Flashcards in Lipid Synthesis and Storage (Biochem) Deck (47)
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1
What is the rate-limiting enzyme of FA synthesis?
- 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
Essential FA
- linoleic C18:2 (9,12)
- linolenic C18:3 (9,12,15) (omega 3 family)
- found in fish oil, flax seed oil
3
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)
4
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
5
FA synthesis occurs in the
cytoplasm
6
when FA are used in metabolism, they are first ___
- activated by attaching coenzyme A (CoA)
- Fatty acyl CoA synthetase catalyzes this activation step
7
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)
8
Excess glucose can be converted to
- FA in the liver
- and subsequently sent to adipose tissue for storage
9
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)
10
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
11
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
12
Both of the major enzymes of FA synthesis are also affected by insulin. these are:
- Acetyl CoA carboxylase (dephosphorylated, activated)
- FA synthase (induced)C
13
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
14
What FA do we make from scratch?
- Palmitate (16:0)
- Acetyl CoA carboxylase: Acetyl CoA to malonyl CoA
- FA synthase: malonyl CoA to Palmitate
15
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
16
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
17
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
18
FA synthesis is regulated on 3 levels
- allosterically
- genetically
- by phosphorylation
19
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
20
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
21
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
22
Glycerophospholipids
- 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
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
24
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
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
