Lipid Metabolism and Pathways

Question 1

Metabolism of triglycerides

Answer 1

Depends on metabolic requirements
There are 2 major metabolic pathways:
Triglycerides broken into free fatty acids and glycerol
Synthesis of fatty acids form acetyl-CoA

Question 2

Oxidation of TGs

Answer 2

2 stages to achieve complete oxidation of fatty acids to CO2 and H2O:
Removal of glycerol and oxidation of long chain fatty acids to 2-carbon fragments in the form of acetyl CoA - this is beta oxidation
Oxidation of acetyl CoA to CO2 in the citric acid cycle
Transfer of electrons from reduced electron carriers to mitochondrial respiratory chain

Question 3

Beta oxidation of fatty acids: attachment to Co-A

Answer 3

Occurs in mitochondria and peroxisomes
Step 1: fatty acids activated by attachment to CoA (in cytosol)
Step 2: transfer of acyl groups across mitochondrial membrane (rate limiting)
Step 3: progressive oxidation of fatty acids by removal of 2-carbon units to form acetyl-CoA which enters the citric acid cucle
Each cycle shortened by 2Cs
Each cycle forms 1 molecule of acetyl CoA, 1 FADH2 and 1 NADH
This step is catalysed by a group of dehydrogenase enzymes - mutations in these can cause SIDS

Question 4

Fatty acid synthesis

Answer 4

Occurs mainly in liver and adipocytes - in cytosol
Long carbon chain molecules built up from 2 carbon units derived from acetyl CoA
But acetyl CoA is in mitochondria
Citrate –> acetyl CoA –> malonyl CoA
(second part: carboxylation)
Malonyl COA and acetyl CoA both bind to fatty acid synthase
Condensation reactions involving malonyl CoA add further C2 units

Question 5

Cholesterol

Answer 5

Deposition in arteries associated with HD and stroke
In healthy organism, balance maintained between biosynthesis, utilisation and transport - keeping harmful deposition to a minimum
Physiological roles: membranes, steroid hormones, bile acids
Bile acids aid in: lipid digestion, lipid absorption and cholesterol excretion

Question 6

Structure of cholesterol

Answer 6

Amphipathic (except when cholesterol ester - storage molecule) 
Synthesized from acetyl CoA and eliminated as bile acids
Cholesterol acyltransferase (ACAT) catalyses formation of cholesterol esters

Question 7

Cholesterol biosynthesis

Answer 7

In liver (mostly), intestine and adrenal cortex
Acetyl CoA -> HMG-CoA -> (using enzyme HMG-CoA reductase) -> mevalonate (C6) -> squalene (C30) -> cholesterol (C27)
Rate determining step: HMG-CoA to mevalonate
Uses HMG CoA reductase:
Cholesterol (and mevalonate) are feedback inhibitors (target site for statin drugs)
HMG-CoA reductase activity regulated by insulin/glucagon

Question 8

Transport of Lipids

Answer 8

Chylomicrons: deliver dietary TGs to muscle and adipose tissue and dietary cholesterol to the liver
VLDL: transport endogenous TGs and cholesterol
LDL: transport cholesterol from liver to tissues
HDL: transport cholesterol from tissues to liver (remove cholesterol)

Question 9

Liver uptake by cells

Answer 9

Chylomicrons and VLDL particles give up lipid (TGs) to tissues by the action of tissue bound lipases
The liver recognises remnants of these particles by their ApoE content and takes them up for recycling
LDL particles contain ApoB-100, which is recognised by cell surface receptors
Uptake of cholesterol results in decrease in cholesterol and LDLR synthesis

Question 10

Regulation of LDL receptors

Answer 10

PCSK9 binds to LDL receptors and results in its degradation
Prevents LDL receptors being recycled back to cell membrane
Overall effect is to reduce amount of LDL - and cholesterol, being taken into the cell