Lipid Metabolism 2

Cholesterol - structure and function

The steroid with 4 linked hydrocarbon rings

Hydrocarbon Tail and hydroxyl group at opposite ends

  • highly hydrophobic and insoluble in water

Function

  • modulates membrane fluidity

  • some nerve cells have 25% in PM

  • Precursor to steroid hormones and bile salts

  • some organs in the body need cholesterol

Cholesterol - Synthesis

Synthesized mainly in The liver from Acetyl CoA

  • Requires ATP and NADH

  • lots of Acetyl CoA needed to build a larger carbon group

1. Acetyl CoA converted to Mevalonate (cytoplasm)

  • committed step in cholesterol synthesis

  • 2 Acetyl CoA or Ketones = Acetoacetyl CoA + Acetyl CoA + (HMG-CoA synthase the enzyme)

  • Mevalonate is used to synthesize Isopentenyl pyrophosphate (in the cytoplasm)

    1. 3 ATP requiring steps and 1 Decarboxylation

    step 3. 6 molecules of isopentenyl pyrophosphate condense to form squalene (ER)

  • a-b. two additional isomeric forms of IP are in equilibrium

  • 19 steps are required to get to the final stage of cholesterol

  1. Lanosterol converted into cholesterol (ER)

    • lanosterol is converted into cholesterol in a complex process, 19 19-step pathway

SYNTHESIS AND REGULATION

MG CoA is important in making cholesterol.

ubiquitin will tire the HMG for degradation with high cholesterol

DIETARY ORIGINS

Sources

  • meats

  • diary

  • hard cheese

  • Cakes

  • food with palm oil and coconut oil

uptake

  • absorbed from the intestine by sterol transporters

  • cholesterol is esterified by Acyl-CoA: Cholesterol acyltransferase 9(ACAT2)

  • incorporated into chylomicrons - lipoprotein

  • chylomicrons

ACYL CoA attached to co-enzyme A

cholesterol esters = chylomicrons

Lipoproteins

  • soluble protein-lipid particles

  • proteins component used to target specific tissue

    Low-density lipoprotein

    helps to target specific tissues

  1. Chylomicrons

    • Dietary lipids and cholesterol

  2. low-density protein

    • supplies cholesterol to tissues

  3. High-density lipoprotein

    • removes free cholesterol tissue

    • transports cholesterol to the liver

  4. The liver eliminates cholesterol from the body

    • as bile salts or unchanged

HDL gets rid of cholesterol

Cholesterol Transport

chylomicrons produced in the GUT (small intestine)

Cholesterol UPtake

LDL = low-density lipoprotein

supplies cholesterol tissues

Receptor-mediated endocytosis

  1. LDL receptor Binding

  2. internalization

  3. LDL hydrolysis

METABOLIC FATE

Steroid hormones

vitamin D

Bile Salts (Liver - gall bladder)

gall bladder has Hydrophilic (Polar) for the water and hydrophobic (non-polar) parts to help break down fats in the digestive system

DISEASES

  • Familial Hypercholesterolemia

    • Absence of LDL receptor

    • Decrease in cholesterol

    • Cholesterol Collects in various tissues

    • LDL becomes oxidized and ingested by macrophages

    • high cholesterol in macrophages acts as a detergent and forms a Foam structure

    • Foam cells become trapped in blood vessels leading to cardiovascular disease

  • regulations - HMG-CoA reductase; expression, degradation, phosphorylation

DIGESTION OF LIPIDS

Fatty Acids are the main lipid constituent of the diet

the primary role of energy metabolism:

  • beta-oxidation

  • energy storage

a) Luminal phase

  • lipases secreted near the tongue and stomach. they act as soon as food enters the mouth to break down.

  • emulsification

  • Bile salts used to form micelles- allow lipase access

  • pancreatic lipases complete hydrolysis in the duodenum and jejunum

  • Free fatty acids and MAO absorption at duodenum and jejunum

  • tri glycerol to Diglycerol to mono glycerol

DISEASE

  • pancreatic lipase deficiency

  • Autosomal recessive

  • oily/greasy stools identified in infancy

  • difficulty gaining weight

possible use in Future medicines

  • inhibition of lipases

  • weight loss/ reduced obesity

B) Mucosal phase

  • fatty acids = Acyl CoA derivatives

  • fatty acids +CoA = ATPtoAMP +PPi = Fatty acids to triacylglycerol

  • NPC1 like intercellular cholesterol transporter 1

    • in membrane protein

    • endocytosis of cholesterol and fatty acids from the gut

C) Secretion and Transport

  • in the gut, triacylglycerols accumulate in chylomicrons (a type of lipoproteins)

  • chylomicrons exocytosed into blood via the lymphatic system

  • Blood lipases hydrolyze chylomicrons into fatty acids

  • fatty acids are taken up by tissues

Lipoprotein

% protein

% Triacylglycerol

% cholesterol/CE

Chylomicron

1-2

85-90

4-8

VLDL

5-10

50-65

15-25

IDL

10-20

20-30

40-45

LDL

20-25

7-15

45-50

HDL

40-55

3-10

15-20

Apolipoproteins

1 Act like a postcode

2 regulate lipase activity

enzymes interact with the lipoproteins

FFA gets cleaved away from the chylomicrons

certain Lipoproteins will carry some apolipoproteins.

  1. APOLIPOPROTEINS

    • Associate with lipoprotein lipases

  2. ANGIOPROTEIN-LIKE PROTEINS(similar to angiogenesis hormones)

    • angptl4, angptl3 and angptl8

    • ANGPTL4 - converts active lipoprotein lipase dimer to inactive monomer

Lipoprotein lipase control in different tissues. brown adipose tissue breaks down more fats for heat.

during exercise, the muscle tissue is fed with fat

during fasting the heart is more reliant on the fat stored.

DISEASE

Chylomicron retention disease

  • mutation in genes

  • autosomal recessive

  • chylomicrons trapped within enterocytes

  • developed during early childhood

  • weight gain and slow growth

  • frequent diarrhoea

  • Low blood cholesterol

  • may lead to an enlarged liver