METABOLISM OF LIPIDS

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METABOLISM OF LIPIDS
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Things to know

• How metabolic oxidation of lipids releases large
  quantities of energy through production of
  acetyl-CoA, NADH, and FADH2
• How lipids represent an even more efficient way
  of storing chemical energy

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Introduction

• Triacylglycerols main storage form of lipids
  bond between fatty acid and other molecules can
  be hydrolysed using lipases enzyme
• Phosphoacylglycerols membrane component
  phospholipases
• Spider/snake venom phospholipases- tissue
  damage and rbc lysis- prevent clot formation

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Release of fatty acids
2 Marks
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Fatty acid oxidation

• Begin with activation of molecule
• Thioester bond is formed between the carboxyl
  group of coenzyme A (CoA-SH) by acyl-CoA
  synthethase (require ATP)
• The activated form of fa acyl-CoA

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?-oxidation

• Fatty acids in the from of acyl-CoA molecules are
  broken down to generate acetyl-CoA, intermediate
  for TCA cycle
• Involve 4 steps

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• For f.a with even number of carbon, the product
  is acetyl coa.
• So for a 18C f.a
• 8 cycle
• 9 AC
• C18 1AC
• C16 1AC
• C14 1AC
• C12 1AC
• C10 1AC
• C8 1AC
• C6 1AC
• C4 1AC
• C2 1AC

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B oxidation products
TCA Cycle
Final products
17 FADH2 35 NADH 9 GTP 148 ATP PER ONE
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Comparison

• One mole of glucose (6C) Produce 36/38 ATP
• 3mole of glucose (18C) 108ATP/114ATP

• One mole of f.a 18C
• Produce already 149 ATP!

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They dont need water

• Metabolic water is produced during oxidation of
  f.a
• Camel lipid stored in humps
• Kangaroo rats diets of seed- rich lipid but no
  water can live indefinitely without having to
  drink

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Ketone bodies

• Are produced when excess of acetyl CoA occur
  arises from B-oxidation
• Occur when not enough OAA is available to enter
  TCA
• Happen when organisms has high intake of lipid
  and low intake of carb in diets
• Brain can metabolize ketone bodies (20
  requirements)

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Ketone bodies

• Acetone can be detected in breath ketosis
• Ketone bodies acidic their presence overwhelm
  the buffering capacity
• Acetoacetate can be converted to acetyl-CoA to
  enter TCA
• Ketonaemia- rise of ketone bodies in blood above
  normal level
• Ketonuria when blood level of ketone bodies
  rises above renal threshold, they are excreted in
  urine
• Ketosis accumulation of abnormal amount of
  ketone bodies in tissues and body fluid

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Causes

• starvation- simples form of ketosis occurs due
  to depletion of carb reserve, coupled with
  mobilization of FFA and oxidation to produce
  energy
• In pathologic states
• in DM clinical and experimental
• in some types of alkalosis ketosis may occur
• pregancy toxaemia in sheep and lactating cattle
• 3. Non pathological states- high fat feeding and
  severe exercise in the postabsorbtive state

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Ketosis

• Ketosis can be abolished by increasing the
  metabolism of carb in diet
• DM- give insulin
• Ketogenic substances ALL FFA
• 40 of aa ketogenic
• Antiketogenic all carb, insulin, glucogenic aa,
  glycerol

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CHOLESTEROL
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Cholesterol

• Membrane structure
• Precursor for steroid hormones and bile acids

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Biosynthesis of cholesterol

• Cholesterol is synthesized in many tissues
• Mainly in liver and intestine
• Acetyl CoA is the precursor
• More than half is synthesized in body
• Remainder from diet

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Cholesterol synthesis
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Regulation of cholesterol synthesis

• Is important to prevent accumulation and abnormal
  deposition of cholesterol in the body
• Is primarily regulated by the enzyme HMG-CoA
  reductase
• HMG-CoA reductase is inhibited by cholesterol
  itself
• Fasting inhibit the enzyme and activate the
  HMG-CoA lyase to form ketone bodies
• The feeding of cholesterol reduces the hepatic
  biosynthesis of cholesterol
• Cholesterol drugs atorvastatin inhibit HMG-Coa
  Reductase

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Hormonal effect

• Insulin increase HMG-CoA reductase actvity
• Glucagon and glucocorticoid decrease the enz
  activity
• Thyroid hormones stimulate the hormone activity

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Other factors influence cholesterol level in blood

• Dietary fats diet in saturated fat increase
  cholesterol level
• Dietary cholesterol
• Dietary carbohydrates
• Hereditity
• Blood groups higher in A and AB than O and B
• Dietary fibers- cause excretion of cholesterol
  and bile acids in feces reduce serum
  cholesterol
• Exercise lower cholesterol and increase HDL
• Hypolipidaemic drug block formation of
  cholesterol

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Fate of cholesterol

• Conversion to bile acids - excreted
• Conversion to neutral sterols excreted
• Conversion 7-dehydrocholesterol in skin, UV
  light will convert it to Vit D
• Formation of adrenocorticol hormones
• Formation of androgens, estrogens, progesterone

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Lipid transport and storage

• Fats from diets and lipids synthesized must be
  transported to tissues and organ utilize and
  store
• They are carried in blood plasma as plasma
  lipoproteins (macromolecular complexes of
  specific apolipoprotein)
• Diff combination produce diff densities,
  chylomicrons ltVLDLltLDLltHDL
• Lipoproteins transport lipid from intestines as
  chylomicrons and from liver as VLDL to most
  tissues for oxidation and adipose tissuefor
  storage
• Lipid is mobilized from tissue as free f.a

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Types of apoproteins

• HDL apo-A-I and apo-A-II
• LDL and LDL apo-B100
• Chylomicrons apoB48

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Functions of apoprotein

• Make the lipoprotein molecules water miscible
  (hydrophilic)
• May acts as activator or inhibitor of specific
  enzymes. E.g
• Apo-A-I and Apo-A-II act as LCAT activator
• apo-C-I and C-II act as activator of lipoprotein
  lipase
• apo-C-III- inhibitor of lipoprotein lipase
• apo-B-100 and apo-E- bind with specific receptor
  on hepatic cells- lead to hepatic uptake

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Synthesize of chylomicrons and VLDL

• CM in intestinal mucosal cells
• VLDL in liver
• LDL- LDL is formed by degradation of VLDL (by
  losing some if its TG and apo)
• Rich in cholesterol and cholesterol esters (bad
  cholesterol) transport cholesterol to
  extrahepatic tissues
• Cholesterol delivered by LDL to cells inhibit
  HMG-CoA reductase inhibit cholesterol
  synthesize

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Major fx

• Chylomicrons
• Carrier of exogenous TG. Transport mainly TG, PL,
  cholesterol ester and fat soluble vit from
  intestinal to liver and adipose tissues. Carrier
  for dietary lipids
• 2. VLDL
• Carrier of endogenous TG mainly transports TG
  synthesized in hepatic cells from the liver to
  extrahepatic tissues for storage
• 3. LDL
• Transport and delivers cholesterol to
  extrahepatic tissues
• Regulate cholesterol synthesis in extrahepatic
  tissues cholesterol delivered by LDL to cells
  inhibit HMG-CoA reductase rate limiting enzyme
  for cholesterol synthesis

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Fate of LDL

• LDL are taken into cell by endocytosis through
  receptor recognition
• The presence of LDL receptor on the cell surface
  is important for uptake of LDL
• LDL is hydrolysed to aa, cholesterol and fa
• Free cholesterol membrane component and inhibit
  the production of HMG-CoA reductase- suppressed
  synthesis of cholesterol and also inhibit the
  synthesis of receptors reduce intake of LDL.
  LDL level in blood increase deposit as plaques

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Fate of LDL

• Cholesterol not needed for membrane can be stored
  as fatty acid ester catalyzed by acyl-CoA
  cholesterol acyltransferase (ACAT)
• The presence of free cholesterol increases the
  enzymatic activity of ACAT

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Catabolism

• Lipoprotein lipases hydrolyzes TG from
  chylomicron to produce free fa and glycerol
• The released fa are taken by cells
• Lipoprotein lipases activity declines in
  adipocytes during starvation - reduce uptake of
  lipid by adipose tissue
• Starvation enhances Lipoprotein lipases activity
  in cardiac and muscle to oxidize more fa
  

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HDL

• Is synthesized in liver cells and in intestinal
  mucosa cells. Apo-A , Apo-E and Apo-C as the
  carrier
• Strip off the cellular cholesterol from
  peripheral cells and muscles of arteries
• Activates the LCAT- esterification of cholesterol
  to HDL
• Transported to liver- catabolism

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HDL

• Provide Apo-C and Apo-E to VLVL and chylomicrons
  to be acted upon lipoprotein lipase
• Stimulate synthesis of prostacylin synthesis by
  endothelial cells inhibits platelet aggregation
  and prevent thrombus formation
• Helps in removal macrophages from arterial wall

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Bile acids

• Bile helps in digestion and absorption of lipids
• Stored in gallbladder
• Bile acids -Steroid acids found in bileFx
• Lowering surface tension emulsification of fats
• Accelerate the action of pancreatic lipase
• Form micelles with fa-helps absorption
• Aid in absorption of fat soluble vit

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Bile acids

• Keep cholesterol in solution
• In GB, cholesterol is solubilized and held in
  micelles with the help of conjugated bile salts
  and phospholipids
• Bile salts content decreased imbalance of
  micelles- cholesterol leak out crystallize and
  form gall stones
• Gall stones formed due to precipitation of
  cholesterol

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Atherosclerosis

• Excess LDLs invade tissues of the artery and
  become modified. The modified molecule stimulate
  the production of adhesion molecules, sticking
  out into the blood stream. Attract monocytes and
  T cells to the site.
• Monocytes mature into active macrophages and
  produce many inflammatory molecules to digest LDL
• Fat filled macrophages (foam cells) earliest
  form of atherosclerotic plaque

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Atherosclerosis

• Inflammatory molecules promote growth of plaque
  and form a fibrous cap over the lipid core. The
  fibrous cap seal off the fatty core from the
  blood
• Foam cells weaken the cap by secreting digesting
  matrix molecules. If the weakened cap ruptures,
  tissue factors display on the foam cells will
  interact with clot promoting element in the
  blood causing a clot (thrombus)

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• Familial cholesteralaemia defective gene that
  code for receptor develop atherosclerosis
  earlier

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TASK

• DISCUSS ON HYPERCHOLESTROLAEMIA IN ANIMAL what
  animal involve? Due to what? Diet? Genetic
  defect?
• Discuss on ketosis in animal explain the
  mechanism
• Discuss