Lipid metabolism and pathways

Question 1

Lipid function

Answer 1

• Essential components of cell membranes e.g. phospholipids, glycolipids, cholesterol
  
  • Energy generation and storage i.e. triglycerides
  • Inter- and Intra-cellular signalling events e.g. precursor of steroid hormones
  • Metabolism e.g. bile acids

Question 2

TG

Answer 2

Major form of metabolic energy storage in humans

Hydrophobic in nature

Question 3

Metabolic pathways

Answer 3

Series of connected enzymatic reactions that produce specific products

Metabolite = reactants, intermediates and products

Question 4

Metabolite

Answer 4

reactants, intermediates and products

Question 5

TG - digestion and absorption

Answer 5

TG emulsified by bile acids

TGs are hydrolysed by enzyme Pancreatic Triacylglycerol lipase

Question 6

Pancreatic triacylglycerol lipase

Answer 6

Hydrolyse Gs

Question 7

TG metabolism

Answer 7

Oxidation in mitochondria to release energy in ATP form

Synthesis of TG from acetyl-CoA

Question 8

Oxidation of TGs

Answer 8

Oxidation of long chain fatty acids to 2C fragments (acetyl-CoA)

Oxidation of acetyl-CoA to CO2 in citric acid cycle

Transfer electrons from reduced electron carriers to mitochondrial respiratory chain

Question 9

B-oxidation

Answer 9

Process releases free energy - successive removal of 2C fragments from fatty acids

Mitochondria and peroxisomes

Fatty acids activated by attachment to CoA (Cytosol)
Transfer Acyl-CoA across mitochondrial membrane (rate limiting)
Progressive oxidation of FA by removal of 2C units to form A-CoA

Question 10

Each cycle (shorten by 2C) produces:

Answer 10

A-CoA
FADH2
NADH

Question 11

Fatty acid synthesis

Answer 11

Occurs mostly in liver and adipocytes

Longer chain carbon molecules built from 2C

Occurs in cytosol (A-CoA in mitochondrial)

Question 12

FA biosynthesis

Answer 12

Citrate -> Acetyl CoA -> Malonyl CoA

Both A-CoA and M-CoA bind to FA synthase
Condensation reaction adds to 2C - involves M-CoA

Question 13

Rate limiting steps

B-oxidation
FA synthesis

Answer 13

B-oxidation: transfer A-CoA into mitochondria

FA synthesis: Form M-CoA from A-CoA (acetyl CoA carboxylase)

Question 14

Activation of A-CoA carboxylase

Answer 14

Insulin favours dephosphorylation of A-CoA carboxylase

Complex control of gene expression of lipogenic enzymes

Excess dietary intake of some polyunsaturated fatty acids can repress the synthesis of these enzymes in the liver

Question 15

Cholesterol

Answer 15

Amphipathic
Synthesised by A-CoA and eliminated as bile acids
Storage = cholesterol esters

Question 16

Cholesterol role

Answer 16

Important lipid membrane component

Precursor of steroid hormones

Source of bile acids

Question 17

Bile acids role

Answer 17

Lipid digestion
Lipid absorption
Cholesterol excretion

Question 18

Statins

Answer 18

Competitive inhibitor of HMG-CoA reductase

Bulky - prevent binding with substrate

Lovastatin (Mevacor), Compactin, Pravastatin (pravachol), Simvastatin (Zocor).

Synthetic Statins: Atorvastatin (Lipitor), Fluvastatin (Lescol)

Question 19

Lovastatin

Answer 19

Natural

Mevacor

Question 20

Mevacor

Answer 20

Lovastatin

Natural

Question 21

Compactin

Answer 21

Natural

Question 22

Pravastatin

Answer 22

Pravachol

Natural

Question 23

Pravachol

Answer 23

Pravastatin

Natural

Question 24

Simvastatin

Answer 24

Zocor

Natural

Question 25

Zocor

Answer 25

Simvastatin | Natural

Question 26

Atorvastatin

Answer 26

Lipitor | Synthetic

Question 27

Fluvastatin

Answer 27

Lescol | Synthetic

Question 28

Transport of lipids around body

Answer 28

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

Question 29

Transport lipids in blood

Answer 29

Short Chain FA transported bounded to blood proteins Bulk transport (neutral lipids) insoluble in water, require special carrier proteins (lipoprotein) Lipoproteins are composed of hydrophilic, hydrophobic and amphipathic molecules

Question 30

Lipid transport

Answer 30

* 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 from tissues to liver i.e. remove cholesterol from tissues

Question 31

Tangier disease

Answer 31

Cells laden with cholesterol and few HDL are formed bc of mutation in ABCA1 enzyme - allows cholesterol efflux from cells

Question 32

ABCA1 enzyme

Answer 32

Allows cholesterol efflux from cells

Question 33

Lipid uptake in cells

Answer 33

* Chylomicrons and VLDL particles  give up lipid (TG) 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 re-cycling * LDL particles contain ApoB-100, which is recognised by cell surface LDL receptors

Question 34

ApoB-100

Answer 34

Recognised by cell surface LDL receptors

Question 35

Further regulation of cholesterol uptake - control LDL receptors

Answer 35

PCSK9 binds to LDL  receptor and results in its degradation PCSK9: Less LDL receptor on cell membranes and higher plasma LDL-C

Question 36

PCSK9

Answer 36

Less LDL receptor on cell membranes and higher plasma LDL-C  proprotein convertase subtilisin/kexin type 9

Question 37

Antibodies for PCSK9

Answer 37

Evolocumab (Repatha) and alirocumab (Praluent) are monoclonal antibodies that bind to PCSK9 - produce profound reduction in circulating LDL cholesterol