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
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
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)
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
5
Q
FA synthesis occurs in the
A
cytoplasm
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
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)
8
Q
Excess glucose can be converted to
A
- FA in the liver
- and subsequently sent to adipose tissue for storage
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)
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
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
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
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
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
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
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
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
18
Q
FA synthesis is regulated on 3 levels
A
- allosterically
- genetically
- by phosphorylation
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
Q
Function of Chylomicrons
A
- function: transport dietary TG and cholesterol (and cholesterol esters) from intestine to tissues
- chylomicrons are lipoproteins
26
Q
Glycerol Kinase
A
- 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
Q
Function of VLDL
A
- transports TG from liver to tissues
- VLDL are lipoproteins
28
Q
Function of IDL (intermediate-density lipoprotein)
A
- picks up cholesterol from HDL to become LDL
- picked up by liver
- IDL = VLDL remnants
- IDL are lipoproteins
29
Q
Function of LDL
A
- delivers cholesterol into cells
- LDL are lipoproteins
30
Q
Function of HDL
A
- 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
Q
Important apolipoproteins
A
- apoA: activates LCAT
- apoB: involved in receptor-lipoprotein interactions
- apoC: activator of lipoprotein lipase
32
Q
Cholesterol Synthesis
A
- most occurs in liver
- rate-limiting enzyme = HMG-CoA reductase
- HMG-CoA reductase is inhibited by statin drugs
33
Q
Cholesterol is a precursor for
A
- Vitamin D
- cell membranes
- bile salts/acids
34
Q
Primary Hyperlipidemia Type I
- deficiency
- inheritance
- lipid and lipoprotein elevated in blood
- features
A
- 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
Q
Primary Hyperlipidemia Type IIa
- deficiency
- inheritance
- lipid and lipoprotein elevated in blood
- features
A
- 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
Q
MC hyperlipidemia
A
- 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
Q
Role of Vitamin E
A
- 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
Q
Diabetes, Alcoholism and G6Phosphatase deficiency can all produce less severe hypertriglyceridemia with an increase in VLDL and chylomicrons. Factors contributing to hyperlipidemia are:
A
- decreased glucose uptake in adipose tissue
- overactive hormone-sensitive lipase (HSL)
- underactive LPL
39
Q
a hypolipidemia
A
- 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
Q
Cholesterol metabolism
A
- 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
Q
What type of inhibition do statins use?
A
Statins inhibit HMG-CoA reductase via COMPETITIVE inhibition
42
Q
HMG-CoA reductase
A
- 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
Q
A/E of Statins
A
- 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
Q
Farnesyl PPi
A
- 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
Q
ACAT
A
- rate-limiting enzyme in pathway that packages cholesterol for storage
- stimulated by cholesterol
46
Q
What is the only way for the body to get rid of cholestrol
A
- bile acids
- also, the body can’t metabolize cholesterol, so it is converted to cholesterol esters
47
Q
LDL Receptors
A
- 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
