| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Cholesterol-sphingomyelin interaction in membrane and apolipoprotein-mediated cellular cholesterol efflux Ito, J., Y. Nagayasu, et al. (2000), J Lipid Res 41(6): 894-904. Abstract: Helical apolipoproteins interact with cellular surface and generate high density lipoprotein (HDL) by removing phospholipid and cholesterol from cells. We have reported that the HDL is generated by this reaction with the fetal rat astrocytes and meningeal fibroblasts but cholesterol is poorly available to this reaction with the astrocytes (Ito et al. 1999. J. Neurochem. 72: 2362;-2369). Partial digestion of the membrane by extracellular sphingomyelinase increased the incorporation of cholesterol into thus-generated HDL from both types of cell. This increase was diminished by supplement of endogenous or exogenous sphingomyelin to the cells. The sphingomyelinase treatment decreased cholesterol in the membrane mainly in the detergent-resisting domain. The intracellular cholesterol used by acylCoA:cholesterol acyltransferase increased by the sphingomyelinase treatment in the absence of apoA-I, more remarkably in the fibroblast than in the astrocytes. ApoA-I suppressed this increase completely in the astrocytes, but only partially in the fibroblast. The effect of the sphingomyelin digestion was more prominent for the apolipoprotein-mediated reaction than the diffusion-mediated cellular cholesterol efflux. Thus, cholesterol molecules restricted by sphingomyelin in the domain of the plasma membrane appear to be primarily used for the HDL assembly upon the apolipoprotein;-cell interaction. |
| Cholesterol-sphingomyelin interactions in cells--effects on lipid metabolism Slotte, J. P. (1997), Subcell Biochem 28: 277-93. |
| Cholesterol-transfer protein located in the intestinal brush-border membrane. Partial purification and characterization Thurnhofer, H., J. Schnabel, et al. (1991), Biochim Biophys Acta 1064(2): 275-86. Abstract: Cholesterol absorption by small intestinal brush border membrane vesicles from taurocholate mixed micelles is a second-order reaction. From a comparison of reaction rates and order before and after proteinase K treatment of brush-border membrane vesicles, it is concluded that cholesterol absorption is protein-mediated. It is shown that the desorption of cholesterol from taurocholate mixed micelles is by a factor of about 10(4) faster than that from egg phosphatidylcholine bilayers. When brush border membrane vesicles are stored at room temperature, intrinsic proteinases are activated and proteins are liberated from the brush border membrane. These proteins collected in the supernatant catalyze cholesterol and phosphatidylcholine exchange between two populations of small unilamellar phospholipid vesicles. One of the active proteins present in the supernatant is purified by a two-step procedure involving gel filtration on Sephadex G-75 SF and affinity chromatography on a Nucleosil-phosphatidylcholine column. The protein thus obtained is pure by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. It has an apparent molecular weight of slightly less than 14,000 as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis and a value of 11,500 determined by gel filtration on Sephadex G-75 SF. |
| Cholesteryl ester enrichment of plasma low-density lipoproteins in hamsters fed cereal-based diets containing cholesterol Carr, T. P., G. Cai, et al. (2000), Proc Soc Exp Biol Med 223(1): 96-101. Abstract: Male Syrian hamsters were fed 0.02, 0.03, or 0.05% cholesterol to test the hypothesis that moderate cholesterol intake increases the cholesteryl ester content of the plasma low-density lipoproteins (LDL). Dietary cholesterol levels of 0.02%-0.05% were chosen to reflect typical human intakes of cholesterol. Hamsters were fed ad libitum a cereal-based diet (modified NIH-07 open formula) for 15 weeks. Increasing dietary cholesterol from 0.02% to 0.05% resulted in significantly increased plasma LDL and high-density lipoprotein cholesterol concentration, increased liver cholesterol concentration, and increased total aorta cholesterol content. The cholesteryl ester content of plasma LDL was determined as the molar ratio of cholesteryl ester to apolipoprotein B and to surface lipid (i.e., phospholipid + free cholesterol). Increasing dietary cholesterol from 0.02% to 0.05% resulted in significantly increased cholesteryl ester content of LDL particles. Furthermore, cholesteryl ester content of LDL was directly associated with increased total aorta cholesterol, whereas a linear relationship between plasma LDL cholesterol concentration and aorta cholesterol was not observed. Thus, the data suggest that LDL cholesteryl ester content may be an important atherogenic feature of plasma LDL. |
| Cholesteryl ester transfer activity in hamster plasma: increase by fat and cholesterol rich diets Stein, Y., Y. Dabach, et al. (1990), Biochim Biophys Acta 1042(1): 138-41. Abstract: We investigated the presence of cholesteryl ester transfer activity (CETA) in plasma of hamsters kept on various dietary regimens. In hamsters kept on a regular diet, CETA activity was about 5 units/4 mg protein of d greater than 1.21 g/ml fraction of plasma, as compared to about 35 units present in human d greater than 1.21 g/ml fraction. Addition of 15% margarine or butter alone or together with 2% cholesterol resulted in a 2-3-fold increase in plasma CETA. The increase in plasma CETA was correlated with plasma cholesterol levels (r = 0.78; P less than 0.001) and plasma triacylglycerol levels (r = 0.56, P less than 0.001). Hamsters consuming the cholesterol + butter-supplemented diets had the highest plasma CETA, cholesterol and triacylglycerol levels, while CETA in plasma of rats and mice remained nondetectable even after 4 weeks on the diet. The causal relation between hypercholesterolemia, hypertriglyceridemia and evaluation in CETA in hamsters remains to be elucidated. |
| Cholesteryl ester transfer and cholesterol esterification in type 1 diabetes: relationships with plasma glucose Chang, C. K., T. K. Tso, et al. (2001), Acta Diabetol 38(1): 37-42. Abstract: The activities of two crucial enzymes of reverse cholesterol transport, cholesterol ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), and their relationships with lipid profile and fasting plasma glucose were examined in 35 type 1 diabetic children. The CETP and LCAT activities were significantly lower (p<0.05) in the 4 subjects with normal fasting plasma glucose levels (<6.39 mmol/l) than in the 28 with high plasma glucose levels (CEPT activity, 10.63+/-3.81 vs. 32.18+/-13.94 nmol/ml h; LCAT activity, 25.52+/-4.53 vs. 39.52+/-12.52 nmol/ml h; both p<0.05). The subjects with high plasma glucose levels also had higher total and LDL-cholesterol than those with normal glucose levels. CETP activity was positively correlated with fasting plasma glucose, CETP concentration, LCAT activity, total cholesterol, free cholesterol, LDL-C, and LDL-cholesteryl ester, while negatively correlated with cholesteryl ester to free cholesterol ratio, LDL triglyceride to protein ratio, and LDL triglyceride to cholesteryl ester ratio. LCAT activity was found to positively correlate with CETP activity, total cholesterol, free cholesterol, LDL-C, CETP concentration, and LDL-cholesteryl ester, while it negatively correlated with cholesteryl ester to free cholesterol ratio. The results observed in type 1 diabetic subjects suggest that (1) accelerated LCAT and CETP activities may result in the accumulation of LDL-cholesteryl ester; and (2) fasting plasma glucose may be a major determinant of CETP activity. |
| Cholesteryl ester transfer protein (CETP) deficiency and increased HDL cholesterol levels (hyperalphalipoproteinemia) Inazu, A., J. Koizumi, et al. (1996), Rinsho Byori 44(4): 322-6. Abstract: Four different CETP gene mutations have been identified as causes of increased levels of HDL cholesterol by us and other investigators; two splice donor site mutations involving intron 14, one missense mutation of D442G in exon 15, and one nonsense mutation of Q309X in exon 10. Two splice donor site mutations are G(+1)-to-A transition (Int14A) and T insertion at +3 position (Int14T), and both mutations result in null phenotype as well as a nonsense mutation. By contrast, the D442G mutation is partially defective in plasma CETP activity. Both Int14A and D442G are common mutations in the general Japanese population with high frequencies of the heterozygotes of 1% and 7%, respectively. Heterozygous CETP deficiency is sufficiently common to explain 5% of the variation in HDL-C level in the general Japanese population, in addition to well-known environmental factors. CETP common mutations may be useful for risk-assessment of coronary heart disease, as a negative and genetic risk factor. |
| Cholesteryl ester transfer protein (CETP) mRNA abundance in human adipose tissue: relationship to cell size and membrane cholesterol content Radeau, T., P. Lau, et al. (1995), J Lipid Res 36(12): 2552-61. Abstract: Cholesteryl ester transfer protein (CETP) has a well-defined role in plasma neutral lipid transport. CETP synthesized by human adipose tissue may contribute to the plasma CETP pool. CETP mRNA abundance increases in subcutaneous adipose tissue in response to cholesterol feeding and we have hypothesized that CETP gene expression is regulated by a specific pool of cellular sterol. In the present study, we have quantified CETP mRNA levels in subcutaneous adipose tissue of 10 female subjects using a solution hybridization RNase protection assay. Particulate (membrane cholesterol) and lipid droplet cholesterol (core cholesterol) were determined by gas chromatography. CETP mRNA abundance in these adipose tissue specimens correlated significantly with membrane cholesterol expressed as a fraction of membrane protein (r = 0.67, P = 0.031). There was also a linear relationship between CETP mRNA abundance and membrane cholesterol to core triglyceride ratio (r = 0.77, P = 0.009) and a strong correlation between the percentage of cellular cholesterol in the membrane fraction (ratio of membrane to core cholesterol) and CETP mRNA abundance (r = 0.91, P = 0.0002). In contrast, there was a negative relationship between each of lipid droplet cholesterol and triglyceride and CETP mRNA levels. Human adipose tissue maintained in organ culture for several days was shown to secrete CETP into the culture medium. Incubation with cholesterol-rich chylomicron remnants elicited a dose-dependent increase in both membrane and core cholesterol and a concomitant increase in the level of CETP mRNA. These studies demonstrate that adipose tissue CETP mRNA abundance is a function of membrane cholesterol concentration rather than lipid droplet cholesterol and that CETP mRNA increases with adipocyte cholesterol enrichment via chylomicron remnants. CETP gene expression is highest in small lipid-poor adipocytes, suggesting that CETP synthesized and secreted by adipocytes may have a role in promoting cellular cholesterol accumulation. |
| Cholesteryl ester transfer protein activity and atherogenic parameters in rabbits supplemented with cholesterol and garlic powder Kwon, M. J., Y. S. Song, et al. (2003), Life Sci 72(26): 2953-64. Abstract: The current study was conducted to examine the effect of garlic supplementation on CETP activity, along with its anti-atherosclerotic effect in cholesterol-fed rabbits. Rabbits were fed a 1% cholesterol diet for 12 weeks, including a 1% garlic powder supplement. The garlic-supplemented group exhibited significantly lower CETP activity than the control group during the experimental period (P < 0.05). Among the atherogenic parameters, the total cholesterol, TG, LDL-C, VLDL-C, and atherogenic index were all significantly lower in the garlic group than in the control group during the experimental period (P < 0.05), whereas the HDL-C concentration was significantly higher in the garlic group than in the control group after 12 weeks (P < 0.05). Atherosclerotic lesion area in the aorta arch was also significantly lower in the garlic group (P < 0.05). In the morphological examination, the garlic-supplemented group exhibited far fewer fat droplet deposits than the control group. Furthermore, the garlic supplement also lowered the aortic and hepatic cholesterol, and triglyceride. Accordingly, the current results suggest that garlic exerts hypocholesterolemic and/or antiatherogenic and that plasma CETP activity might be a risk marker related with atherogenesis. As such, the inhibition of CETP activity may delay the progression of atherosclerosis, thereby supporting the atherogenicity of CETP and the inhibitory activity of garlic supplementation against CETP. |
| Cholesteryl ester transfer protein and high density lipoprotein responses to cholesterol feeding in men: relationship to apolipoprotein E genotype Martin, L. J., P. W. Connelly, et al. (1993), J Lipid Res 34(3): 437-46. Abstract: The apolipoprotein (apo) E isoform is an important determinant of the plasma lipoprotein distribution of apoE and of the metabolism of apoE-containing lipoproteins. We have determined the effects of apoE genotype on the plasma lipoprotein response to cholesterol feeding in 30 young normal male subjects (5 E3/2, 11 E3/3, 14 E4/3) under rigorously controlled dietary conditions. Two diets, differing only in cholesterol content (low cholesterol (LC): 80 mg cholesterol/1000 kcal and high cholesterol (HC): 320 mg cholesterol/1000 kcal), were compared using a random crossover design. At the end of the HC as compared to the LC period, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and HDL2-C increased by an average of 15%, 21%, 7%, and 23%, respectively, for the three genotype groups combined (P < 0.001 for each). The LDL-C response to dietary cholesterol did not differ among the apoE genotypes. However, the increase in HDL-C varied significantly according to the apoE genotype (E3/2: 0 change, E3/3: +4%, E4/3: +12%; P < 0.05). The plasma cholesteryl ester transfer protein (CETP) response to cholesterol feeding also differed amongst the three apoE genotype groups (E3/2: +37%, E3/3: +18%, E4/3: +9%) (P < 0.05). ApoE genotype has significant and opposite effects on plasma CETP and HDL-C responses to dietary cholesterol in men. |
| Cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase activities in hispanic and anglo postmenopausal women: associations with total and regional body fat Greaves, K. A., S. B. Going, et al. (2003), Metabolism 52(3): 282-9. Abstract: Reverse cholesterol transport is one process by which high-density lipoprotein (HDL) cholesterol has been hypothesized to play a role in reducing the risk of coronary heart disease. This study was designed to examine cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT) activities, 2 modulators of reverse cholesterol transport, in Hispanic and Anglo postmenopausal women. The associations between plasma CETP and LCAT activities and body composition were also examined. Of the 199 subjects, 33% were of Hispanic origin and 47% were undergoing hormone replacement therapy (HRT). Body composition was measured by dual-energy x-ray absorptiometry (DXA) and anthropometry. Plasma CETP activity was higher in Hispanic compared to Anglo women, although the difference was eliminated when data were adjusted for abdominal fat. Hispanic women had lower plasma HDL cholesterol concentrations, higher total cholesterol:HDL cholesterol ratios and triglyceride concentrations, and greater susceptibility of low-density lipoprotein (LDL) particles to oxidation. Hispanic women also had a significantly greater relative deposition of body fat on the trunk and intra-abdominally than did Anglo women, even after adjusting for total body fat. There were no significant ethnic differences in LCAT activity. Plasma CETP and LCAT activities were negatively correlated with HDL cholesterol and positively correlated with total cholesterol, LDL cholesterol, and triglycerides, as well as total and regional body composition variables. In conclusion, results suggest a greater risk for coronary heart disease in Hispanic women compared to Anglo women. |
| Cholesteryl ester transfer protein biosynthesis and cellular cholesterol homeostasis are tightly interconnected Izem, L. and R. E. Morton (2001), J Biol Chem 276(28): 26534-41. Abstract: Cholesteryl ester transfer protein (CETP) mediates triglyceride and cholesteryl ester (CE) transfer between lipoproteins, and its activity is strongly modulated by dietary cholesterol. To better understand the regulation of CETP synthesis and the relationship between CETP levels and cellular lipid metabolism, we selected the SW872 adipocytic cell line as a model. These cells secrete CETP in a time-dependent manner at levels exceeding those observed for Caco-2 or HepG2 cells. The addition of LDL, 25OH-cholesterol, oleic acid, or acetylated LDL to SW872 cells increased CETP secretion (activity and mass) up to 6-fold. In contrast, CETP production was decreased by almost 60% after treatment with lipoprotein-deficient serum or beta-cyclodextrin. These effects, which were paralleled by changes in CETP mRNA, show that CETP biosynthesis in SW872 cells directly correlates with cellular lipid status. To investigate a possible, reciprocal relationship between CETP expression and cellular lipid homeostasis, CETP biosynthesis in SW872 cells was suppressed with CETP antisense oligonucleotides. Antisense oligonucleotides reduced CETP secretion (activity and mass) by 60% compared with sense-treated cells. When CETP synthesis was suppressed for 24 h, triglyceride synthesis was unchanged, but cholesterol biosynthesis was reduced by 20%, and acetate incorporation into CE increased 31%. After 3 days of suppressed CETP synthesis, acetate incorporation into the CE pool increased 3-fold over control. This mirrored a similar increase in CE mass. The efflux of free cholesterol to HDL was the same in sense and antisense-treated cells; however, HDL-induced CE hydrolysis in antisense-treated cells was diminished 2-fold even though neutral CE hydrolase activity was unchanged. Thus, CETP-compromised SW872 cells display a phenotype characterized by inefficient mobilization of CE stores leading to CE accumulation. These results strongly suggest that CETP expression levels contribute to normal cholesterol homeostasis in adipocytic cells. Overall, these studies demonstrate that lipid homeostasis and CETP expression are tightly coupled. |
| Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice Foger, B., M. Chase, et al. (1999), J Biol Chem 274(52): 36912-20. Abstract: Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased high density lipoprotein (HDL) cholesterol levels but paradoxically, enhanced atherosclerosis. We have hypothesized that the absence of cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the accumulation of dysfunctional HDL leading to impaired reverse cholesterol transport and the development of a pro-atherogenic state. To test this hypothesis we cross-bred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (-39% and -13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol levels. CETP normalized both the plasma clearance of (3)Hcholesteryl esters ((3)HCE) from HDL (fractional catabolic rate in days(-1): LCAT-Tg = 3.7 +/- 0.34, LCATxCETP-Tg = 6.1 +/- 0.16, and controls = 6.4 +/- 0.16) as well as the liver uptake of (3)HCE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and controls = 63%) in LCAT-Tg mice. On the pro-atherogenic diet the mean aortic lesion area was reduced by 41% in LCATxCETP-Tg (21.2 +/- 2.0 micrometer(2) x 10(3)) compared with LCAT-Tg mice (35.7 +/- 2.0 micrometer(2) x 10(3); p < 0.001). Adenovirus-mediated expression of scavenger receptor class B (SR-BI) failed to normalize the plasma clearance and liver uptake of (3)HCE from LCAT-Tg HDL. Thus, the ability of SR-BI to facilitate the selective uptake of CE from LCAT-Tg HDL is impaired, indicating a potential mechanism leading to impaired reverse cholesterol transport and atherosclerosis in these animals. We conclude that CETP expression reduces atherosclerosis in LCAT-Tg mice by restoring the functional properties of LCAT-Tg mouse HDL and promoting the hepatic uptake of HDL-CE. These findings provide definitive in vivo evidence supporting the proposed anti-atherogenic role of CETP in facilitating HDL-mediated reverse cholesterol transport and demonstrate that CETP expression is beneficial in pro-atherogenic states that result from impaired reverse cholesterol transport. |
| Cholesteryl ester transfer protein expressed in lecithin cholesterol acyltransferase-deficient mice Wu, C. A., M. Tsujita, et al. (2002), Arterioscler Thromb Vasc Biol 22(8): 1347-53. Abstract: OBJECTIVE: Regulation of plasma cholesteryl ester transfer protein (CETP) concentration was studied in lecithin-cholesterol acyltransferase (LCAT)-knockout mice. METHODS AND RESULTS: LCAT-knockout mice were cross-bred with CETP transgenic mice. The offspring (n=63) were classified for LCAT genotype and plasma CETP levels (no CETP, low CETP, and high CETP). High density lipoprotein (HDL) decreased as LCAT decreased in each CETP-level group. In the lcat(+/+) and lcat(+/-) mice, plasma CETP varied from 0 to 30 micro g/mL, whereas it was <10 micro g/mL in the lcat(-/-) mice. HDL cholesterol and phospholipid decreased and HDL triglyceride and apolipoprotein B increased in CETP in the lcat(+/+) and lcat(+/-) mice, whereas there was no difference in HDL between low and high CETP. An effect of CETP on HDL was not detected in the lcat(-/-) mice because of the absence of mature HDL. Genomic DNA and mRNA of CETP were correlated and were similar in the lcat(-/-) and lcat(+/+) mice. Plasma CETP was correlated with its genomic DNA and mRNA, but the slope of the increase was much lower in the lcat(-/-) mice. Whereas plasma CETP mostly associates with HDL in the lcat(+/+) mouse, it is found free in the lcat(-/-) mouse. CONCLUSIONS: Plasma CETP is posttranscriptionally downregulated in the lcat(-/-) mice, presumably by its extremely low HDL. |
| Cholesteryl ester transfer protein gene polymorphism is a determinant of HDL cholesterol and of the lipoprotein response to a lipid-lowering diet in type 1 diabetes Dullaart, R. P., K. Hoogenberg, et al. (1997), Diabetes 46(12): 2082-7. Abstract: The TaqIB cholesteryl ester transfer protein (CETP) gene polymorphism (B1B2) is a determinant of HDL cholesterol in nondiabetic populations. Remarkably, this gene effect appears to be modified by environmental factors. We evaluated the effect of this polymorphism on HDL cholesterol levels and on the lipoprotein response to a linoleic acid-enriched, low-cholesterol diet in patients with type 1 diabetes. In 44 consecutive type 1 diabetic patients (35 men), CETP polymorphism, apolipoprotein (apo) E genotype, serum lipoproteins, serum CETP activity (measured with an exogenous substrate assay, n = 30), clinical variables, and a diet history were documented. The 1-year response to diet was assessed in 14 type 1 diabetic patients, including 6 B1B1 and 6 B1B2 individuals. HDL cholesterol was higher in 10 B2B2 than in 14 B1B1 homozygotes (1.63 +/- 0.38 vs. 1.24 +/- 0.23 mmol/l, P < 0.01). HDL cholesterol, adjusted for triglycerides and smoking, was 0.19 mmol/l higher for each B2 allele present. CETP activity levels were not significantly different between CETP genotypes. Multiple regression analysis showed that VLDL + LDL cholesterol was associated with dietary polyunsaturated:saturated fatty acids ratio (P < 0.02) and total fat intake (P < 0.05) in the B1B1 homozygotes only and tended to be related to the presence of the apo E4 allele (P < 0.10). In response to diet, VLDL + LDL cholesterol fell (P < 0.05) and HDL cholesterol remained unchanged in 6 B1B1 homozygotes. In contrast, VLDL + LDL cholesterol was unaltered and HDL cholesterol decreased (P < 0.05) in 6 B1B2 heterozygotes (P < 0.05 for difference in change in VLDL + LDL/HDL cholesterol ratio). This difference in response was unrelated to the apo E genotype. Thus, the TaqIB CETP gene polymorphism is a strong determinant of HDL cholesterol in type 1 diabetes. This gene effect is unlikely to be explained by a major influence on the serum level of CETP activity, as an indirect measure of CETP mass. Our preliminary data suggest that this polymorphism may be a marker of the lipoprotein response to dietary intervention. |
| Cholesteryl ester transfer protein gene: two common mutations and their effect on plasma high-density lipoprotein cholesterol content Akita, H., H. Chiba, et al. (1994), J Clin Endocrinol Metab 79(6): 1615-8. Abstract: Cholesteryl ester transfer protein regulates high-density lipoprotein cholesterol (HDL-C) level, and genetic deficiency causes hyperalphalipoproteinemia (HALP). The G to A mutation in the intron 14 splice donor (I14A) has been known to be a common mutation in HALP. Recently, another mutant, D442G (Asp 442 to Gly), was ascertained. The allelic frequencies of I14A and D442G were investigated using 226 unrelated patients with HDL-C of 1.03 mmol/L (40 mg/dL) or greater. Of these, 44 had a mutation I14A and/or D442G. The I14A was found in 15, including 4 compound heterozygotes (I14A/D442G) in patients with HDL-C of 2.05 mmol/L (80 mg/dL) or greater. All I14A homozygotes (n = 5) were present in the group with HDL-C of 3.08 mmol/L (120 mg/dL) or greater, and the allelic frequency paralleled the increase in HDL-C level. D442G was identified in 33, including the 4 compound heterozygotes. Its allelic frequency appeared as two clusters, one at HDL-C around 1.79-2.03 mmol/L (70-79 mg/dL) and the other at HDL-C of 2.82 mmol/L (110 mg/dL) or greater; the latter consisted exclusively of compound heterozygotes. Allelic frequency in the general population for I14A and D442G was 0.81% and 4.62%, respectively. These data suggest that D442G is a common mutation and that, although I14A is responsible for the most severe HALP, D442G leads to a relatively smaller increase in HDL-C. |
| Cholesteryl ester transfer protein modulates the effect of liver X receptor agonists on cholesterol transport and excretion in the mouse Masson, D., B. Staels, et al. (2004), J Lipid Res 45(3): 543-50. Abstract: Human plasma, unlike mouse plasma, contains the cholesteryl ester transfer protein (CETP) that may influence the reverse cholesterol transport. Liver X receptor (LXR), an oxysterol-activated nuclear receptor induces CETP transcription via a direct repeat 4 element in the CETP gene promoter. The aim of the study was to assess in vivo the impact of LXR activation on CETP expression and its consequences on plasma lipid metabolism and hepatic and bile lipid content. Wild-type and humanized mice expressing CETP were treated for five days with T0901317 LXR agonist. This treatment produced marked rises in both hepatic CETP mRNA and plasma CETP activity levels. Interestingly, the LXR agonist-mediated, 2-fold rise in both total and HDL cholesterol levels in treated wild-type mice was not observed in CETPTg mice, and the accumulation of cholesterol in the liver of CETPTg mice was reversed by LXR agonist treatment. Moreover, LXR activation induced a 2-fold increase in hepatic LDL-receptor expression in wild-type and CETPTg mice, and it produced a significantly greater rise in biliary cholesterol concentration in CETPTg mice as compared with wild-type mice. In conclusion, induction of CETP constitutes a major determinant of the effect of LXR agonists on cholesterol transport and excretion. |
| Cholesteryl ester transfer protein mutations, protein activity and HDL-cholesterol concentration Hill, S. A., C. Thomson, et al. (1998), Clin Chem Lab Med 36(8): 629-32. Abstract: We have examined a group of North American subjects, selected to include individuals with a wide variety of HDL-cholesterol concentrations for: 1) mutations in the genes coding for cholesteryl ester transfer protein and hepatic lipase, 2) apolipoprotein E genotype, 3) total cholesterol and triglycerides, 4) HDL-triglycerides. Cholesteryl ester transfer protein activity was also estimated, using a novel technique that does not require separation of substrate and product. Transfer activity was shown to have a monophasic distribution, with a mean activity of 21 pmol substrate transferred/3 h/microl plasma. The cholesterol ester transfer activity of the group with HDL-cholesterol >1.60 mmol/l was significantly less than those with HDL-cholesterol <1.60 mmol/l. The cholesteryl ester transfer protein G1533A mutation was detected at an overall allele frequency of 2.91%. The mutation was more frequent in the group with HDL-cholesterol <1.60 mmol/l than in those >1.60 mmol/l. It was also more frequent in those with protein activity > 30 pmol/ 3h/microl plasma than in those with activity <30. These data suggest that this mutation in cholesteryl ester transfer protein is associated with increased transfer activity and reduced HDL-cholesterol concentrations. The cholesteryl ester transfer protein activity assay described here is simple and convenient. Subject to further evaluation and correlation with the present labour and time intensive assays, this commercially available assay offers the potential of rapid, simple analysis of large numbers of samples. |
| Cholesteryl ester transfer protein promoter single-nucleotide polymorphisms in Sp1-binding sites affect transcription and are associated with high-density lipoprotein cholesterol Thompson, J. F., D. B. Lloyd, et al. (2004), Clin Genet 66(3): 223-8. Abstract: Genetic variation in the human cholesteryl ester transfer protein (CETP) promoter has been shown to be associated with high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular disease. Some of this variation occurs in Sp1/Sp3 binding sites in the proximal promoter. We find that both the known promoter polymorphism at -629 and the previously uncharacterized polymorphism at -38 are associated with HDL-C levels in vivo and affect transcription in vitro. While the -629 polymorphism is common in all ethnic groups, the -38 polymorphism is found at significant levels (6.4%) only among African Americans. Those homozygous for the less common -38A allele have higher HDL-C levels than those with the more frequent -38G allele. This association was found in a population of African Americans at risk of cardiovascular disease and then replicated in a different population chosen from among patients with extremes of HDL-C. When studied in vitro, the most transcriptionally active allele (-629C/-38G) yields 51% more reporter protein than the least active allele (-629A/-38A) in HepG2 cells. These transcriptional effects reflect the projected impact of increased CETP expression on HDL-C phenotypes seen in vivo. |
| 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 Brousseau, M. E., J. J. O'Connor, Jr., et al. (2002), Arterioscler Thromb Vasc Biol 22(7): 1148-54. Abstract: OBJECTIVE: We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP) TaqIB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level. METHODS AND RESULTS: We tested for associations between the CETP TaqIB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (< or =40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (-27%, P<0.03), whereas more men in VA-HIT had the B1B1 genotype (15%, P<0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6+/-4.8 mg/dL), followed by B1B2 men (32.0+/-5.3 mg/dL), and, last, by B1B1 men (30.9+/-4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (-34%, P=0.006). CETP TaqIB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (P=0.08). CONCLUSIONS: Our data demonstrate that in men with CHD and HDL deficiency, the CETP TaqI B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk. |