1. Post-Absorptive Lipid Metabolism

2. 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

4. Lipid Metabolism

6. Lipid Absorption

11. 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

12. 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)

13. 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

14. 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

15. 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

16. De novo Fatty Acid Synthesis
glucose
Fatty Acids
NADPH
pyruvate
FAS
Acetyl Co A
ACC
TCA
Citrate
Acetyl Co A
monogastrics
ruminants
Acetate

17. Why glucose is not a C-source for fatty acid synthesis in ruminants
Limiting enzymes
Citrate lyase
Malate dehydrogenase
Use of glucose for fat synthesis
Supply NADPH
Synthesis of glycerol

18. Acetyl CoA Carboxylase (ACC)
Allosteric modification
Activated by: Citrate
Inhibited by: LCFA
Covalent Modification
Activated by: Dephosphorylation
Inhibited by: Phosphorylation
ACC

19. FAS

20. 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

21. PPP
NADPH
FAS
ATP Citrate Lyase

22. Species comparison of fatty acid synthesis
Principal Tissue Site
Carbon Source
Poultry
Human
Pig
Mouse
Sheep
Cattle
Liver
Adipose
Glucose
Acetate

23. 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

25. LPL action on TG rich lipoproteins
Glycerol + 3 Fatty acids
capillary
Lipoprotein lipase
Cell
I.e. adipocyte
muscle
mammary
Chylomicrons
VLDL
Fatty acids
Triglycerides

26. LPL Mediated Fatty Acid Uptake

27. 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

28. 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 adipocyte
TAG stores, sends to serum. Incr by glucagon, epinephrine.
TAG 2-MAG + FFA serum
• Regulation of LPL Activity:
factor adipose muscle
starvation down up
Well Fed up down
insulin up down

29. Energy Content of Human Carcass
 -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 ,000 kCal in proteins (muscles) kCal in glycogen 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.

30. Lipolysis Overview Epinephrine Fatty Acids Glycerol
 Adenylate Cyclase
 cAMP
 Hormone Sensitive Lipase
Triglyceride  Fatty acids glycerol

32. 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. Biochem. J. (2004) 379, 11-22

33. Re-esertification vs. Mobilization
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.