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 edit
With the emergence of the lipid raft hypothesis, the role of cholesterol[1] 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 [2]. The cholesterol has been shown to condense the domain and stabilises its functional structure [3]. The physical consequences of cholesterol enrichment on strength and thickness of lipid rafts were modelled and demonstrated by de Meyer et al [4].
Effect of Cholesterol Lowering on Cell Function edit
The mediation of lipid membrane form and function by cholesterol affect the ability of a cell to perform exocytosis and endocytosis. [5]. 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:
- 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 [6]. 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[7] confirming earlier observations of a link between long term statin use and insulin supression.
The effect of statins on glucose levels is well documented[8][9]. 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[10].In a retrospective analysis of the JUPITER trial Ridker[11] 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.
- 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. [12]
- Inconclusive results in the use of statins for the reduction of bone loss [13] and statin-associated fractures [14] 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[15][16]
- 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. [17][18]
- Neurological and synaptic secretions [19]
- Behaviours and Neurological Functions [20][21]
Cytoskeleton edit
Depletion of membrane cholesterol has been shown [22] 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 edit
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.[23]
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.
[24]
[25]
References edit
- ^ Simons K, Ikonen E. Functional rafts in cell membranes. Nature 1997; 387: 569-72
- ^ Pike LJ. Rafts defined: a report on the Keystone Symposium on Lipid Rafts and Cell Function. J Lipid Res 2006; 47: 1597-8
- ^ Barenholz Y. Cholesterol and other membrane active sterols: from membrane evolution to "rafts". Prog Lipid Res 2002; 41: 1-5.
- ^ de Meyer F, Smit B. Effect of cholesterol on the structure of a phospholipid bilayer. Proc Natl Acad Sci U S A 2009; 106: 3654-8
- ^ Wainwright G., Mascitelli L.,MD, Goldstein M. R.,MD (2009). "Cholesterol-Lowering Therapies and Cell Membranes". Arch Med Sci. 5.
{{cite journal}}: CS1 maint: multiple names: authors list (link)(in press). - ^ Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001; 103: 357-
- ^ Fuzhen Xia, Li Xie, Anton Mihic, Xiaodong Gao, Yi Chen, Herbert Y. Gaisano and Robert G. Tsushima (2008). "Inhibition of Cholesterol Biosynthesis Impairs Insulin Secretion and Voltage-Gated Calcium Channel Function in Pancreatic β-Cells". Endocrinology. 149 (10): 5136–5145. doi:10.1210/en.2008-0161. PMID 18599549.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Sukhija R, Prayaga S, Marashdeh M, et al. Effect of statins on fasting plasma glucose in diabetic and nondiabetic patients J Investig Med 2009; 57: 495-9.
- ^ Szendroedi J, Anderwald C, Krssak M, et al. Effects of high-dose simvastatin therapy on glucose metabolism and ectopic lipid deposition in nonobese type 2 diabetic patients. Diabetes Care 2009; 32: 209-14.
- ^ Ishikawa M, Okajima F, Inoue N, et al. Distinct effects of pravastatin, atorvastatin, and simvastatin on insulin secretion from a beta-cell line, MIN6 cells. J Atheroscler Thromb 2006;13: 329-335.
- ^ P M Ridker (May 2009). "The JUPITER Trial, Results, Controversies, and Implications for Prevention". Circ Cardiovasc Qual Outcomes. 2 (3): 279–285. doi:10.1161/CIRCOUTCOMES.109.868299. PMID 20031849.
{{cite journal}}: CS1 maint: date and year (link) - ^ Steve Klopfleisch, Doron Merkler, Matthias Schmitz, Sabine Klo¨ppner, Mariann Schedensack, Gunnar Jeserich, Hans H. Althaus, and Wolfgang Bru¨ck (December 2008). "Negative Impact of Statins on Oligodendrocytes and Myelin Formation In Vitro and In Vivo". The Journal of Neuroscience. 28 (50): 13609–13614. doi:10.1523/JNEUROSCI.2765-08.2008. PMC 6671750. PMID 19074034.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ Demer LL. Boning up (or down) on statins. Arterioscler Thromb Vasc Biol 2001; 21: 1565-6
- ^ Filiz Sivas · Ebru Alemdaroflu · Eda Elverici ·Tuba Kuluf · Küroat Özoran (November 2008). "Serum lipid profile: its relationship with osteoporotic vertebrae fractures and bone mineral density in Turkish postmenopausal women". Rheumatology International. 29 (8): 885–890. doi:10.1007/s00296-008-0784-4. PMID 19043717.
{{cite journal}}: CS1 maint: date and year (link) - ^ Mark R. Goldstein, MD, Luca Mascitelli, MD Francesca Pezzetta, MD (May 2009). "Methicillin-resistant Staphylococcus aureus: A link to statin therapy?". Cleveland Clinic Journal of Medicine. 75 (5): 328.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ M. Michal Peterson, Jessica L. Mack, Pamela R. Hall, Anny A. Alsup, Susan M. Alexander, Erin K. Sully, Youhanna S. Sawires, Ambrose L. Cheung, Michael Otto, and Hattie D. Gresham (December 2008). "Apolipoprotein B Is an Innate Barrier against Invasive Staphylococcus aureus Infection". Cell Host & Microbe. 4 (5): 555–566. doi:10.1016/j.chom.2008.10.001. PMC 2639768. PMID 19064256.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism Am J Cardiovasc Drugs 2008; 8: 373-418
- ^ Elizabeth M. Adler (October 2008). "Neuromuscular Junction A Complex Role for Lrp4". Science Signaling. 1 (42): 364. doi:10.1126/scisignal.142ec364.
{{cite journal}}: CS1 maint: date and year (link) - ^ Pfrieger FW. Role of cholesterol in synapse formation and function Biochim Biophys Acta 2003; 1610: 271-80.
- ^ Edgar PF, Hooper AJ, Poa NR, Burnett JR. Violent behavior associated with hypocholesterolemia due to a novel APOB gene mutation. Mol Psychiatry 2007; 12: 258-63
- ^ Lalovic A, Levy E, Luheshi G, et al. Cholesterol content in brains of suicide completers. Int J Neuropsychopharmacol 2007; 10: 159-66.
- ^ Maosong Qi; et al. (2009). "Cholesterol-Regulated Stress Fiber Formation". J Cell Biochem. 106 (6): 1031–1040. doi:10.1002/jcb.22081. PMID 19229870.
{{cite journal}}: Explicit use of et al. in:|author=(help) - ^ Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. . Garland Science, 2002.
- ^ Lang T, Bruns D, Wenzel D, Riedel D, Holroyd P, Thiele C & Jahn R. (2001). "Snares are concentrated in cholesterol-dependent clusters that define docking and fusion sites for exocytosis". EMBO J. 20 (9): 2202–2213. doi:10.1093/emboj/20.9.2202. PMC 125434. PMID 11331586.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Lang, Thorsten (2007). " SNARE proteins and 'membrane rafts' ". J Physiol. 585 (Pt 3): 693–698. doi:10.1113/jphysiol.2007.134346. PMC 2375502. PMID 17478530.