acids and bile salts are excreted in the fecesSome cholesterol is also secreted into the bile

Synthesis of bile acids is one of the predominant mechanisms for the excretion of excess cholesterolHowever, the excretion of cholesterol in the form of bile acids is insufficient to compensate for an excess dietary intake of cholesterol.

Some of the cholesterol in the intestine is modified by bacteria before excretionThe primary compound made is coprostanol, a reduced derivative of cholesterol

BILEConsists of a watery mixture of organic and inorganic compoundsLecithin and bile salts (conjugated bile acids) are quantitatively the most important organic components of bileCan pass directly from the liver where it is synthesized to the duodenum through the common bile duct, or be stored in the gallbladder

STRUCTURE OF BILE ACIDSContains 24 carbons with 2 or 3 hydroxyl groups and a side chain that terminates in a carboxyl groupHas a pKa of 6 and is not fully ionized at physiologic pHAmphipathic, with the hydroxyl groups above the plane of the steroid ring and the methyl groups below the planeAct as emulsifying agents to prepare fats for degradationPRIMARY BILE ACIDS

The reaction catalyzed by the 7-hydroxylase is the rate limiting step in bile acid synthesis This step is down-regulated by cholic acid and up-regulated by cholesterol

SYNTHESIS OF BILE SALTSBefore the bile acids leave the liver, they are conjugated to a molecule of either glycine or taurine by an amide bond between the carboxyl group of the bile acid and the amino group of the added compoundConjugation takes place in peroxisomes

The ratio of glycine to taurine forms in the bile is 3:1The salt forms are fully ionized (negatively charged) at physiologic pHBecause of their enhanced amphipathic nature, bile salts are more effective solubilizers

ACTION OF INTESTINAL FLORA ON BILE SALTSBacteria in the intestine can remove glycine and taurine and regenerate bile acidsThey can also form secondary bile acids through deconjugation and dehydroxylation DEOXYCHOLIC ACID FROM GLYCOCHOLIC ACIDOHLITHOCHOLIC ACID FROMCHENODEOXYCHOLIC ACIDOH

ENTEROHEPATIC CIRCULATION OF BILE ACIDS AND BILE SALTSOf the 15 to 30 grams of bile salts secreted from the liver, more than 95% are reabsorbed through the ileum, pass through the portal vein, and are reused Only 0.5 g are lost in the fecesBecause bile acids are hydrophobic, they are carried by albumin noncovalently through the circulation

Bile acid sequestrants like cholestyramine bind bile acids in the gut and prevent their reabsorption, promoting cholesterol excretionDietary fiber also binds bile acids and promotes their excretion

CLINICAL ASPECTS

ATHEROSCLEROSIS AND CORONARY HEART DISEASEAtherosclerosis is due to the deposition of cholesterol and cholesteryl ester from the plasma lipoproteins to the artery wallsA high HDL and low LDL protects a person from this complication. This is one of the benefits provided by exercise

DYSLIPOPROTEINEMIASDue to various defects in lipoprotein formation, transport, or destructionNot all are harmfulDiseases such as Diabetes Mellitus, Hypothyroidism, Kidney disease, and atherosclerosis exhibit abnormal lipoprotein patterns that resemble dyslipoproteinemias

CHOLELITHIASIS (GALLSTONES)Occurs when more cholesterol enters the bile than can be solubilized by the bile salts and lecithin presentSurgery is the treatment of choice, but administration of chenodeoxycholic acid may help to supplement the bodys supply of bile acids