Lipid metabolism and pathway

Question 1

Biological functions of lipids

Answer 1

Cell membranes- phospholipids, glycolipids and cholesterol.

Generation and storage- triglycerides.

Cell signaling events- precursor for steroid hormones.

Metabolism- bile acids

Question 2

Triglycerides

Answer 2

90% of dietary lipids

Metabolic storage

Hydrophobic

Question 3

Digestion of triacylglycerols

Answer 3

1. Emulsification: broken down into smaller pieces by bile acids- increases SA for enzymic digestion
2. Hydrolysis: Pancreatic triacylglycerol lipase.
3. Absorption: products (fatty acids, mono/diacylglycerols), absorbed by intestinal mucosa.

Question 4

Pancreatic triacylglycerol lipase

Answer 4

Enzyme that hydrolyses triacylglycerol into a mixture of fatty acids and mono/diacylglycerols

Question 5

Which structure absorbs products of triglyceride digestion?

Answer 5

Intestinal mucosa

Question 6

Summary of the oxidation of TGs

Answer 6

Location: mitochondria

Process:
TG—–> ATP, CO2 and H2O.

Question 7

3 steps of oxidation

Answer 7

1. Beta-oxidation:
   Oxidation of fatty acid chain, 2 cardons at a time to form acetyl-CoA.
2. Citric acid cycle: Acetyl CoA is oxidised to CO2.
3. Electron transfer from reduced electron carriers to mitochondrial respiratory chain.

Question 8

Beta-oxidation

Answer 8

Location: mitochondria, peroxisomes.

Step 1: CoA attaches to fatty acids and activate it.

Rate determining step, Step 2: Transfer of acetyl-CoA across mitochondrial membrane

Step 3, progressive oxidation: 2 carbon units removed at a time to form acetyl-CoA-----> enters citric acid cycle.
This step forms:
1 aceyl-CoA
1 FADH2
1 NADH

Question 9

Transfer of fatty acids across the mitochondrial membrane

Answer 9

Carnitine shuttle transports long fatty acids- greater than 10 Cs.

There is a supply of CoA in both the cytosol and mitochondrial matrix- CoA not transported across inner mitochondrial membrane.

1. Fatty acid is activated by acyl CoA via acyl CoA synthase—-> Fatty acyl-CoA
2. Carnitine acyltransferase 1 causes CoA-SH to unbind and carnitine to bind to fatty acyl.
3. Fatty acyl carnitine is transferred across membrane into mitochondrial matrix via carnitine carrier protein.
4. Transferase II (matrix side of inner membrane), causes carnitine to unbind from fatty acyl carnitine and S-CoA to bind in the matrix.
5. This allows fatty acyl-CoA to progress into beta oxidation

Question 10

Fatty acid synthesis

Answer 10

Location: Cytosol of mainly hepatocytes and adipocytes, essentially in all cells.

Build up of long fatty acid chains 2 C a time- from acetyl CoA

Acetyl CoA source from mitochondria.

1. Citrate is converted to acetyl CoA
2. Carboxylation: Acetyl CoA converted to malonyl CoA- rate limiting step.
3. Acetyl CoA and malonyl CoA both bind to fatty acid synthase to form fatty acids.

Question 11

Transport of acetyl CoA out of the mitochondria

Answer 11

Citrate malate cycle:

1. Acetyl CoA is converted into citrate via citrate synthase in mitochondrial matrix.
2. Citrate exits the cell via tricarboxylate transporter. into cytosol.
3. Citrate converted into oxaloacetate via citrate lyase.
   Also produces Acetyl-CoA, when bound to CoA.
4. Maltate dehydrogenase converts OAA to malate.
5. Malic enzyme converts malate to pyruvate.

Question 12

Rate determining steps in fatty acid oxidation

Answer 12

Beta oxidation- transfer of acyl-CoA into mitocohondria.

Question 13

Rate determining steps fatty acid synthesis

Answer 13

Carboxylation of malonyl CoA to form acyl CoA

Uses acyl CoA carboxylase

Question 14

Control of fatty acid synthesis

Answer 14

Regulated by glucagon and insulin- controls phosphorylation

Insulin favours dephosphorylation which activates acyl CoA carboxylase

Question 15

Roles of cholesterol

Answer 15

Component of biological membranes

Precursor for steroid hormones

Source of bile acids

Question 16

Roles of bile acids

Answer 16

Lipid digestion

Lipid absorption

Cholesterol excretion

Question 17

Summary of cholesterol biosynthesis

Answer 17

1. Acteyl CoA converted to HMG-CoA.
2. HMG-CoA converted to mevalonate (c6), using HMG-CoA reductase.
3. Mevalonate is converted to Squalene (C30)
4. Squalene is converted to cholesterol (C27).

Question 18

Stage 1 of cholesterol biosynthesis: conversion of Acetyl-CoA to mevalonate

Answer 18

1. Acyl CoA is converted to HMG-CoA
2. HMG-CoA converted to mevalonate using HMG-CoA reductase
   - This step oxidises NADPH to NADP+.
   - Rate determining step, target from statins.

Question 19

Statins

Answer 19

Competitive inhibitors of HMG-CoA reductase

Natural and synthetic statins

Question 20

Natural statins

Answer 20

Derived from yeast

Lovastatin (mevacor)

Compactin

Pravastatin (pravachol)

Simvastatin (Zocor)

Question 21

Natural statins

Answer 21

Atorvastatin

Fluvastatin

Question 22

Reasons for transporting lipids around the body

Answer 22

Dietary lipids- energy production and storage in cells.

Dietary lipids—> cell membrane synthesis.

Movement of lipids from adipose to tissue for energy production.

Excretion: peripheral tissues to the liver.

Question 23

Albumin

Answer 23

Blood protein that transports short-chain fatty acids in the blood.

Question 24

Lipoprotein

Answer 24

Main transport of lipids in the body.

Composition:
Triacylglycerols and cholesterol esters in the central core.

Outer layer-
Amphipathic phospholipids
Cholesterol
Apolipoproteins

Question 25

What lipoprotein mainly carries cholesterol?

Answer 25

LDL

Question 26

Chylomicrons

Answer 26

Delivery dietary TGs to muscle and adipose tissue

Also delivers dietary cholesterol to the liver.

Question 27

VLDL

Answer 27

Very low density lipoprotein

Transports endogenous TGs and cholesterol in the blood.

When lipid content depletes in VLDL, it becomes IDL.

Question 28

LDL

Answer 28

Transports cholesterol from the liver to tissues

Question 29

HDL

Answer 29

High density lipoprotein

Transports cholesterol from tissue to liver- reverse cholesterol transport.

Question 30

Tangier disease

Answer 30

Genetic disorder that causes severe reduction of HDL in the bloodstream.

Due to mutation in ABCA1 enzyme which allows cholesterol to leave cells.

Question 31

Lipoprotein lipase

Answer 31

Enzyme that allows the release of TG at tissues.

Found in chylomicrons and VLDL- allows them to drop TG.

Question 32

ApoB-100

Answer 32

An apolipoprotein that is found on LDL particles.

ApoB-100 is recognised by LDL receptors in the liver and on other cells.

Question 33

ApoE

Answer 33

An apolipoprotein found on all lipoproteins.

Recognised by the liver which takes them up for recycling.

Question 34

Cholesterol uptake by cells

Answer 34

LDL receptors on cells recognise ApoB-100 on LDL.

This causes the LDL particle to be taken in with LDL receptors- LDL receptors are recycled.

LDL is broken down to release cholesterol in the endosome.

Increase in cholesterol uptake = decrease in cholesterol synthesis via HMG-CoA reductase

Question 35

Familial hypercholesterolaemia

Answer 35

Genetic condition that causes a mutation in the LDL receptor or ApoB-100.

Prevents uptake of LDL, hence cholesterol.

Causes individuals with this disease to have very high serum cholesterol and increased risk of CVD.

Question 36

PCSK9

Answer 36

A protein that binds to LDL receptors and degrades the receptors.

Prevents recycling of receptors, thus less cholesterol is taken in.

This causes higher plasma LDL-C.