Altered relationship of plasma triglycerides to HDL cholesterol in patients with HIV/HAART-associated dyslipidemia: further evidence for a unique form of metabolic syndrome in HIV patients.
ABSTRACT: Plasma triglycerides (TG) and HDL-C are inversely related in Metabolic Syndrome (MetS), due to exchange of VLDL-TG for HDL-cholesteryl esters catalyzed by cholesteryl ester transfer protein (CETP). We investigated the relationship of TG to HDL-C in highly-active antiretroviral drug (HAART)-treated HIV patients.Fasting plasma TG and HDL-C levels were compared in 179 hypertriglyceridemic HIV/HAART patients and 71 HIV-negative persons (31 normotriglyceridemic (NL) and 40 hypertriglyceridemic due to type IV hyperlipidemia (HTG)). CETP mass and activity were compared in 19 NL and 87 HIV/HAART subjects.Among the three groups, a plot of HDL-C vs. TG gave similar slopes but significantly different y-intercepts (9.24±0.45, 8.16±0.54, 6.70±0.65, sqrt(HDL-C) for NL, HIV and HTG respectively; P<0.001); this difference persisted after adjusting HDL-C for TG, age, BMI, gender, glucose, CD4 count, viral load and HAART strata (7.18±0.20, 6.20±0.05 and 4.55±0.15 sqrt(HDL-C) for NL, HIV and HTG, respectively, P<0.001). CETP activity was not different between NL and HIV, but CETP mass was significantly higher in HIV (1.47±0.53 compared to 0.93±0.27?g/mL, P<0.0001), hence CETP specific activity was lower in HIV (22.67±13.46 compared to 28.46±8.24nmol/?g/h, P=0.001).Dyslipidemic HIV/HAART patients have a distinctive HDL-C plasma concentration adjusted for TG. The weak inverse relationship between HDL-C and TG is not explained by altered total CETP activity; it could result from a non-CETP-dependent mechanism or a decrease in CETP function due to inhibitors of CETP activity in HIV patients' plasma.
Project description:HIV patients on antiretroviral therapy (HIV/ART) exhibit a unique atherogenic dyslipidemic profile with hypertriglyceridemia (HTG) and low plasma concentrations of high-density lipoprotein (HDL) cholesterol. In the Heart Positive Study of HIV/ART patients, a hypolipidemic therapy of fenofibrate, niacin, diet, and exercise reduced HTG and plasma non-HDL cholesterol concentrations and raised plasma HDL cholesterol and adiponectin concentrations. We tested the hypothesis that HIV/ART HDL have abnormal structures and properties and are dysfunctional.Hypolipidemic therapy reduced the TG contents of low-density lipoprotein and HDL. At baseline, HIV/ART low-density lipoproteins were more triglyceride (TG)-rich and HDL were more TG- and cholesteryl ester-rich than the corresponding lipoproteins from normolipidemic (NL) subjects. Very-low-density lipoproteins, low-density lipoprotein, and HDL were larger than the corresponding lipoproteins from NL subjects; HIV/ART HDL were less stable than NL HDL. HDL-[(3)H]cholesteryl ester uptake by Huh7 hepatocytes was used to assess HDL functionality. HIV/ART plasma were found to contain significantly less competitive inhibition activity for hepatocyte HDL-cholesteryl ester uptake than NL plasma were found to contain (P<0.001).Compared with NL subjects, lipoproteins from HIV/ART patients are larger and more neutral lipid-rich, and their HDL are less stable and less receptor-competent. On the basis of this work and previous studies of lipase activity in HIV, we present a model in which plasma lipolytic activities or hepatic cholesteryl ester uptake are impaired in HIV/ART patients. These findings provide a rationale to determine whether the distinctive lipoprotein structure, properties, and function of HIV/ART HDL predict atherosclerosis as assessed by carotid artery intimal medial thickness.
Project description:Apolipoprotein A-V (apoA-V), a minor protein associated with lipoproteins, has a major effect on triacylglycerol (TG) metabolism. We investigated whether apoA-V complexed with phospholipid in the form of a reconstituted high-density lipoprotein (rHDL) has potential utility as a therapeutic agent for treatment of hypertriglyceridemia (HTG) when delivered intravenously.Intravenous injection studies were performed in genetically engineered mouse models of severe HTG, including apoav-/- and gpihbp1-/- mice. Administration of apoA-V rHDL to hypertriglyceridemic apoav-/- mice resulted in a 60% reduction in plasma TG concentration after 4 hours. This decline can be attributed to enhanced catabolism/clearance of very-low-density lipoprotein (VLDL), where VLDL TG and cholesterol were reduced ?60%. ApoA-V that associated with VLDL after injection was also rapidly cleared. Site-specific mutations in the heparin-binding region of apoA-V (amino acids 186 to 227) attenuated apoA-V rHDL TG-lowering activity by 50%, suggesting that this sequence element is required for optimal TG-lowering activity in vivo. Unlike apoav-/- mice, injection of apoA-V rHDL into gpihbp1-/- mice had no effect on plasma TG levels, and apoA-V remained associated with plasma VLDL.Intravenously injected apoA-V rHDL significantly lowers plasma TG in an apoA-V deficient mouse model. Its intravenous administration may have therapeutic benefit in human subjects with severe HTG, especially in cases involving apoA-V variants associated with HTG.
Project description:OBJECTIVE:Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity. METHODS AND RESULTS:First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes. CONCLUSIONS:HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.
Project description:BACKGROUND: CETP is a plasma protein that modulates atherosclerosis risk through its HDL-cholesterol reducing action. The aim of this work was to examine the effect of the PPARalpha agonist, ciprofibrate, on the CETP gene expression, in the presence and absence of apolipoprotein (apo) CIII induced hypertriglyceridemia, and its impact on the HDL metabolism. RESULTS: Mice expressing apo CIII and/or CETP and non-transgenic littermates (CIII, CIII/CETP, CETP, non-Tg) were treated with ciprofibrate during 3 weeks. Drug treatment reduced plasma triglycerides (30-43%) and non-esterified fatty acids (19-47%) levels. Cholesterol (chol) distribution in plasma lipoprotein responses to ciprofibrate treatment was dependent on the genotypes. Treated CIII expressing mice presented elevation in VLDL-chol and reduction in HDL-chol. Treated CETP expressing mice responded with reduction in LDL-chol whereas in non-Tg mice the LDL-chol increased. In addition, ciprofibrate increased plasma post heparin lipoprotein lipase activity (1.3-2.1 fold) in all groups but hepatic lipase activity decreased in treated CETP and non-Tg mice. Plasma CETP activity and liver CETP mRNA levels were significantly increased in treated CIII/CETP and CETP mice (30-100%). Kinetic studies with 3H-cholesteryl ether (CEt) labelled HDL showed a 50% reduction in the 3H-CEt found in the LDL fraction in ciprofibrate treated compared to non-treated CETP mice. This means that 3H-CEt transferred from HDL to LDL was more efficiently removed from the plasma in the fibrate treated mice. Accordingly, the amount of 3H-CEt recovered in the liver 6 hours after HDL injection was increased by 35%. CONCLUSION: Together these data showed that the PPARalpha agonist ciprofibrate stimulates CETP gene expression and changes the cholesterol flow through the reverse cholesterol transport, increasing plasma cholesterol removal through LDL.
Project description:OBJECTIVE: Using a mouse model for human-like lipoprotein metabolism, we observed previously that reduction of the hepatic triglyceride (TG) content resulted in a decrease in plasma cholesteryl ester transfer protein (CETP) and an increase in HDL levels. The aim of the current study was to investigate the effects of prolonged caloric restriction in obese patients with type 2 diabetes mellitus, resulting in a major reduction in hepatic TG content, on plasma CETP and HDL levels. RESEARCH DESIGN AND METHODS: We studied 27 obese (BMI: 37.2 ± 0.9 kg/m(2)) insulin-dependent patients with type 2 diabetes mellitus (14 men and 13 women, aged 55 ± 2 years) who received a 16-week very low calorie diet (VLCD). At baseline and after a 16-week VLCD, plasma lipids, lipoproteins, and CETP were measured. Furthermore, functionality of HDL with respect to inducing cholesterol efflux from human monocyte cells (THP-1) was determined. RESULTS: A 16-week VLCD markedly decreased plasma CETP concentration (-18%; P < 0.01) and increased plasma apolipoprotein (apo)AI levels (+16%; P < 0.05), without significantly affecting plasma HDL-cholesterol and HDL-phospholipids. Although a VLCD results in HDL that is less lipidated, the functionality of HDL with respect to inducing cholesterol efflux in vitro was unchanged. CONCLUSIONS: The marked decrease in hepatic TG content induced by a 16-week VLCD is accompanied by a decrease in plasma CETP concentration and an increase in apoAI levels, without improving the cholesterol efflux properties of HDL in vitro.
Project description:Impaired scavenger receptor class B type I (SR-BI)-mediated uptake of HDL-cholesterol esters (HDL-CE) induces adrenal insufficiency in mice. Humans contain an alternative route of HDL-CE clearance, namely through the transfer by cholesteryl ester transfer protein (CETP) to apolipoprotein B lipoproteins for subsequent uptake via the LDL receptor. In this study, we determined whether CETP can compensate for loss of adrenal SR-BI. Transgenic expression of human CETP (CETP Tg) in SR-BI knockout (KO) mice increased adrenal HDL-CE clearance from 33-58% of the control value. SR-BI KO/CETP Tg and SR-BI KO mice displayed adrenal hypertrophy due to equally high plasma adrenocorticotropic hormone levels. Adrenal cholesterol levels and plasma corticosterone levels were 38-52% decreased in SR-BI KO mice with and without CETP expression. SR-BI KO/CETP Tg mice also failed to increase their corticosterone level after lipopolysaccharide challenge, leading to an identical >4-fold increased tumor necrosis factor-alpha response compared with controls. These data indicate that uptake of CE via other routes than SR-BI is not sufficient to generate the cholesterol pool needed for optimal adrenal steroidogenesis. In conclusion, we have shown that CETP-mediated transfer of HDL-CE is not able to reverse adrenal insufficiency in SR-BI knockout mice. Thus, SR-BI-mediated uptake of serum cholesterol is essential for optimal adrenal function.
Project description:BACKGROUND: Hypertriglyceridemia (HTG) is defined as a triglyceride (TG) plasma level exceeding 150 mg/dl and is tightly associated with atherosclerosis, metabolic syndrome, obesity, diabetes and acute pancreatitis. The present study was undertaken to investigate the mitochondrial, sub-mitochondrial and cellular proteomic impact of hypertriglyceridemia in the hepatocytes of hypertriglyceridemic transgenic mice (overexpressing the human apolipoproteinC-III). METHODS: Quantitative proteomics (2D-DIGE) analysis was carried out on both "low-expressor" (LE) and "high-expressor" (HE) mice, respectively exhibiting moderate and severe HTG, to characterize the effect of the TG plasma level on the proteomic response. RESULTS: The mitoproteome analysis has revealed a large-scale phenomenon in transgenic mice, i.e. a general down-regulation of matricial proteins and up-regulation of inner membrane proteins. These data also demonstrate that the magnitude of proteomic changes strongly depends on the TG plasma level. Our different analyses indicate that, in HE mice, the capacity of several metabolic pathways is altered to promote the availability of acetyl-CoA, glycerol-3-phosphate, ATP and NADPH for TG de novo biosynthesis. The up-regulation of several cytosolic ROS detoxifying enzymes has also been observed, suggesting that the cytoplasm of HTG mice is subjected to oxidative stress. Moreover, our results suggest that iron over-accumulation takes place in the cytosol of HE mice hepatocytes and may contribute to enhance oxidative stress and to promote cellular proliferation. CONCLUSIONS: These results indicate that the metabolic response to HTG in human apolipoprotein C-III overexpressing mice may support a high TG production rate and that the cytosol of hepatocytes is subjected to an important oxidative stress, probably as a result of FFA over-accumulation, iron overload and enhanced activity of some ROS-producing catabolic enzymes.
Project description:Early highly active antiretroviral therapy (HAART) is recommended for HIV-1-infected infants. There are limited data on lipid changes during infant HAART.Nonfasting total (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol and triglycerides (TG) were measured at 0, 6 and 12 months. Correlates of lipid levels and changes post-HAART were assessed using linear regression.Among 115 infants, pre-HAART median age was 3.8 months, CD4% was 19% and weight-for-age Z score was -2.42. Pre-HAART median lipid levels were: TC, 108.7 mg/dL; LDL, 42.5 mg/dL; HDL, 29.4 mg/dL and TG, 186.9 mg/dL. Few infants had abnormally high TC (6.2%) or LDL (5.6%), but many had low HDL (76.5%) or high TG (69.6%). Higher pre-HAART weight-for-age and height-for-age Z scores were each associated with higher pre-HAART TC (P = 0.04 and P = 0.01) and LDL (P = 0.02 and P = 0.008). From 0 to 6 months post-HAART, TC (P < 0.0001), LDL (P < 0.0001) and HDL (P < 0.0001) increased significantly, and 23.1% (P = 0.002), 14.0% (P = 0.2), 31.3% (P < 0.0001) and 50.8% (P = 0.2) of infants had abnormally high TC, high LDL, low HDL and high TG, respectively. Changes in TC and HDL were each associated with higher gain in weight-for-age Z score (P = 0.03 and P = 0.01) and height-for-age Z score (P = 0.01 and P = 0.007). Increased change in LDL was associated with higher gain in height-for-age Z score (P = 0.03). Infants on protease inhibitor-HAART had smaller HDL increase (P = 0.004).Infants had substantive increases in lipids, which correlated with growth. Increases in HDL were attenuated by protease inhibitor-HAART. It is important to determine clinical implications of these changes.
Project description:BACKGROUND:The triglycerides (TG) to high-density lipoprotein (HDL)-cholesterol (HDL-C) ratio (TG/HDL-C) is a well-known predictor for cardiovascular diseases (CVDs) with great heritability background. The cholesteryl ester transfer protein (CETP) and hepatic lipase (LIPC) gene affect TG/HDL-C ratio. This study aims to explore the association between haplotypes (H) in CETP (based on 5 single nucleotide polymorphisms (SNPs)) and LIPC (based on 6 SNPs) genes and the TG/HDL-C ratio and its components, among Roma and Hungarian general populations. METHODS:The prevalence of haplotypes and their effect on HDL-C, TG and TG/HDL-C ratio were calculated in both populations and compared. RESULTS:Ten haplotypes in CETP and 6 in LIPC gene were identified. Three haplotypes in CETP and 3 in LIPC have significant effect on HDL-C level, whereas two in CETP and 3 in LIPC on TG level. The H6 in CETP (? = 0.52, p = 0.015; odds ratio (OR) = 1.87, p = 0.009) and H5 in LIPC (? = 0.56, p < 0.001; OR = 1.51, p = 0.002) have a significant increasing effect on TG/HDL-C ratio and have shown higher prevalence among the Roma, as compared to Hungarian general population. The H2 in the CETP gene has a decreasing effect on the TG/HDL-C ratio (OR = 0.58, p = 0.019) and is significantly less frequent among the Roma. CONCLUSIONS:Accumulation of harmful haplotypes in CETP and LIPC genes might have a role in the elevated TG/HDL-C ratio in the Roma population, which contributes to a higher risk in the development of cardiovascular diseases.
Project description:A high degree of inter-individual variability in plasma lipid level response to hormone therapy (HT) has been reported. Variations in the oestrogen receptor alpha gene (ESR1) and in genes involved in lipid metabolism may explain some of the variability in response to HT. Subjects Postmenopausal Caucasian women (n = 208) participating in a placebo-controlled randomized trial of 3.2 years of hormone therapy (HT).Plasma triglyceride (TG), remnant lipoprotein cholesterol (RLP-C), and high-density lipoprotein cholesterol (HDL-C) levels and HDL subpopulations were assessed at baseline and at follow up. Single nucleotide polymorphisms (SNPs) in ESR1 and in the ATP binding cassette A1 (ABCA1), cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), and scavenger receptor class B type I (SRB1) genes were assessed for their association with baseline plasma levels and HT-related changes in levels of RLP-C and HDL subpopulations.Carriers of the ESR1 PvuII or IVS1-1505 variants had lower plasma TG concentrations and higher plasma HDL-C and alpha-1 and prealpha-1 HDL particle levels at baseline and showed greater increases in HDL-C, apo A-I and alpha-1 particle levels after HT than wild-type carriers. Carriers of the N291S and D9N variants in the LPL gene had significantly higher remnant lipoproteins and lower alpha-2 HDL particle levels at baseline. The CETP TaqIB SNP was a significant determinant of baseline plasma HDL-C and HDL subpopulation profile.Single nucleotide polymorphisms in ESR1, CETP and LPL had significant effects on baseline plasma levels of TG-rich and HDL subpopulations. With the exception of ESR1 SNPs, variation in genes involved in lipid metabolism has a very modest effect on lipoprotein response to HT.