Post-Absorptive Lipid Metabolism

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Post-Absorptive Lipid Metabolism
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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 TGs in GIT
• Lipoprotein Lipase
• Breaks down TGs from chylomicron and VLDL in the
  capillary
• ?-oxidation
• Breaking down of fatty acids into acetyl-CoA
• Hormone Sensitive Lipase
• Breaks down TGs within the adipocyte
• NEFA
• Non-esterified fatty acids fatty acids mobilized
  (exiting) the adipocyte

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Lipid Metabolism
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Lipid Absorption
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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

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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)
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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

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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

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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

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

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

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PPP
NADPH
FAS
ATP Citrate Lyase
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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
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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

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LPL action on TG rich lipoproteins
Glycerol 3 Fatty acids
TG
capillary
Lipoprotein lipase
Cell I.e. adipocyte muscle mammary
Chylomicrons VLDL
Fatty acids
Triglycerides
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LPL Mediated Fatty Acid Uptake
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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 CoAs
• Oxidized by energy needing cells
• Stimulated by epinephrine AND the lack of insulin

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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
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 -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 -Triacylglycero
ls 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
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Lipolysis Overview
Epinephrine
Fatty Acids
Glycerol
? Adenylate Cyclase
? cAMP
? Hormone Sensitive Lipase
Triglyceride ????? Fatty acids
glycerol
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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
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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 FAs 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.