CETP Gene and Its Role in Diabetes Mellitus Type II - A Review

¹Department of Biotechnology, A.P.J. Abdul Kalam Technical University, Uttar Pradesh, India

²Department of Pathology, King George’s Medical University, Uttar Pradesh, India

*Corresponding Author:

Mohd Wamique, Ph.D Scholar
Department of Biotechnology
A.P.J. Abdul Kalam Technical University
Lucknow, Uttar Pradesh, India
E-mail: wamiquekhan007@gmail.com

Received date: January 11, 2016; Accepted date: April 09, 2016; Published date: April 28, 2016

Citation: Wamique M, Ali W (2016) CETP Gene and Its Role in Diabetes Mellitus Type II - A Review. J Community Med Health 6:425. doi:10.4172/2161-0711.1000425

Copyright: © 2016 Wamique M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Plasma lipoproteins are continuously remodelled through the actions of enzymes and lipid transfer proteins. In particular, the transfers of cholesteryl esters (CE) and triglycerides (TG) are facilitated by a specialized protein known as the cholesteryl ester transfer protein (CETP).

Genetic polymorphisms of the enzymes and proteins involved in lipid metabolism like cholesteryl ester transfer protein CETP have been shown to affect plasma lipid concentrations. CETP modifies HDL, LDL and very low density lipoprotein (VLDL) levels. It transfers cholesterol esters (CE) from CE rich particles (HDL and LDL) to triglyceride rich particles (VLDL) in exchange of triglyceride from the latter. Several genetic polymorphisms have been reported which may be associated with alteration in CETP activity. TaqI B polymorphism has been most widely studied, which results from a silent mutation in nucleotide 277, in intron 1 of the gene. The polymorphism has been associated with decreased CETP mass and an increase in HDL-cholesterol. The TaqI polymorphism B1 allele of CETP has been shown to be an independent risk factor for development of cerebral vascular disease, in patients with T2DM.

Keywords

CETP; Lipoprotein; Diabetes mellitus; Polymorphism

Abbreviations

T2DM: Type 2 Diabetes Mellitus; HDL: High Density Lipoprotein; LDL: Low Density Lipoprotein; CETP: Cholestryl Ester Transfer Protein; CE: Cholesterol Esters; VLDL: Very Low Density Lipoprotein; TG: Triglycerides

Introduction

Plasma CETP facilitates the transfer and exchange of cholesteryl ester (CE) and triglyceride (TG) between the plasma lipoproteins, and plays an important role in HDL-CE and apo A-I catabolism. In some primary and secondary hyperlipidemias (e.g., familial hypercholesterolemia, dysbetalipoproteinemia, hypertriglyceridemia, and nephrotic syndrome) and during postprandial lipemia, accelerated CETP-mediated CE transfer results in increased CE net mass transfer from HDL to VLDL or chylomicron, possibly contributing to reduced HDL-CE levels and CE enrichment of potentially atherogenicchylomicron and VLDL remnants [1]. Apolipoprotein E (Apo E) plays a central role in clearance of lipoprotein remnants by serving as a ligand for LDL and apo E receptors. HDL has a unique ability to facilitate cholesterol efflux from cells, including those within atherosclerotic lesions, and subsequently to transport excess cholesterol to the liver [2]. There are several well-known environmental factors influencing HDL-C levels. Alcohol consumption, exercise, and female sex increase HDL-C levels. On the other hand, smoking, obesity, male sex, and diets high in polyunsaturated fat decrease HDLC levels. These environmental factors often influence HDL levels through the activities of lipases or lipid transfer proteins [3,4].

In a normolipidemic population, the plasma CETP concentration differ mostly over a 3-fold range and is influenced by environmental factors. Plasma CETP has been shown to be elevated in smokers and to be decreased by heavy alcohol drinking and physical training [5-8]. CETP is known to transfer CE from HDL to very low density lipoprotein (VLDL) in exchange for triglyceride (TG). While the CE in the VLDL/LDL pool is delivered to the liver and eliminated from the body as a component of bile, the TG in low density lipoprotein (LDL) and HDL is hydrolyzed by hepatic lipase (HL) resulting in smaller, denser particles [9]. HL is involved in the metabolism of IDL (intermediate density lipoprotein) and large LDL to sdLDL particles and in the conversion of HDL2 to HDL3, in addition to its key role in reverse cholesterol transport [10].

Association between Taq1B polymorphism and HDL-C concentration was found to depend upon the environmental factors that modulate HDL-C. It was blunted by obesity and smoking [11,12] while it was found conserved and even improved in alcohol drinkers. Additionally, the association of Taq1B polymorphism with HDL-C was recently considered as independent of that with CETP concentrations. However, in none of these studies was the net mass CET measured, and only HDL-C concentration was examined as a direct consequence of the CETP-mediated reaction [13].

Polymorphism Effect of CETP Gene

Genetic polymorphisms of the enzymes and proteins involved in lipid metabolism like cholesteryl ester transfer protein CETP have been shown to affect plasma lipid concentrations [14]. Genetic polymorphisms have been shown which may be associated with alteration in CETP activity. TaqI B polymorphism has been mostly studied, which results from a silent mutation in nucleotide 277, in intron 1 of the gene. The polymorphism has been associated with decreased CETP mass and an increase in HDL-cholesterol [15-17]. A recently described relatively uncommon mutation in the CETP gene promoter causes decreased transcriptional activity and marked hyper alpha-lipoproteinemia, reflecting impaired reverse cholesterol transport [18]. Genetic deficiency of CETP results in reduced CE contents in VLDL, intermediate density lipoprotein, and LDL, producing a potentially antiatherogenic lipoprotein profiles [19,20]. This mutant allele frequency is high in Japanese subjects with HDL-C levels 60 mg/dl.

Polymorphisms in the CETP gene have been associated with CETP activity, HDL and LDL particle size and risk of CAD [21]. The I405 V missense polymorphism (rs5882) in the CETP gene has been associated with increase in HDL-C and lipoprotein subclasses [22]. The -629C/A promoter polymorphism (rs1800775), on the contrary affects 50% of CETP activity and has showed HDL-C raising effect [6]. The I405 V polymorphism has been reported to be associated with LDL size [23]. In a study by Bruce et al. [24] in a subpopulation with high plasma TG, the HDL-C levels were significantly higher in theVVgroup and sowas the CHD prevalence. The V allele has been associated with decreased CETP activity as a result of which the transfer of CE from HDL-C to LDL and VLDL in exchange for TG would be affected. This would lead to an increase in HDL-C concentration and simultaneously increase the proportion of TG in VLDL and LDL. The latter being a good substrate for HL and would result in formation of sdLDL [17,25]. The increased sdLDL concentration in our II carriers as compared to VV carriers. Two other CETP gene mutations have been characterized. One of these is a missense mutation, changing the codon of amino acid 442 from aspartate to glycine (D442G).

The locus has also been reported to modulate the risk for diabetic complications in patients with T2DM and effect seems to be different between men and women [26]. Another polymorphism D442G (Asp442-->Gly) in exon 15 of CETP is located close to the active site of the enzyme and leads to reduced plasma CETP mass and specific activity [27] The mutation is more prevalent in Japanese subjects with high HDL-levels (>100 mg/dL) [28-30].

Effects of CETP polymorphisms on lipids and lipoproteins profile and CETP activity have been reported. Ordovas et al showed that Taq1B polymorphism of CETP gene is associated with changes in lipoprotein size, CETP activity and HDL-C levels. -971 G/A polymorphism has been shown to be significantly invovled in plasma HDL-C levels and CETP concentrations [27].

Conclusion

No association of CETP TaqI B polymorphism with the disease was found but B1B2 genotype was risk factor for hypertension along with diabetes. However, B1B1 was found to be protective.

Plasma CETP mass and activity are elevated in CVD patients and with high CVD risk, resulting in decreased HDL and increased triglycerides (TG). CETP quantity and activity also reflect atherosclerosis status. Some pilot studies have revealed a positive correlation between the carotid intima media thickness (IMT) and CETP concentration. Three single nucleotide polymorphisms in the CETP gene are associated with decreased CETP activity and elevated HDL-C levels in carriers and inversely related with coronary risk, making CETP inhibitors reasonable HDL-C based therapeutic agents. CETP inhibitors comprise of a drug class which, includes: torcetrapib, dalcetrapib (JTT-705), anacetrapib, evacetrapib. They could inhibit CETP activity and thus increase the formation of high density lipoprotein levels in various degrees. There are some early clinical trials showing the inspiring results of CETP inhibitors in the treatment of patients with dyslipidemia.

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