User:Glynwiki/Cholesterol Depletion



Cholesterol depletion is when cholesterol levels in the body have been artificially lowered too far. Natural low cholesterol levels and associated clinical symptoms are defined as the hypocholesterolemia. Medically induced hypocholesterolemia is increasingly associated in the elderly with long-term statin use. The inhibition of de novo cholesterol is associated with functional failure of cholesterol-rich lipid rafts in processes such as exocytosis and endocytosis.

Cholesterol-mediated membrane processes
With the emergence of the lipid raft hypothesis, the role of cholesterol in membrane function became a focus of new research into exocytosis and endocytosis. It was later clarified that the rafts were cholesterol and and sphingolipid based domains supporting a variety of trans-membrane functions. The cholesterol has been shown to condense the domain and stabilises its functional structure. The physical consequences of cholesterol enrichment on strength and thickness of lipid rafts were modelled and demonstrated by de Meyer et al.

Effect of Cholesterol Lowering on Cell Function
The mediation of lipid membrane form and function by cholesterol affect the ability of a cell to perform exocytosis and endocytosis. . The current trend in cardiovascular medicine to promote cholesterol reduction has caused a number of researchers in other fields to comment on the non-cardiovascular effect this has on lipid raft functions in cell membranes.

Here are other instances of research associating basic cholesterol-depletion research with the clinical implications:

The effect of statins on glucose levels is well documented. Working directly with squalene epoxidase inhibition allowed Xia et al to inhibit cholesterol synthesis in the membrane without the complications of CoQ10 depletion associated with the earlier statin studies of Ishikawa et al .In a retrospective analysis of the JUPITER trial Ridker discusses the effects of statin therapy on incident diabetes, having presented data showing that statins significantly promote diabetes in 6 out of the 7 trials listed.
 * A loss of insulin exocytosis capability in pancreatic b cells. A retrospective analysis of a five year trial showed a 30% increase in the incidence of Diabetes associated with a cholesterol reduction therapy . More recently Xia et al used a squalene epoxidase inhibitor demonstrated a causal link between membrane cholesterol lowering and the impairment of insulin granule release by cholesterol mediated exocytosis confirming earlier observations of a link between long term statin use and insulin supression.


 * The impairment of the exocytosis of myelin has been cited as an explanation of the reduced Myelination by oligodendrocytes and Schwann cells in neural maintenance.
 * Inconclusive results in the use of statins for the reduction of bone loss and statin-associated fractures  have implications for both the osteocyte and osteoblast action in Bone remodeling. Both cell's functions being mediated by cholesterol-rich lipid raft through exocytosis and endocytosis functions.
 * The loss of exocytotic secretions of Apolipoprotein B and its role in Immunosuppression, has been cited with regard to invasive skin infection
 * The diminished exocytosis of agrin and LRP4 secretions at the neuromuscular junction has implications for associated Neuromuscular junction disease symptoms, simmilar to Myasthenia Gravis, observed in long term statin use.
 * Neurological and synaptic secretions
 * Behaviours and Neurological Functions

Cytoskeleton
Depletion of membrane cholesterol has been shown to activate the formation of Stress fibers and the membrane cholesterol level was shown to be a critical regulator of membrane-cytoskeletal dynamics and function.

Membrane cholesterol
A key enzyme target for the control of cholesterol biosynthesis is HMG-CoA reductase which is found in membrane walls of the Endoplasmic reticulum and the mitochondrion wall. This is significant because the Cell membrane contains between 20% and 50% cholesterol molecules.

Large amounts of de-novo cholesterol are required to create the form and function of the membranes throughout the cell. SNARE (protein) processes and Vesicle-associated membrane protein (VAMP) processes, exocytosis, endocytosis and Ion channel all require cholesterol-rich lipid rafts to function.