The Role of CETP in Health - Essay Example

Cholesterylester transfer protein (CETP) Introduction Cholesterylester transfer protein (CETP) is considered a hydrophobic glycoprotein which is released primarily from the liver and is secreted into the plasma targeting high-density lipoprotein (HDL) (Tall, 1993). It supports the transport of cholesteryl esters, triglycerides, and phospholipids within the plasma lipoproteins (Barter, et.al., 1982). Through the CETP, lipids are transferred from one lipoprotein to another. The CETP in the plasma mostly emanate from the HDL based on the reaction affected by LCAT with most of the triglycerides reaching the plasma to support chylomicrons and VDLs (Barter, et.al., 2003). The general impact of the CETP is for the massive movement of cholesteryl esters from the HDLs to the TRLs and the LDLs and for the triglycerides from TRLs to the LDLs and HDLs. In effect, CETP-supported movements from HDL to VLDL and LDL help provide an indirect link where the HDL cholesteryl esters can be brought to the liver (Barter, et.al., 2003). Role in health and dietary choices High-density lipoprotein can help prevent the occurrence of atherosclerosis and other cardiovascular diseases. Since these diseases present with low HDL, the medical inhibition of CETP is being considered as a means of increasing HDL levels (Brousseau, et.al., 2004). A 2004 study indicated how a small molecular agent torcetrapib decreased HDL levels on its own and with a statin; it also decreased LDL when it was used with a statin (Brousseau, et.al., 2004). However, studies on cardiovascular endpoints in relation to the use of torcetrapib did not however show encouraging results (Brousseau, et.al., 2004). While lipid levels were indeed changed, an increase in blood pressure was still seen and there was no impact on the atherosclerosis (Nissen, et.al., 2007). In yet another study, its use alongside atorvastatin led to higher rates of mortality among patients (US Food and Drug Administration, 2006). A study by Zhong, et.al., (1996) discusses how rare mutations causing more reactions from the CETP have been associated to increased atherosclerosis. On the other hand, polymorphism of the CETP gene causing lower plasma levels have also been associated to longevity including a metabolic reaction to nutritional interventions (Darabi, et.al., 2009). Such mutation however has been known to increase the occurrence of coronary heart disease among patients with elevated levels of triglycerides (Bruce, et.al., 1998). Mutations in the D442G which depresses CETP levels and increases HDL levels also increases the risk for coronary heart disease (Zhong, et.al., 1996). CETP is an important part of the reverse cholesterol transport, or the clearing of cholesterol form the tissues (MacLean, et.al., 2013). The atherogenic role of CETP has been debated these many years due to the fact that the higher and lower CETP expression has been associated with the increased risk of vascular diseases. In effect, the atherogenic quality of the CETP depends much on the metabolic context where it affects the metabolism of lipoprotein. Obesity is considered a metabolic issue which is affecting the population significantly (MacLean, et.al., 2013). This condition manifests with a mild increase in vascular disease affectations, including increased plasma CETP activities. It is not clear whether such increase in CETP activity impacts on the changing lipoprotein profiles including the elevated vascular disease risks or if it is a normal effect of higher cholesterol levels seen in these patients (MacLean, et.al., 2013). Obese patients having type 2 diabetes actually have an increased risk for vascular diseases and its complications, including higher levels of cholesterol in their plasma; they also have lower levels of CETP in their plasma (MacLean, et.al., 2013). Researchers hypothesize that lower plasma CETP levels among obese patients having diabetes affects their ability to reduce their elevated levels of cholesterol (MacLean, et.al., 2013). As a result, atherosclerosis remains an ominous threat for these patients. CETP is also known for transporting cholesterol from peripheral tissues into the liver to be properly metabolized and excreted into the bile through the process of reverse cholesterol transport. In effect, CETP supports proatherogenic and antiatherogenic functions based on metabolic settings (Tall, 1998). Some studies have also established a link between polymorphisms in the human CETP gene as well as the plasma CETP and the HDL levels (Corbex, et.al., 2000). There are different diet modifications which have been introduced in order to manage high cholesterol levels in humans. Diets rich in fatty fish, wholegrain, and bilberries have been investigated by Lankinen, et.al., (2014). Major changes in lipid metabolites were seen in the Healthy Diet group; this reflects higher levels of polyunsaturated fatty acids with matching increase in n-3 PUFAs. Moreover, for the group comparisons, it was established that a rising trend for variables relating to large HDL particles for the HealthyDiet group and in assessing this further, it was established that the increase in fish in the diet was related significantly to higher levels of HDL (Lankinen, et.al. 2014). There are however ethical considerations on the use of human subjects for related studies on CETP. There are major risks to human subjects on the manipulation of CETP levels, especially for those who are obese or those who have cardiovascular diseases. Studies discussed above have recognized that patients may experience higher blood pressure levels especially when they also have atherosclerosis and other related diseases. As research subjects, elevated levels of CETP may decrease their HDL levels, but it may not decrease their blood pressure; risks of death have also been observed for some patients under these observations. Ethical requisites of research cannot therefore guarantee the safety of the patients. Still, any studies carried out without actual human subjects would not yield results which are as reliable or as valid as studies with human research subjects. Methodology Primers from literature can be designed based on amplification by PCR. This process would include a review of related literature and using available studies as secondary sources of literature. DNA extraction can be secured through the application of current available methods for extraction. Data review and assessment shall follow such extraction. An amplification of the genomic sequencing of the gene through PCR would also be undertaken in order to support the results which have to be secured for the study and from the research subjects. PCR products from the gel shall then be cleaned up where necessary. The products shall then be sent for sequencing. The sequencing process would be necessary in order to provide reliable results for this study. The assessment of results from the database shall be used to identify the genotype status for the sample. References Barter, P. and Rye, K., 1996. High density lipoproteins and coronary heart disease. Atherosclerosis, 121: 1–12. Barter, P. J., Brewer, H. B., Chapman, M. J., Hennekens, C. H., Rader, D. J. and Tall, A. R., 2003. Cholesteryl ester transfer protein a novel target for raising HDL and inhibiting atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology, 23(2), 160-167. Brousseau, M., O’Connor, J., Ordovas, J., Collins, D., Otvos, J., 2002. Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial. Arterioscler Thromb Vasc Biol, 22: 1148–1154. Corbex, M., Poirier, O., Fumeron, F., Betoulle, D., Evans, A., Ruidavets, J., and Arveiler, D. 2000. Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene-environment interaction. Genet Epidemiol, 19: 64–80. Darabi, M., Abolfathi, A., Noori, M., Kazemi, A., Ostadrahimi, A., and Rahimipour, A., 2009. Cholesteryl ester transfer protein I405V polymorphism influences apolipoprotein A-I response to a change in dietary fatty acid composition. Horm Metab Res 41 (7): 554–8. Lankinen, M., Kolehmainen, M., Jääskeläinen, T., Paananen, J., Joukamo, L., Kangas, A. J., and Schwab, U., 2014. Effects of Whole Grain, Fish and Bilberries on Serum Metabolic Profile and Lipid Transfer Protein Activities: A Randomized Trial (Sysdimet). PloS one, 9(2), e90352. MacLean, P. S., Bower, J. F., Vadlamudi, S., Osborne, J. N., Bradfield, J. F., Burden, H. W., and Barakat, H. A., 2003. Cholesteryl ester transfer protein expression prevents diet-induced atherosclerotic lesions in male db/db mice. Arteriosclerosis, thrombosis, and vascular biology, 23(8), 1412-1415. Nissen, S., Tardif, J., Nicholls, S., Revkin, J., Shear, C., Duggan, W., Ruzyllo, W., Bachinsky, W., and Lasala, G., 2007. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 356 (13): 1304–16. Tall, A., 1993. Plasma cholesteryl ester transfer protein. J Lipid Res, 34: 1255–74. Tall, A., 1998. An overview of reverse cholesterol transport. Eur Heart J, 19(suppl A):A31–5. US Food and Drug Administration, 2006. Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety [online]. Available at: http://www.fda.gov/bbs/topics/news/2006/new01514.html [Accessed 5 September 2014]. Zhong, S., Sharp, D., Grove, J., Bruce, C., Yano, K., Curb, J., and Tall, A., 1996. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest, 97: 2917–2923. Read More