Lipid Synthesis and Storage (Biochem) Flashcards Preview

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Flashcards in Lipid Synthesis and Storage (Biochem) Deck (47):

What is the rate-limiting enzyme of FA synthesis?

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


Essential FA

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


Omega 3 FA

- 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)


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

- 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


FA synthesis occurs in the



when FA are used in metabolism, they are first ___

- activated by attaching coenzyme A (CoA)
- Fatty acyl CoA synthetase catalyzes this activation step


Lipid Digestion

- 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)


Excess glucose can be converted to

- FA in the liver
- and subsequently sent to adipose tissue for storage


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

- Glucokinase (induced)
- PFK-1/PFK-2 (PFK-2 dephosphorylated)
- Pyruvate dehydrogenase (dephosphorylated)


citrate shuttle

- 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


malic enzyme

- 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


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

- Acetyl CoA carboxylase (dephosphorylated, activated)
- FA synthase (induced)C


Acetyl CoA carboxylase

- 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


What FA do we make from scratch?

- Palmitate (16:0)
- Acetyl CoA carboxylase: Acetyl CoA to malonyl CoA
- FA synthase: malonyl CoA to Palmitate


citrate lyase

- 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


FA synthase

- 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


Mechanism by which Alcoholics may develop fatty liver

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


FA synthesis is regulated on 3 levels

- allosterically
- genetically
- by phosphorylation


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

- 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


TG synthesis

- 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


Sources of Glycerol 3P for synthesis of TG

- 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



- 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)


Cholesterol Digestion

- 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


Glycerol 3P dehydrogenase

- 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


Function of Chylomicrons

- function: transport dietary TG and cholesterol (and cholesterol esters) from intestine to tissues
- chylomicrons are lipoproteins


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.


Function of VLDL

- transports TG from liver to tissues
- VLDL are lipoproteins


Function of IDL (intermediate-density lipoprotein)

- picks up cholesterol from HDL to become LDL
- picked up by liver
- IDL = VLDL remnants
- IDL are lipoproteins


Function of LDL

- delivers cholesterol into cells
- LDL are lipoproteins


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


Important apolipoproteins

- apoA: activates LCAT
- apoB: involved in receptor-lipoprotein interactions
- apoC: activator of lipoprotein lipase


Cholesterol Synthesis

- most occurs in liver
- rate-limiting enzyme = HMG-CoA reductase
- HMG-CoA reductase is inhibited by statin drugs


Cholesterol is a precursor for

- Vitamin D
- cell membranes
- bile salts/acids


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


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


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


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


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


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


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


What type of inhibition do statins use?

Statins inhibit HMG-CoA reductase via COMPETITIVE inhibition


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)


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


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.



- rate-limiting enzyme in pathway that packages cholesterol for storage
- stimulated by cholesterol


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


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