Transcript LB Fat metabolism A

Post-Absorptive Lipid
Metabolism
Lipid Metabolism Terms
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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
glucose
-glycerolĞP
glucose
cholesterol
cholesterol
fatty acids
MAG
cholesterol ester
FA-CoA
TAG
Chylomicrons
lysolecithin
Lymphatics
lecithin
apoproteins
short chain
FAs </= C10
FA
+
albumen
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
Clearance of lipid from circulation is mediated by adipose,muscle and
liver: via the enzyme Lipoprotein Lipase (LPL)
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.
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
De novo Fatty Acid Synthesis
glucose
Fatty Acids
NADPH
pyruvate
FAS
Acetyl Co A
ACC
TCA
Citrate
monogastrics
Acetyl Co A
ruminants
Acetate
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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
Acetyl CoA Carboxylase (ACC)
Allosteric modification
Activated by: Citrate
Inhibited by: LCFA
Covalent Modification
Activated by: Dephosphorylation
Inhibited by: Phosphorylation
ACC
FAS
Fatty Acid Synthase (FAS)
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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
PPP
NADPH
FAS
ATP Citrate Lyase
Species comparison of fatty acid
synthesis
Species
Poultry
Human
Pig
Mouse
Sheep
Cattle
Principal Tissue Site
Liver
Liver
Adipose
Adipose
Adipose
Adipose
Carbon Source
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
LPL action on TG rich lipoproteins
Glycerol + 3 Fatty acids
TG
capillary
Lipoprotein lipase
Cell
Chylomicrons
VLDL
I.e. adipocyte
muscle
mammary
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 adipocyte
TAG stores, sends to serum. Incr by glucagon, epinephrine.
TAG
2-MAG + FFA
serum
• Regulation of LPL Activity:
factor
starvation
Well Fed
insulin
adipose
down
up
up
muscle
up
down
down
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
25,000 kCal in proteins (muscles)
600 kCal in glycogen
400 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.
Lipolysis Overview
Epinephrine
Fatty Acids
 Adenylate Cyclase
 cAMP
 Hormone Sensitive Lipase
Triglyceride 
Fatty acids +
glycerol
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 multiphosphorylated, 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
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 reesterified 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.