Lipids

Question 1

Functions of the range of lipid types?

Answer 1

Fats and oils store energy

Phospholipids (inc.sphingolipids) form membranes

Steroids and fatty acids have regulatory roles as vitamins and hormones.

Thermal insulation

Myelin electrical insulation

Oil in skin repels water

Question 2

What are the 2 essential fatty acids?

Answer 2

linoleic (an omega 6) and linolenic (an omega 3) acids

Question 3

Why are fatty acids normally stored as triglycerides?

Answer 3

High levels of FAs are toxic

Question 4

Explain differences between saturated and unsaturated fatty acids:

Answer 4

Saturated fatty acids have variable number of methylene groups (CH2) with terminal methyl group and no C=C double bonds. Normally palmitic acid C₁₆, or stearic acid C₁₈ most common. Increasing mass increases VDW increases melting point.

Unsaturated fatty acids have one (monoenoic) or more (polyenoic) C=C double bond that, in normal cis-conformation puts rigid 30^o bend which interferes with packing –> decreased VDW, decreased melting point with greater unsaturation –> oils.

[Monounsaturated fatty acids always have C=C between carbons 9 and 10!]

Question 5

Where do you find mono and poly unsaturated fats in diet?

Answer 5

Monoenoic found in olives/olive oil

Polyenoic found in vegetable oils and some nuts (walnuts)

Question 6

Structure and variety of Triacylglycerols/triglycerides?

Answer 6

Glycerol molecule attached to 3 fatty acid chains by ester bonds.

Simple triglycerides: FAs are all the same.

Mixed have 2/3 different FAs

Anhydrous storage, greatly reduced therefore much energy.

Question 7

Structure of Phospholipids and membrane sphingolipids?

Answer 7

Phospholipids are amphipathic, have polar head group with one FA tail replaced by a phosphate group. (also can have serine,choline,ethanolamine attached)

Sphingolipids derived from sphingosine, addition of a fatty acid chain to amino group makes them ceramides, addition of phosphocholine or phosphoethanolamine makes sphingomyelin. (monosaccharide moiety –> cerebroside, oligosaccharide –>ganglioside)

Question 8

Basics of cholesterol synthesis?

Answer 8

All human cells can synthesise cholesterol from Acetyl-CoA, via melavonate, in cytoplasm

Liver is major site of synthesis

Requires a lot of energy from 36 ATP, and 16 NADPH reducing power (from Pentose phosphate pathway), to convert 18 Acetyl-CoA into cholesterol.

Cholesterol can then be converted into sex hormones (and other corticosteroids)

Question 9

Fat soluble Vitamins?

Answer 9

ADEK. hydrocarbon rings.

A (retinol) = ring with polar group on long hydrocarbon side chain

D = like cholesterol

E = 2 fused rings with a hydrocarbon side chain

K = like E but with quinone ring (variable side chain)

Question 10

Role of LCAT (lecithin-cholesterol acyltransferase)

Answer 10

Synthesised by liver and secreted into plasma, binds HDLs

Converts free cholesterol from peripheral cells to cholesteryl esters for reverse cholesterol transport in HDLs

(controlled by ApoI (activating) and ApoII (inactivating))

Question 11

Basic differences in composition between types of lipoproteins?

Answer 11

Large Chylomicrons (exogenous pathway) and VLDLs (endogenous) transport large quantities of TAGs

Smaller LDL is cholesterol rich and very small HDL is largely protein (but transports cholesterol)

Question 12

Role/location of different apolipoproteins?

A-I and AII. B-48, B-100, C, E?

Answer 12

A-I and A-II found on HDL.

B-48 controls chylomicron peripheral uptake (binds apoB receptors) and remnant uptake by liver controlled by ApoE

B-100 found on lipoproteins synthesised by liver (VLDL, becoming IDL then LDL)

C family found primarily on HDL until fat intake (then found on LDL etc) (range of enzyme regulation functions)

Question 13

What is lipoprotein (a) and what is its structure?

Answer 13

It is an LDL-like lipoprotein who’s presence in high levels is associated with increased cardiovascular disease risk as it transports cholesterol contributes to atherosclerosis.

ApoB-100 with specific Apo(a) glycoprotein bound to it by disulfide bridge. This glycoprotein has Kringles (repeat units)

Question 14

What is HTGL?

Answer 14

Hepatic triglyceride lipase present on hepatocyte membranes. Removes TAGs from TAG rich lipoproteins (VLDL/IDL) after LPL has acted on them.

Question 15

Function/mechanism of lipoprotein receptors like ApoB/E receptor (LDL receptor)?

Answer 15

To endocytose lipoproteins so that cells can degrade them to obtain nutrients (FAs and Cholesterol)

LDL receptor recognises ApoB-100 (and also ApoE on chylomicron and VLDL remnants)

Clathrin mediated endocytosis (vesicle coated in clathrin proteins that shape it for transport)

Vesicle uncoated, LDL receptors separated from Apolipoproteins and recycled to membrane. Lysosome fuses and digests lipoprotein containing vesicle.

Question 16

Role and journey of Chylomicrons?

Answer 16

Chylomicrons formed in intestinal cells (include ApoB48)

Secreted into lymph, reach blood through thoracic duct!

TAGs hydrolysed/removed by LPL on peripheral tissues (adipose/muscle)

[HDL donates APOC-2 needed for LPL activity, and takes it back when remnants formed!]

Remnants endocytosed by liver for breakdown.

Question 17

Formation and role of VLDLs?

Answer 17

Formed in liver around ApoB-100 using MTP (microsomal triglyceride transfer protein) to transfer endogenously synthesised TAGs to ApoB-100

Question 18

LDL formation and role:

Answer 18

Formed as TAGs removed from VLDLs by LPL.

ApoB-100 acquires necessary conformation to bind receptors and is cause endocytosis.

80% of this occurs back at liver, but in the ‘overflow pathway’ some of this LDL is endocytosed by peripheral tissues and can end up in artery walls.

Question 19

HDL formation and role, and uptake?

Answer 19

Pre-beta (flat) HDLs synthesised by liver.

CERP (cholesterol efflux regulator protein) exports cholesterol from peripheral cells.

LCAT (on ApoA-I on HDL) converts free cholesterol to cholesteryl esters for uptake into HDL.

now alpha-HDL₃, becomes larger alpha-HDL₂ as CETP (cholesteryl ester transfer protein) exchanges some cholesterol for TAGs from TAG-rich VLDL/chylomicrons.

HDL₂ uptaken by liver scavenger receptors (and metabolised by HTGL)

Question 20

What is familial hypercholesterolaemia, FH?

Answer 20

Various mutations, normally in the LDL receptor (ApoB/E receptor) causes high levels of LDL and total blood cholesterol. (LDL and remnants not endocytosed by liver or elsewhere)

This carries increased risk of atherosclerosis leading to cardiovascular diseases.

(As LDL uptake by liver normally suppresses cholesterol synthesis receptor mutation leads to increased cholesterol synthesis)

Question 21

What is familial combined hyperlipidaemia?

Answer 21

Most common inherited lipid disorder (around 1 in 200 prevalence)

Results from increased ApoB-100 synthesis and sometimes deficient LPL.

leading to increased production of VLDL therefore much LDL.

Question 22

What is familial dysbetalipoproteinaemia?

Answer 22

Mutation in ApoE gene leading to decreased uptake of remnants (fuel transport pathway) by LDL receptor.

Increased Cholesterol and Triglycerides in blood, increased risk of atherosclerotic disease processes.

Question 23

T2DM effects on lipid profile?

What is metabolic syndrome?

Answer 23

Increased VLDL synthesis increases remnant concentration

Decreased HDL concentration.

(often normal LDL as overflow pathway unnaffected)

Metabolic syndrome is characterised by at least 3 from: central obesity, high fasting blood glucose, hypertriglyceridemia, low HDL, and hypertension.

Question 24

Process of atherosclerosis?

Answer 24

1. Initial damage to endothelium: (cause uncertain, smoking, high blood glucose risk factors?) LDL and monocytes (by rolling attachment extravasation etc) enter vessel wall
2. Dysfunctional endothelial cells express adhesion factors in response to antigen/inflammation. Selectins for rolling, integrins (like VCAM-1) for adhesion, and Monocyte chemoattractant protein-1, MCP-1 (CCL2) to encourage extravasation.
3. M-CSF (released by endothelial cells of VSMCs) encourages monocytes to differentiate into macrophages which produce reactive oxygen species: oxidise LDL in the vessel wall!
4. Macrophage scavenger receptors uptake LDL and they become foam cells.
5. Dying foam cells release lipid pools form the centre of plaques
6. VSMC synthesise collagenous matrix –> fibrous cap.
7. Cap rupture can lead to coagulation –> thrombus