What are the sources of cholesterol?
Diet and synthesised by liver from Acety CoA
How is cholesterol excreted?
How is cholesterol regulated in the body?
Negative feedback - inhibits further synthesis of itself by inhibiting HMG-CoA reductase
Insulin/glucagon control - insulin → increases synthesis; glucagon → decreases synthesis
Long term control - inhibition of HMG-CoA reductase → decrease cholesterol
also: reduced cellular uptake by inhibition of cholesterol receptor expression
What is the basic lipoprotein structure?
Non-polar lipid core - mostly TAGs and cholesterol esters
Polar (hydrophilic) outer coat
What is a chylomicron?
Takes TAGs from small intestine → tissues
What do VLDLs do?
Take TAGs from liver → tissues
What is IDL?
Remnant of VLDL and can form LDLs
What are LDLs?
Take cholesterol esters from IDL → tissues
What is HDL?
Free cholesterol scavenger in periphery → liver
How are long chain FAs transported from the intestine?
Converted to TAGs, packaged into chylomicrons → secreted into lacteals
how are short and medium chain FAs transported from the intestine?
Secreted into bloodstream as FFAs
Increase in FFAs in blood → insulin secretion → encourage uptake by liver/muscle/tissue
Decrease FFAs in blood between meals → adipocyte release of FFAs
Diagram for major groups of lipoproteins and their actions
What does the exogenous lipid transport pathway include?
Takes lipids from small intestine → tissues via chylomicrons
- Chylomicrons secreted into lymph system by intestinal mucosal cells
- Chylomicrons acquire apolipoproteins from HDL circulating in blood (apoC and apoE)
- CMs and TAGs broken down → FFAs by lipoprotein lipase (apoC) for the tissues to absorb
- Remnants taken up by liver (apoE)
What is involved in the endogenous pathway?
Takes TAGs and Cholesterol to tissues via VLDL → IDL → LDL
- VLDL synthesised in the liver (TAGs + apolipoproteins/cholesterol)
- TAGs removed by lipoprotein lipase in capillaries → IDL
- Majority IDL donates apolipoproteins to HDL → becomes LDL
- LDL taken up by peripheral tissues (provide cholesterol)
What does reverse cholesterol transport invovle?
Transports free/used cholesterol back to the liver
HDL scavengers: free cholesterol in peripheries → liver
Provides apolipoproteins to CMs, VLDL, IDL
What is the clinical definition of familial hypercholesterolaemia?
Increased total cholesterol or LDL
+ Tendon Xanthoma in patient or close relative
What is xanthelasma?
Yellow flat plaques on upper/lower eyelids - lipid-containing macrophages condensing around the socket
Usually due to high cholesterol/atheromatous disease
What is corneal arcus?
Grey opaque line surrounding margin of cornea
Common in Type II Diabetes
What is the pathophysiology of Familial Hypercholesterolaemia?
Genetic disorder - autosomal dominant, though varying effect with homo/heterozygous
Causes LDL Receptor dysfunction - prevents proper uptake of LDL by cells
What investigations can be used for diagnosis of Familial Hypercholesterolaemia?
Total cholesterol >7.5mmol/l
Plus tendon xanthoma → diagnosis
What is the treatment for Familial Hypercholesterolaemia?
Treatment of associated conditions
Statins - decrease cholesterol synthesis and increase LDL uptake; increase atherosclerotic plaque stability
Fibrates - decrease hepatic secretion + increase peripheral uptake → decrease serum triglyceride
Increase gallstone risk by increasing choleseterol content of bile