Lipid disorders and metabolism Flashcards

1
Q

What are the dietary lipids

A

Triglycerides
Cholesterol
Phospholipids

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2
Q

Describe the sturcture of triglicerides

A

3 FA chains attached to a glycerol backbone by an ester bond

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3
Q

What are the sources for maintaining plasma TAG/FFA

A

> FA synthesis
Dietary lipids
TAG in adipose tissue

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4
Q

What processes do plasma TAG/FFA contribute to?

A

> Production of ketone bodies
beta-oxidation (ATP production)
Phospholipid synthesis for membranes
Stored as TAG in adipose tissue

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5
Q

Where are lipids digested?

A

Lipid digestion occurs in the small intestine

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6
Q

What enzymes are required for lipid digestion?

A

Pancreatic lipase and colipase

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7
Q

What is the clinical importance of enzymes used in lipid digestion?

A

Lipase is a target for orlistat

Orlistat acts as a lipase inhibitor, preventing fat absorption and limits calorie intake

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8
Q

What is the emulsifying agent required in lipid digestion?

A

Bile salts

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9
Q

Where are bile salts secreted?

A

Through the bile duct by the liver

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10
Q

What are bile salts synthesised from?

A

Cholesterol

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11
Q

What is the function of bile salts?

A

To emulsify fats into micelles

Increase surface area for the enzymes to work on, increasing efficiency of digestion

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12
Q

What are bile acids conjugated form?

A

Taurine/glycine

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13
Q

How are lipids absorbed?

A

As chylomicrons transported to liver, adipose tissue removed the lipid component (FA stored as TAG) leaving cholesterol-rich chylomicron remnant

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14
Q

When will there be more chylomicrons?

A

post-prandial period for absorption of dietary lipids

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15
Q

When will there be fewer chylomicrons

A

During fasting state

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16
Q

How is TAG transported?

A

In lipoproteins

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17
Q

How is FFA transported?

A

Albumin-bound

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18
Q

What is the purpose of lipoproteins?

A

To transport lipids safely

- prevents loose fatty acids acting as detergents in the circulation

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19
Q

What is NEFA?

A

Nonesterified fatty acids

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20
Q

Why are NEFA transported in chylomicrons?

A

Need to be transported in chylomicrons as they are dangerous - could break down cell walls

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21
Q

What is beta oxidation?

A

The generation of energy from fatty acids

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22
Q

Where does beta oxidation occur?

A

Within the mitochondrion

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23
Q

What is the function of CoA in fatty acyl-CoA

A

Addition of CoA to form fatty acyl-CoA
- Traps FFA within the cell (same principle as G6P)

CoA makes FFA soluble and removes the danger of detergent action

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24
Q

How does fatty acyl-CoA cross the inner mitochondrial membrane?

A

Requires carrier molecule carnitine, as mitochondrion unable to transport fatty acyl-CoA

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25
Q

Where can you find a high carnitine content?

A

In the muscle

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26
Q

How does carnitine transport fatty acyl-CoA across the inner mitochondrial membrane?

A

Carnitine palmitoyl transferase (CPT) as catalysts

Carnitine swaps with CoA to form FA carnitine + CoA via CPT 1

This is swapped back via CPT 2

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27
Q

What happens to fatty acyl-CoA in beta-oxidation?

A

Fatty acyl-CoA are degraded by oxidation at the b-carbon

Process occurs in rounds reducing chain by 2 carbons each time

2 carbons removed and used to make acetyl CoA

28
Q

What are the products of beta oxidation?

A

Each turn produces 1 FADH2, NADH and acetly CoA (2 carbons)

29
Q

How is ATP produced as a result of beta-oxidation?

A

Acetyl CoA if further oxidised to yield ATP - TCA/oxidative phosphorylation

30
Q

What is the benefit of using beta-oxidation?

A

High yield of ATP
- C16 yields 106 ATP vs 36 for glucose

Fatty acids excellent source of ATP
Fatty acids can be stored densely
ATP also available from glycerol backbone

31
Q

How are triglycerides synthesised?

A

Through the esterification of 3 fatty acids and glycerol

32
Q

What are the main enzymes involved in triglyceride synthesis?

A

> Lipoprotein lipase

> Diacylglycerol Acyl Transferase

33
Q

What is the role of Lipoprotein lipase?

A

Hydrolyses circulating TAG in chylomicrons/VLDL

Extracellular enzyme

34
Q

What is the role of Diacylglycerol Acyl Transferase?

A

Re-esterifies FFA and glycerol to TAG

Intracellular enzyme

35
Q

How is glycerol obtained?

A

From glycolysis - DHAP

Normally synthesised from glucose rather than breakdown of TAG

36
Q

What is lipolysis?

A

The breakdown of triglyceride into glycerol and 3 fatty acids

37
Q

What enzyme has an important role in lipolysis?

A

Hormone sensitive lipase in adipose tissue

38
Q

What are the regulatory measures for hormone-sensitive lipase?

A

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

Inhibited by insulin by stimulating cAMP breakdown

39
Q

Describe lipolysis

A

Adipose tissue is highly innervated with noradrenergic nerves (release NA)

In fasting -> release NA, raising intracellular cAMP and causing activation of PKA -> phosphorylates and activates HSL to stimulate lipolysis

40
Q

When does lipolysis occur?

A

In the fasted state

41
Q

What happens to the products of lipolysis?

A

FFA are delivered to the liver for gluconeogenesis?

42
Q

What tissue type like FFA as a fuel?

A

Muscle, particularly red fibres

43
Q

How are fatty acids synthesised?

A

From glucose

Built 2C at a time (max 16C)

44
Q

What are the regulatory enzymes in fatty acid synthesis?

A

Acetyl CoA carboxylase (ACC)

Fatty acid synthase

45
Q

What is the role of Acetyl CoA carboxylase (ACC)?

A

Forms malonyl CoA (3C structure)

Malonyl CoA also inhibits FA oxidation -> prevents FA oxidation while FA are being synthesised, as this would waste energy

Reciprocal regulation

46
Q

How is Malonyl CoA formed?

A

By Acetyl CoA carboxylase (ACC)

Uses biotin (vitamin b7)
deficiences are rare, but will cause disregulation of lipid metabolism
47
Q

How does Malonyl CoA inhibit FA oxidation?

A

> Acetyl CoA is coupled to malonyl CoA
- uses energy that would otherwise produce ATP

> 7 consecutive steps by multifunctional enzyme
- Fatty acid synthase

> Requires NADPH (pentose phosphate pathway)

> Occurs in cytoplasm

48
Q

Why are ketones produced?

A

Ketone formation is an “overflow” pathway for acetyl CoA use if there is not enough oxaloacetate for acetyl CoA to enter krebs

49
Q

What dietary condition leads to ketone formation?

A

Diets with very low carbohydrate content

50
Q

What are ketone bodies?

A

3 water soluble molecules produced by the liver from fatty acids

> Acteoacetate
beta hydroxybutyrate
Acetone

51
Q

How are ketone bodies formed?

A

Acetyl CoA + Acetyl CoA => acetoacetyl CoA

acetoacetyl CoA - CoA => Acetoacetate

Acetoacetate can be converted to acetone and beta hydroxybutrate

52
Q

What tissues use ketone bodies as an energy source?

A

The brain

The heart

53
Q

How are phospholipids synthesised?

A

Same as beginning steps of triglyceride synthesis to form DAG, which is then combined with an alcohol

From this you get different phospholipids

54
Q

What are the different phospholipids formed?

A
Phosphatidylethanolamine
Phosphatidylserine
Phosphatidylglycerol
Phosphatidylinositol
Phosphatidylcholine
55
Q

Which cells have high levels of phospholipid synthesis?

A

Rapidly-dividing cells as they have to make lots of membranes

NB - potential target for new cancer drugs?

56
Q

What are essential fatty acids?

A

Fatty acids that cannot be synthesised
Obtained from the diet (originally classed as vitamin F)

Polyunsaturated w-3 or w-4
(depends on location of double c-c bond on fatty acyl chain)

57
Q

What are the functions of essential fatty acids?

A

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

58
Q

What is the link between w-3 fatty acids and CVD?

A

some evidence for protection against hear and circulatory disease

reduces plasma TAG

59
Q

What is the link between w-6 fatty acids and CVD?

A

May lower low-density lipoprotein (LDL)

Some evidence that high levels may lower HDL (detrimental effect)

60
Q

What are the hormones regulate lipid metabolism?

A

Insulin and noradrenaline

61
Q

How does insulin regulate lipid metabolism?

A

Stimulates FA synthesis, TAG synthesis
Suppresses lipolysis

Insulin stimulates:
> GLUT4-mediated transport of glucose
> Acetyl CoA carboxylase activity
> Increases expression of FAS
> Increases activity of LPL (in adipose only)

Inhibition of lipolysis by:
stimulates breakdown of cAMP

62
Q

How does noradrenaline regulate lipid metabolism?

A

Stimulates lipolysis

Noradrenaline stimulates:
> cAMP synthesis
> cAMP-dependent protein kinase (PKA) activation
> PKA-mediated phosphorylation and activation of HSL

63
Q

What are the levels of LPL in different tissues in the fed state?

A

increased LPL synthesis and activity in adipocytes

decreased LPL synthesis and activity in skeletal and heart muscle

64
Q

What are the levels of LPL in different tissues in the fasted/exercised state?

A

decreased LPL synthesis and activity in the adipocytes

increased LPL synthesis and activity in the muscle

65
Q

What are potential affects of elevated FA with obesity?

A

Lipolysis is overactive and adipose storage capacity for TAG is exceeded

FA are taken up and stored in liver and possibly muscle

66
Q

How can elevated FA levels lead to the development of T2DM?

A

Metabolites of FA impair insulin signalling, driving the extreme insulin resistance that causes diabetes
- primarily cause by impact in the liver

Causes impaired insulin action in liver, adipose and muscle

  • increased lipolysis, gluconeogenesis
  • decreased glucose uptake, glycogen synthesis

Excess FA may also directly impair insulin secretion by the beta cell

Hyperglycaemia results