IMED1003 - Cholesterol Absorption (1)

Lipids are structurally and functionally diverse macromolecules

COMPLEX FATTY ACIDS (COMPLEX LIPIDS)

- Storage Lipids: Triglycerides

- Membrane Lipids: Glycolipids and Phospholipids

DO NOT CONTAIN FATTY ACIDS:

- Vitamins

- Pigments

- Cholesterol

Cholesterol Structure

- sterol made by animals (including humans)

- membrane component

- production of other molecules (Vitamin D, steroid hormones, Bile Salts)

- Lipoprotein particles (mobilisation, transport of lipids in bloodstream)

DIAGRAM ON SLIDE 4

- its a molecule with a hydroxyl group (polar head) and steroid nucleus (made of 4 fused cyclohexane rings)

Major Role of Cholesterol - Membrane Component

- 85% of cholesterol in body is used as a membrane component

- interacts with fatty acids in phospholipid membrane

- decreases membrane fluidity, permeability

- component of subcellular membranes (nucleus, mitochondria, endoplasmic reticulum, golgi apparatus, lysosome, vesicles)

Myelin sheath is rich in cholesterol

- Composition: 40% in cholesterol

- Decreased membrane permeability (whcih is good because we want the impulse to jump)

- role as insulation of axons facilitates efficient signalling in neurons

- Brain: tissue containing most cholesterol

Cholesterol facilitates membrane function, including cell signalling

- molecules within membrane are organised into functional "microdomains"

- Lipid rafts: regions of increased stability due to composition of lipids (these are the microdomains)

Cholesterol:

- enhances membrane stability: increased packing and order

- binds to specific proteins: organising the membrane

- important for cell signalling

Cholesterol Homeostasis

SOURCES:

- dietary (minor)

- synthesis (major)

HYDROPHOBIC: requires lipoproteins for transport in bloodstream. excess of some plasma lipoproteins causes cardiovascular disease

EXCESS CHOLESTEROL IS EXCRETED:

- humans can not catabolise

- homeostasis requires regulation of sources, utilisation and excretion

Cholesterol ADME

DIAGRAM ON SLIDE 10

Absorption of dietary fats requires bile salts

- dietary fats are emulsified by bile acids in the small intestine

- Enterocytes: absorptive cells of small intestine

- in general cholesterol exists in the non-esterified form (unless you eat a lof of animal livers)

Enterocytes absorb dietary cholesterol

- Absorb cholesterol, secrete lipoproteins

- absorb cholesterol from micelles

- esterify cholesterol (CE)

- secrete cholesterol in lipoproteins

- Lipoproteins transported in CE in bloodstream

- excrete free cholesterol, other sterols, into gut

- enterocytes absorb them on the apical side and secrete packaged cholesterol on the basolateral side to be taken up by lympathic system

- this cholesterol ester (CE) is packaged in a chylomicron

Enterocytes - Mechanism of Absorption

NIEMANN-PICK TYPE C1-LIKE 1 receptor (NPC1L1):

- Apical side

- Binds cholesterol in intestinal lumen

Acyl-CoA cholesterol acyltransferase (ACAT):

- esterifies cholesterol to cholesteryl esters (CE)

Secretes CE in chylomicrons:

- chylomicrons comprised of lipids, proteins

- constructed in ER

- requires microsomal triglyceride transfer protein (MTP)

Enterocytes - Regulation of Absorption

NPC1L1 RECEPTOR:

- imports cholesterol via endocytosis

- activated by low cholesterol

- inactivated by high cellular cholesterol

ACAT:

- esterified cholesterol for construction of CM

- activated by high cholesterol

- promotes storage of excess cholesterol in cell (lipid droplets)