Lipid Synthesis and Storage (Biochem) Flashcards

1
Q

What is the rate-limiting enzyme of FA synthesis?

A
  • Acetyl CoA carboxylase
  • ABC enzyme* (requires):
    A: ATP
    B: Biotin
    C: CO2
  • activation by insulin (dephosphorylated)
  • activation by citrate
  • this is like pyruvate carboxykinase, which is aslo an ABC enzyme
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2
Q

Essential FA

A
  • linoleic C18:2 (9,12)
  • linolenic C18:3 (9,12,15) (omega 3 family)
  • found in fish oil, flax seed oil
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3
Q

Omega 3 FA

A
  • ex) Linolenic
  • Assoc w decreased risk of cardiovascular disease and
  • decrease in serum TG
  • found in cold-water fish (salmon, tuna, herring)
  • found in some nuts (walnuts) and seeds (flax seed)
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4
Q

How do omega 3 FA correlate with a decreased risk of cardiovascular disease?

A
  • appear to replace some of the arachidonic acid (an omega 6 FA) in platelet membranes
  • may lowe the production of thromboxane and the tendency of platelets to aggregate
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5
Q

FA synthesis occurs in the

A

cytoplasm

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6
Q

when FA are used in metabolism, they are first ___

A
  • activated by attaching coenzyme A (CoA)

- Fatty acyl CoA synthetase catalyzes this activation step

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7
Q

Lipid Digestion

A
  • upon entry into the intestinal lumen, bile is secreted by the liver to emulsify the lipid contents
  • the pancreas secretes pancreatic lipase, colipase, and cholesterol esterase that degrade the lipids to 2-monoglyceride, FA, and cholesterol
  • these lipids are absorbed and re-esterified to TG and cholesterol esters and packaged into chylomicrons
  • Normally, there should be very little lipid loss in stools
  • defects in lipid digestion result in steatorrhea = excessive ant of lipids in stools (fatty stools)
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8
Q

Excess glucose can be converted to

A
  • FA in the liver

- and subsequently sent to adipose tissue for storage

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9
Q

Insulin promotes many steps in the conversion of glucose to Acetyl CoA in the liver. These include:

A
  • Glucokinase (induced)
  • PFK-1/PFK-2 (PFK-2 dephosphorylated)
  • Pyruvate dehydrogenase (dephosphorylated)
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10
Q

citrate shuttle

A
  • transports acetyl CoA groups from the mito to the cytoplasm for FA synthesis
  • Acetyl CoA combines with Oxaloacetate (OAA) in thematic to form citrate
  • this citrate goes into the cytoplasm (rather than entering the CAC)
  • This process is indirectly promote by insulin and high [ATP]
  • in the cytoplasm citrate lyase splits citrate back into acetyl CoA and OAA
  • the OAA returns to the mitochondria to transport additional CoA into the cytoplasm
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11
Q

malic enzyme

A
  • Converts malate to pyruvate*
  • requires NADP+ and produces NADPH
  • this supplements the cytoplasmic [NADPH]
  • Acetyl CoA can’t exit the mitochondria, so it is converted to citrate to be transported into the cytoplasm
  • citrate is converted back to OAA
  • OAA is converted to malate
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12
Q

Both of the major enzymes of FA synthesis are also affected by insulin. these are:

A
  • Acetyl CoA carboxylase (dephosphorylated, activated)

- FA synthase (induced)C

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13
Q

Acetyl CoA carboxylase

A
  • Acetyl CoA is activated in the cytoplasm for incorporation into FA by acetyl CoA carboxylase
  • is the rate-limiting enzyme of FA biosynthesis
  • stimulated by insulin
  • inhibited by glucagon
  • insulin and glucagon regulate via phosphorylation and dephosphorylation
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14
Q

What FA do we make from scratch?

A
  • Palmitate (16:0)
  • Acetyl CoA carboxylase: Acetyl CoA to malonyl CoA
  • FA synthase: malonyl CoA to Palmitate
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15
Q

citrate lyase

A
  • in the cytoplasm
  • splits citrate back into Acetyl CoA (from glycolysis) and OAA
  • part of the process by which Acetyl CoA enters the cytoplasm for FA synthesis, bc Acetyl CoA can’t leave the mitochondria
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16
Q

FA synthase

A
  • converts malonyl CoA to Palmitate
  • requires NADPH (to reduce the acetyl groups)
  • gives off CO2
  • induced by Insulin
  • contains an acyl carrier protein (ACP) that require the vitamin pantothenic acid (Vitamin B5)
  • the FA is derived ENTIRELY from acetyl CoA
  • ingredients: 8 Acetyl CoA, NADPH, CO2, ATP
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17
Q

Mechanism by which Alcoholics may develop fatty liver

A

Alcohol disrupts VLDL synthesis, so the FA created in the cytoplasm can’t exit the hepatocytes, and develop fatty liver

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18
Q

FA synthesis is regulated on 3 levels

A
  • allosterically
  • genetically
  • by phosphorylation
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19
Q

Fatty acyl CoA can be elongated or desaturated (limited in humans) by:

A
  • enzymes assoc w the SER
  • Cytochrome b5 is involved in the denaturation reactions
  • these enzymes can’t introduce double bonds past position 9 in the FA
20
Q

TG synthesis

A
  • TG = storage forms of FA
  • formed by attaching 3 FA (as fatty acyl CoA) to glycerol
  • occurs primarily in the liver and adipose tissue
  • TG synthesized in the liver are packed as VLDL
  • a small amount of TG may be stored in the liver
  • accumulation of significant TG in tissues other than adipose tissue indicates a pathologic state
21
Q

Sources of Glycerol 3P for synthesis of TG

A
  • reduction of dihydroxyacetone phosphate (DHAP) from glycolysis by Glycerol 3P dehydrogenase
  • G3PH is found in both adipose tissue and the liver
  • phosphorylation of free glycerol by glycerol kinase
  • glycerol kinase is found in the liver but NOT in adipose tissue
22
Q

Glycerophospholipids

A
  • used for membrane synthesis
  • used to produce a hydrophilic surface layer on lipoproteins like VLDL
  • in cell membranes act as a reservoir of 2nd messengers (IP3, DAG, arachidonic acid)
23
Q

Cholesterol Digestion

A
  • TG and cholesterol are transported in blood as lipoproteins
  • from least dense to most dense: chylomicrons, VLDL, IDL (intermediate density lipoprotein), LDL (low-density lipoprotein), HDL
24
Q

Glycerol 3P dehydrogenase

A
  • is a source of glycerol 3P for the synthesis of TG:
  • reduces DHAP from glycolysis to create Glycerol 3P
  • found in both adipose tissue and the liver
25
Function of Chylomicrons
- function: transport dietary TG and cholesterol (and cholesterol esters) from intestine to tissues - chylomicrons are lipoproteins
26
Glycerol Kinase
- is a source of glycerol 3P for the synthesis of TG: - phosphorylates free glycerol to glycerol 3P - found in the liver but NOT in adipose tissue - allows the liver to recycle the glycerol released during VLDL metabolism (when insulin is present) back into new TG synthesis - allows the liver to trap glycerol released into the blood from lipolysis in adipose tissue for subsequent conversion to glucose (this occurs during fasting when glucagon is released) - Adipose tissue lacks GK, and is strictly dependent on glucose uptake to produce DHAP for TG synthesis.
27
Function of VLDL
- transports TG from liver to tissues | - VLDL are lipoproteins
28
Function of IDL (intermediate-density lipoprotein)
- picks up cholesterol from HDL to become LDL - picked up by liver - IDL = VLDL remnants - IDL are lipoproteins
29
Function of LDL
- delivers cholesterol into cells | - LDL are lipoproteins
30
Function of HDL
- picks up cholesterol accumulating in bv - delivers cholesterol to liver and steroidogenic tissues via scavenger receptor (SR-B1) - shuttles apoC-II and apoE in blood - HDL are lipoproteins
31
Important apolipoproteins
- apoA: activates LCAT - apoB: involved in receptor-lipoprotein interactions - apoC: activator of lipoprotein lipase
32
Cholesterol Synthesis
- most occurs in liver - rate-limiting enzyme = HMG-CoA reductase - HMG-CoA reductase is inhibited by statin drugs
33
Cholesterol is a precursor for
- Vitamin D - cell membranes - bile salts/acids
34
Primary Hyperlipidemia Type I - deficiency - inheritance - lipid and lipoprotein elevated in blood - features
- deficiency: familial lipoprotein lipase (rare) - deficiency: apoC-II (rare) - AR - TG (and VLDL) and chylomicrons elevated in blood - features: TG deposits in liver, skin, pancreas - red-orange eruptive xanthomas (over mucous membranes and skin) - fatty liver - acute pancreatitis - abdominal pain after fatty meal - fatty chylomicronemia produces a milky turbidity in the serum or plasma
35
Primary Hyperlipidemia Type IIa - deficiency - inheritance - lipid and lipoprotein elevated in blood - features
- aka familial hypercholesterolemia - LDL (B-100) receptor deficiency - inheritance: AD, 1/500 are heterozygous - LDL and Cholesterol elevated in blood - features: high risk of atherosclerosis and CAD - Homozygous: death before 20 yo common - xanthomas of Achilles tendon - zanthelasmas - corneal arcus
36
MC hyperlipidemia
- Hyperlipidemia secondary to Diabetes = Type V - Pts have elevated serum TG in VLDL and chylomicrons in response to a meal containing carbs and fat, respectively. - Insulin should promote LPL activity in adipose tissue by increasing transcription of its gene - in diabetes, there are abnormally low levels of LPL and - an inability to adequately degrade TG in lipoproteins to facilitate the uptake of FA into adipocytes
37
Role of Vitamin E
- antioxidant - lipid soluble - protects LDL from oxidation and - can also prevent peroxidation of membrane lipids - oxidation of LDL at sites of endothelial damage is thought to be a major stimulus for uptake by macrophages
38
Diabetes, Alcoholism and G6Phosphatase deficiency can all produce less severe hypertriglyceridemia with an increase in VLDL and chylomicrons. Factors contributing to hyperlipidemia are:
- decreased glucose uptake in adipose tissue - overactive hormone-sensitive lipase (HSL) - underactive LPL
39
a hypolipidemia
- low to absent apoB-100 and apoB-48 - very rare - serum TG may be near 0 and cholesterol extremely low - bc chylomicron levels are low, fat accumulates in intestinal enterocytes and in hepatocytes - essential FA and Vit A and E are not well absorbed - Sx: steatorrhea - cerebral ataxia - pigementary degeneration in the retina - acanthocytes (thorny appearing erythrocytes) - possible loss of night vision
40
Cholesterol metabolism
- required for membrane, steroid and bile (in liver) synthesis - most cells derive cholesterol from LDL or HDL, but some may be made de novo (in liver) - synthesized form acetyl CoA in the cytoplasm (in liver) and NADPH is provided by the HMP shunt and magic enzyme - HMG-CoA reductase is found in the ER and converts HMG-CoA to mevalonate - the gene coding HMG-CoA reductase is repressed by cholesterol * Cholesterol also inhibits LDL-receptor gene expression. This is what's missing/defective in Type II Familial hypercholesteremia
41
What type of inhibition do statins use?
Statins inhibit HMG-CoA reductase via COMPETITIVE inhibition
42
HMG-CoA reductase
- rate-limiting enzyme in cholesterol metabolism - in the liver SER - converts HMG-CoA to mevalonate - stimulated by insulin (dephosphorylation) - inhibited by glucagon and statin drugs (via competitive inhibition) - cholesterol represses the expression of the gene coding HMG-CoA reductase and - cholesterol increases degradation of HMG-CoA Reductase - most cells derive cholesterol from LDL or HDL, but some may be made de novo (in liver)
43
A/E of Statins
- myalgia - myositis (increased creatine kinase levels cause inflammation) - rhabdomyolysis - can give coenzyme Q with statins to help reduce muscle pain - pravastatin and fluvastatin are not metabolized by p450
44
Farnesyl PPi
- intermediate produced in cholesterol metabolism - important for synthesis of coenzyme Q (ETC) - synthesis of dolichol PPi, a cofactor for N-linked glycosylation of proteins in the ER - prenylation of proteins that need to be held in the cell membrane by a lipid tail.
45
ACAT
- rate-limiting enzyme in pathway that packages cholesterol for storage - stimulated by cholesterol
46
What is the only way for the body to get rid of cholestrol
- bile acids | - also, the body can't metabolize cholesterol, so it is converted to cholesterol esters
47
LDL Receptors
- LDL binds to LDL receptors (apoB-100) on the hepatocyte bc it's too big to cross the membrane - endocytosis (clathrin-coated pits) - lysosomal fusion - release of free cholesterol - Cholesterol down-regulates LDL receptor gene expression