lipid metabolism and pathways

Question 1

what are the biological functions of lipids

Answer 1

Essential components of cell membranes eg phospholipids, glycolipids and cholesterol
Inter and intra-cellular signalling events eg precursor of steroid hormones
Energy generation and fuel storage eg triglycerides
Metabolism eg bile acids
Consider dietary and endogenously produced lipids

Question 2

what is the structure and biological functions of lipids

Answer 2

storage lipids (neutral) - triglycerides (glycerols and 3 FAs)
Membrane lipids (polar) - phospholipids and glycolipids 
Steroids - cholesterol

Question 3

what are triacyglycerides

Answer 3

Constitute 90% dietary lipids
Major form of metabolic energy storage in humans
Hydrophobic in nature
glycerol and fatty acids

Question 4

how are triglycerides metabolised

Answer 4

Depending on metabolic requirement there are 2 major metabolic pathways
TGs broken into free fatty acids and glycerol. Oxidation of fatty acids in mitochondria to release energy as ATP
Synthesis of fatty acids from acetyl-CoA (joined to glycerol molecule for storage)

Question 5

how are TGs oxidised

Answer 5

3 stages of achieve complete oxidation of fatty acids to CO2 and H2O
1 removal of glycerol and oxidation of long chain fatty acids to 2 carbon fragments in the form of acetyl-CoA, this is B oxidation
2 oxidation of acetyl-CoA to CO2 in the citric acid cycle
3 transfer of electrons from reduced electron carriers to mitochondrial respiratory chains

Question 6

what is B-oxidation of fatty acids

Answer 6

attachment to Co-A
Occurs in mitochondria and peroxisomes
1 Fatty acids activated by attachment to coenzyme A in cytosol
2 transfer of acyl-groups across mitochondrial membrane (rate-limiting step)

Question 7

how is CoA transported into the mitochondria

Answer 7

transported in via carnitine carrier protein into mitochondria and back out

Question 8

how is acetyl-CoA generated

Answer 8

3 progressive oxidation of fatty acids by removal of 2 carbon units to form acetyl-CoA which enters the citric acid cycle
Each cycle shortens chain by 2C
1 acetyl-CoA formed, 1 FADH2 formed and 1 NADH formed
Used to generate energy for the cell
Whole process repeated until completely broken down into Acetyl-CoA

Question 9

what is the step FAD to FADH2 responsible for

Answer 9

this step catalysed by a group of dehydrogenase isozymes, mutations in these can cause SIDS

Question 10

what is fatty acid synthesis

Answer 10

Occurs mainly in liver and adipocytes
Long carbon chain molecules built up from 2 carbon units derived from acetyl-CoA
Occurs in the cytosol
But acetyl CoA is in the mitochondria

Question 11

what is the citrate malate cycle

Answer 11

How acetyl-CoA gets out of the mitochondria
OAA + AcCoA = citrate
tricarboxylate transporter out d mitochondria
citrate (ATP-ADP and CoA-AcCoA) to OAA to malate to pyruvate and back to mitochondria via pyruvate transporter

Question 12

what is fatty acid biosynthesis

Answer 12

Citrate>Acetyl-CoA>Malonyl CoA
Malonyl CoA and acetyl CoA both bind to fatty acid synthase
A series of condensation reactions involving malonyl CoA adds further C2 units

Question 13

how is fatty acid oxidation and synthesis controlled

Answer 13

Rate limiting steps
B oxidation transfer of acyl-CoA into mitochondria
Fatty acid synthesis: formation of malonyl CoA from acetyl-CoA, catalysed by acetyl CoA carboxylase> subject to control by glucagon and insulin

Question 14

what is cholesterol used for

Answer 14

Essential to life
Deposition in arteries associated with heart disease and stroke
In healthy organism, balance maintained between biosynthesis, utilisation and transport – keeping harmful deposition to minimum

Question 15

what is the role of cholesterol and bile acids (salts)

Answer 15

The physiological roles of cholesterol include
Important component of biological membranes, precursor of steroid hormones and sources of bile acids
Bile acids are polar derivatives of cholesterol and aid in
Lipid deposition, lipid absorption and cholesterol excretion

Question 16

what is the structure of cholesterol

Answer 16

Amphipathic lipid (-OH)(hydrophobic and hydrophilic portions)
Synthesised from acetyl-CoA and eliminated as bile acids
Storage is cholesterol ester
found in most tissues
Cholesterol acyltransferases eg Acyl-CoA cholesterol Acyltransferase (ACAT) catalyses formation of cholesterol esters

Question 17

What is cholesterol biosynthesis

Answer 17

4 stages but only need to know major site of synthesis is the liver with lesser amounts made in intestine and adrenal cortex
AcCoA(C2)- HMG-CoA(C8)-(HMG-CoA reductase)- Melanovate (C6)- Squalene(C30) - Cholesterol (C27)

Question 18

What does HMG-CoA reductase do

Answer 18

rate determining step 
cholesterol is feedback inhibitor
mevalonate is feedback inhibitor
target site for statin drugs 
also regulated by insulin/glucagon

Question 19

how are lipids transported around the body

Answer 19

Bring dietary lipids to cells for energy production or storage
Move lipids from storage in adipose tissue for use in energy production
Provide lipids from the diet to cells for synthesising cell membranes
Carry cholesterol from peripheral tissues to the liver for excretion

Question 20

how are lipids transported in the blood

Answer 20

Short chain fatty acids are transported bound to blood proteins like albumin
Bulk transport of neutral lipids, insoluble in water, require special carrier proteins known as lipoproteins
Neutral lipids carried in central core, outer layer of amphipathic phospholipids and cholesterol

Question 21

Characteristics of major classes of lipoproteins

Answer 21

VLDL, IDL, LDL, HDL
Greatest amount of cholesterol carried by LDL
VLDL unload triacylglycerols at the tissues to become IDL to unload further lipids to become LDL

Question 22

Classes of lipoproteins

Answer 22

Seen in the EM after negative staining 
Diameters (nm)
Chylo 50-200
VLDL 28-70
LDL 20-25
HDL 8-11

Question 23

Summary of lipid transport

Answer 23

Chylomicrons deliver dietary TGs to muscle and adipose tissue + dietary cholesterol to the liver
VLDL- transport endogenous TGs and cholesterol
LDL- transport cholesterol from liver to tissues
HDL- transport cholesterol to tissues to liver eg removing cholesterol from tissues (revere cholesterol transport)

Question 24

how are lipids taken up by cells

Answer 24

Chylomicrons and VLDL particles give up lipid (TG) to tissues by 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 LDL receptors (LDLRs)

Question 25

what does LDL uptake do

Answer 25

A source of cholesterol and ensures there is not too much in the blood
uptake of cholesterol results in decrease in cholesterol and LDLR synthesis

Question 26

how are LDLR receptors regulated

Answer 26

expression of LDL receptors increased by SREBPs in response to low cholesterol
PCSK9 Bind to LDL receptor and once LDL and receptor in cell it targets it for degradation

Question 27

Cellular cholesterol homeostasis

Answer 27

Proteins in cell membrane to allow cholesterol excretion, loaded on HDL for return to liver
SREBP exported to Golgi when cholesterol low, activation of SREBP increases HMGCR activity and expression of LDLR