Endocrine Topic 7 - Lipid Metabolism

Question 1

List the types of dietary lipids

Answer 1

Triglycerides
Cholesterol
Phospholipids

Question 2

Describe the structure of triglycerides

Answer 2

Glycerol bound to three fatty acids by ester bonds, fatty acids can be saturated (no double bonds), monounsaturated (one double bond) or polyunsaturated (many double bonds)

Question 3

Where does lipid digestion primarily occur?

Answer 3

In the small intestine

Question 4

Which enzymes break down triglycerides? What is their clinical significance?

Answer 4

Pancreatic lipase and colipase break down TAG into 2 fatty acids and monoglyceride - targets of orlistats

Question 5

What is the first stage in lipid metabolism?

Answer 5

Emulsification of large lipid droplets into small droplets by bile salts (emulsifiers)

Question 6

How are lipids absorbed?

Answer 6

1. Water soluble micelles of fatty acids and monoglycerides and absorbed into intestinal cells
2. TAG reformed in intestinal cell
3. TAG packaged with cholesterol, lipoproteins and other lipids to form chylomicrons
4. Chylomicrons released into lymphatic system by exocytosis

Question 7

How are fatty acids used once absorbed by adipose cells?

Answer 7

Storage as triglycerides, formation of structural phospholipids, oxidation to form ATP

Question 8

What is the function of lipoprotein lipase?

Answer 8

1. Hydrolyses triglycerides in lipoproteins (e.g. in chylomicros and VLDL) into two free fatty acids and one monoglyceride
2. Promotes cellular uptake of chylomicron remnants, cholesterol-rich lipoproteins and free fatty acids

Question 9

Where is lipoprotein lipase found?

Answer 9

On the luminal surface of endothelial cells in capillaries

Question 10

Describe the transport of lipids in chylomicrons

Answer 10

• Triglyceride component of chylomicrons is hydrolysed by lipoprotein lipase, allowing the released FFA to be absorbed by the tissues
• When a large portion of the triacylglycerol core have been hydrolysed, chylomicron remnants are formed and taken up by the liver, transferring dietary fat to the liver

Question 11

Describe the features of fat metabolism which alter plasma TAG (lipoproteins) and FFA (albumin-bound) concentration

Answer 11

• Increased by fatty acid synthesis, dietary lipids and release of TAG from adipose tissue
• Decreased by storage of TAG in adipose tissue, phospholipid synthesis, beta-oxidation and ketone body formation

Question 12

What is the first step in beta-oxidation of fatty acids?

Answer 12

Fatty acids added to acetyl coA to form fatty acyl-coA

Question 13

What is beta-oxidation?

Answer 13

Generation of energy from fatty acids

Question 14

Where does beta-oxidation of fatty acids occur?

Answer 14

• Within the mitochondrion - must cross the inner mitochondrial membrane
• Requires carrier molecule - carnitine

Question 15

From what is carnitine derived?

Answer 15

Derived from lysine and methionine

Question 16

Where is carnitine found in high concentrations?

Answer 16

High in muscle

Question 17

Describe the process of beta oxidation

Answer 17

• Fatty acyl coA degraded by oxidation at the beta-carbon
• Occurs in rounds reducing size of fatty acyl chain by 2 carbons each time
• Produces 1 FADH2, NADH and acetyl coA (2 carbons) per turn
• Ends up with final acetyl coA

Question 18

How does beta oxidation lead to ATP production?

Answer 18

• Acetyl CoA can be further oxidised to yield ATP (TCA cycle/oxidative phosphorylation)
• Fatty acids are an excellent source of ATP

Question 19

Describe triglyceride synthesis

Answer 19

• Esterification of 3 fatty acids and glycerol
• Diacylglycerol acyl transferase re-esterifies
• Glycerol obtained from glycolysis

Question 20

Describe the regulation of hormone-sensitive lipase

Answer 20

Activated by cAMP-dependent phosphorylation in response to adrenaline in fasted state, inhibited by insulin

Question 21

How are fatty acids synthesised?

Answer 21

• Fatty acids built 2 carbons at a time (limit is 16 carbons)
• Key regulatory enzymes are acetyl coA carboxylase (forms malonyl coA) and fatty acid synthase

Question 22

What is the effect of malonyl coA?

Answer 22

Inhibits fatty acid oxidation

Question 23

Describe the process of fatty acid synthesis

Answer 23

• Acetyl coA carboxylase forms malonyl coA
• Acetyl coA couples to malonyl coA
• 7 successive steps by multifunctional enzyme (fatty acid synthase) - active in tissues that make fatty acids
• Requires NADPH from the pentose phosphate pathway
• Occurs in the cytoplasm

Question 24

Why are ketone bodies formed?

Answer 24

• Beta-oxidation leads to substantial amounts of acetyl coA production
• Ketone body formation is an overflow pathway for acetyl coA use
• If oxaloacetic acid is not present, acetyl coA does not go through TCA cycle and will by converted to ketones

Question 25

Give examples of ketone bodies

Answer 25

Acetoacetate, beta-hydroxybutyrate, acetone

Question 26

Describe ketone body formation

Answer 26

Acetyl coA + acetyl coA = acetoacetyl coA Acetoacetyl coA - coA = acetoacetate Acetoacetate can be converted to acetone and beta-hydroxybutyrate

Question 27

Describe formation of phospholipids

Answer 27

Same as first steps of triglyceride synthesis to form DAG, then combined with an alcohol High levels of phospholipid synthesis in rapidly-dividing cells

Question 28

List different phospholipids

Answer 28

``` Phosphatidylethanolamine Phosphatidylglycerol Phosphatidylserine Phosphatidylinositol Phosphatidylcholine ```

Question 29

What are essential fatty acids?

Answer 29

Cannot be synthesised, obtained from diet (originally vitamin F) Polyunsaturated omega-3 or omega-6

Question 30

What is the function of essential fatty acids?

Answer 30

Cell membrane formation Required for proper growth and development Required for brain and nerve function Precursors for eicosanoids - prostanoids and leukotrienes (inflammatory response)

Question 31

How are essential fatty acids related to cardiovascular disease?

Answer 31

Omega-3: Protect vs heart and circulatory disease Reduce plasma TAG Not clear whether sources of omega3 fatty acids other than oily fish provide the same benefits Omega-6: May lower LDL High intakes may also lower HDL

Question 32

What are the key hormones which regulate lipid metabolism?

Answer 32

Key regulation by insulin and (nor)adrenaline

Question 33

What is the effect of insulin in lipid metabolism?

Answer 33

Stimulates fatty acid and TAG synthesis | Suppresses lipolysis

Question 34

What is the effect of (nor)adrenaline in lipid metabolism?

Answer 34

Stimulates lipolysis

Question 35

How does insulin influence lipid metabolism?

Answer 35

Stimulates: GLUT4-mediated transport of glucose Acetyl coA carboxylase activity Increases expression of fatty acid synthase Increases activity of lipoprotein lipase (in adipose)

Question 36

How does (nor)adrenaline influence lipid metabolism?

Answer 36

Stimulates: cAMP synthesis cAMP-dependent protein kinase (PKA) activation PKA-mediated phosphorylation and activation of hormone sensitive lipase

Question 37

How does insulin inhibit lipolysis?

Answer 37

Insulin stimulate breakdown of cAMP, therefore (nor)adrenaline is no longer able to stimulate lipolysis

Question 38

Describe the regulation of lipoprotein lipase in a fed state

Answer 38

Increased LPL synthesis and activity in adipocytes | Decreased LPL synthesis and activity in skeletal and heart muscle

Question 39

Describe the regulation of lipoprotein lipase in a fasted/exercise state

Answer 39

Decreased LPL synthesis and activity in adipocytes | Increased LPL synthesis and activity in muscle

Question 40

What are the potential effects of elevated fatty acids?

Answer 40

Lipotoxicity: Lipolysis overactive/adipose tissue storage for TAG exceeded FA taken up and stored as TG in liver, muscle Metabolites of FA impair insulin signalling Impaired insulin action in liver, muscle adipose - increased lipolysis and gluconeogenesis, decreased glucose uptake and glycogen synthesis Impaired insulin secretion by beta-cell = HYPERGLYCAEMIA