Post-Absorptive Lipid Metabolism

Lipid Metabolism Terms

• Lipogenesis– Making of fat from dietary fat or dietary CHO

• Lipolysis– Breaking down of fat: GIT, capillary and adipocyte

• De Novo lipogenesis– Making of fat from CHO (takes place in liver and adipocyte)– Fat exported from liver as VLDL (very low density lipoprotein)

• Pancreatic lipase– Breaks down TG’s in GIT

• Lipoprotein Lipase– Breaks down TG’s from chylomicron and VLDL in the capillary

-oxidation:– Breaking down of fatty acids into acetyl-CoA

• Hormone Sensitive Lipase– Breaks down TG’s within the adipocyte

• NEFA– Non-esterified fatty acids: fatty acids mobilized (exiting) the adipocyte

Lipid Metabolism

Lipid Absorption

glucoseglucose -glycerolĞP

fatty acids FA-CoA

cholesterolcholesterol

cholesterol ester

MAG

lysolecithin

TAG

FA+

albumen

Lymphatics

short chainFAs </= C10

lecithin

apoproteins

Chylomicrons

Blood

Plasma Lipid

• Transported in two primary vesicles:– Chlyomicrons

• From intestine• Packages dietary lipid

– Very Low Density Lipoprotein (VLDL)• From the liver• Packages:

– Fatty acids derived from excess carbohydrates– Fatty acids taken up from circulation

Plasma Lipid Clearance

Unlike glucose and amino acids, most lipids from a meal do not directly enter the bloodstream. Instead, they are packaged into chylomicrons and released into the lymph. The lymph dumps into the aortic arch (near the heart), where it then is transported through the bloodstream to be cleared (taken up) by:

adipocytes

muscle

liver

Thus, unlike carbohydrates and protein, most lipids do not use the enterohepatic circulatory system. This allows lipids to be cleared by the whole body and avoids overwhelming the liver with lipid.

Clearance of lipid from circulation is mediated by adipose,muscle and liver: via the enzyme Lipoprotein Lipase (LPL)

Regulation of Lipid metabolism

• Well fed: Insulin lipogenesis & lipolysis

• Starving: epinephrine/norepinephrine lipolysis Insulin lipolysis

• Very Low CHO, high PTN diet:– No Insulin lipogenesis– No Insulin lipolysis

Lipid Synthesis (lipogenesis)

Creation of fat is via two primary routes

• 1) De novo fatty acid synthesis– Process by which simple non-lipid nutrients are converted to

long chain fatty acids and stored as triglycerides, especially in adipose tissue

– Monogastrics: glucose is the major source of carbon for fatty acid synthesis

– Ruminants: acetate is the major source of carbon for fatty acid synthesis

• 2) Preformed uptake: incorporation of dietary fat– Most of human adipose is derived from diet

• Both are stimulated by insulin

De novo fatty acid Synthesis

• Two Key Enzymes:– Acetyl CoA Carboxylase (ACC)

• Rate limiting enzyme

– Fatty Acid Synthase (FAS)

• Animals on a high fat diet experience little if any de novo fatty acid synthesis

• Typical western civilization diet is high in fat– agriculture species usually fed a high CHO diet

• Fetal animals have large de novo activity

glucose

pyruvate

Acetyl Co A

TCA Citrate Acetyl Co Amonogastrics

Acetate

ruminants

Fatty Acids

De novo Fatty Acid Synthesis

ACC

FAS

NADPH

• Why glucose is not a C-source for fatty acid synthesis in ruminants

– Limiting enzymesCitrate lyaseMalate dehydrogenase

– Use of glucose for fat synthesis• Supply NADPH• Synthesis of glycerol

ACC

Allosteric modificationActivated by: CitrateInhibited by: LCFA

Covalent ModificationActivated by: DephosphorylationInhibited by: Phosphorylation

Acetyl CoA Carboxylase (ACC)

FAS

Fatty Acid Synthase (FAS)

• 2nd and final step• Multifunctional polypeptide• High in the well-fed state• Not regulated by either allosteric or covalent

modification• Regulated by the amount of [PTN]

– High in fed-state– Low in fasting-state

• Palmitate is usually the end product

FAS

ATP Citrate Lyase

PPP

NADPH

Species comparison of fatty acid synthesis

Species Principal Tissue Site Carbon Source

Poultry

Human

Pig

Mouse

Sheep

Cattle

Liver

Liver

Adipose

Adipose

Adipose

Adipose

Glucose

Glucose

Glucose

Glucose

Acetate

Acetate

Preformed Fatty Acid Uptake

• Dietary derived– Dietary TG packaged in chylomicrons

• Liver derived– Either repackaged TG from chylomicron

remnants or TG synthesized de novo and secreted as VLDL

• TG in both are hydrolyzed by lipoprotein lipase (LPL) in capillary bed

TG

Lipoprotein lipase

Glycerol + 3 Fatty acids

Cell I.e. adipocyte muscle mammary

capillary

ChylomicronsVLDL

LPL action on TG rich lipoproteins

Fatty acids

Triglycerides

LPL Mediated Fatty Acid Uptake

Lipid breakdown (lipolysis)

• The breaking down (hydrolysis) of intracellular triglycerides– Can be reesterified or mobilized

• Mobilization– Net release of fatty acids from adipocytes

• NEFAs are transported in blood bound to albumin

• Undergo -oxidation to produce acetyl CoA’s

• Oxidized by energy needing cells

• Stimulated by epinephrine AND the lack of insulin

Triglyceride breakdown• Lipoprotein Lipase: found on endothelial (vessel) walls lining tissues such as adipose and muscle. Releases FFA from TAGs in CM/VLDL for cellular uptake and usage as either energy (muscle) or storage (adipocyte). Thus insulin & glucagon differentially regulate this enzyme on muscle vs. adipose cells.

TAG 2-MAG + FFA cell

• Hormone-sensitive lipase: Only found INSIDE adipocyte. Releases FFA from adipocyteTAG stores, sends to serum. Incr by glucagon, epinephrine.

TAG 2-MAG + FFA serum

• Regulation of LPL Activity:

factor adipose muscle

starvation down upWell Fed up downinsulin up down

 -Complete oxidation of fatty acids yields ~9 kCal/g, where as, proteins and carbohydrates yield ~4 kCal/g. An average 70 kg man: 100,000 kCal in triacylglycerols

25,000 kCal in proteins (muscles)

600 kCal in glycogen400 kCal in glucose

 -Triacylglycerols constitute about 11 kg of his total body weight. If this amount were stored in glycogen, his total body weight would be 55 kg greater.

-In mammals, the major site of accummulation of triacylglycerols is the cytoplasm of adipose cells (fat cells). Droplets of triacylglycerol coalesce to form a large globule, which may occupy most of the cell volume.

 - Adipose cells are specialized for the synthesis and storage of triacylglycerols and for their mobilization into fuel molecules that are transported to other tissues by the blood.

Energy Content of Human Carcass

Adenylate Cyclase

cAMP

Hormone Sensitive Lipase

Triglyceride Fatty acids + glycerol

Fatty AcidsEpinephrine

Lipolysis Overview

Glycerol

                                                           

                                     

Schematic representation of the activation of lipolysis by lipolytic hormones

Under basal conditions, perilipin (Per) is located on the surface of the single triacylglycerol droplet, with HSL in the cytoplasm. Upon lipolytic stimulation, both perilipin and HSL become multi-phosphorylated, with perilipin being displaced from the droplet, allowing access for HSL. There is also evidence that fatty acids (FA) are removed from HSL by FABPs, preventing accumulation and resultant product inhibition. Biochemical Journal. www.biochemj.org Biochem. J. (2004) 379, 11-22

Adipocytes do not have Glycerol Kinase

Glucose metabolism requires insulin to stimulate GLUT-4 translocation and to stimulate glycolytic enzymes

Therefore, in order for FA’s to be re-esterified there must be glycerol 3-P (generated from glycolysis).

In the well-fed state, any FAs liberated by HSL are re-esterified

In the fasting state fatty acids liberated by HSL are all mobilized.

Re-esertification vs. Mobilization