Cholesterol Depletion

Cholesterol depletion occurs when cholesterol levels in the human 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 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.
===Cholesterol depletion and leakage of the Na+ transmembrane potential===
Reduction in eukaryotic membrane cholesterol causes Na+ to leak dramatically through the membrane. The explanation and mechanism and the mechanism has been written up by Dr Thomas Haines. Haines has shown that this causes a loss of the membrane potential. Haines notes that the attempt to replenish can become runaway reaction which is ultimately lethal to the cell.
Effect on exocytosis and endocytosis
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.
A research review has highighted research associating cholesterol-depletions with significant clinical implications:
* 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 suppression. 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.
* 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, similar to myasthenia gravis, observed in long term statin use.
*Neurological and synaptic secretions
*Behaviours and neurological functions
*The failure of cholesterol supply for the exocytosis of myelin by oligodendrocytes and Schwann cells impairs neural maintenance leading to dementia through neuron loss.
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. processes and Vesicle-associated membrane protein (VAMP) processes, exocytosis, endocytosis and Ion channel all require cholesterol-rich lipid rafts to function.
Low cholesterol and neuron failure
The myelin sheathing around the neuronal network is very rich in cholesterol in healthy brains. This myelin based cholesterol protects the neuron from leakage of energy impulse and other aspects of oxidative stress. The maintenance of this myelin requires a specialised cell called an oligodendrocytes. During infancy oligodenrocytes make enough cholesterol to build the myelin structures. The continued repair and maintenance has requires LDL cholesterol, particularly apolipoprotein E (APOE) brought in via the blood supply passing through the blood brain barrier. The blood brain barrier is known to be rich in LDL receptors bringing in cholesterol to replace oxidised cholesterol which being hydrophilic leaves the myelin to be removed via high density lipoprotein (HDL) transports.
Dr Henry Lorin has noted from reviewed research the link between falling levels of LDL cholesterol (APOE),weight loss, nutrition and loss of neuron function or neurodegeneration in conditions such as Alzheimer's disease

.
Dr Duane Graveline has published research reviews establishing a link between the cholesterol lowering therapies targeting LDLs and numerous reports of adverse cognitive problems.
<ref name="ReferenceA"/>
<br clear="all"/>

Main Menu

See Also

Main Menu