PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients.
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ABSTRACT:
SUBMITTER: Dongiovanni P
PROVIDER: S-EPMC6547640 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivePatients treated with statins for dyslipidemia may still have a residual risk of atherosclerotic cardiovascular disease (ASCVD). To determine whether genetic variants in the cholesteryl ester transport protein (CETP), rs3764261 (C>A), rs708272 (G>A), and rs12149545 (G>A) affect ASCVD risk, we studied the association of these variants with dyslipidemia in statin-treated patients.Patients and methodsWe included 299 adult Thai patients treated with a statin (95 men and 204 women). Genotyping was performed by conducting a TaqMan real-time polymerase chain reaction-based analysis. We used logistic regression models adjusted for potential confounders of age, body mass index, blood pressure, insulin resistance, and statin dosage to analyze the association between CETP variants and atherogenic lipoprotein patterns.ResultsCETP polymorphisms of rs3764261 and rs708272, but not rs12149545, were significantly associated with high-density lipoprotein cholesterol (HDL-C), apoA-I, triglycerides, very low-density lipoprotein (VLDL)-C, and large LDL (LDL1-C) levels as well as mean LDL particle size (all p < 0.020). However, no significant difference was observed in total cholesterol, LDL-C, or apoB levels by CETP variants. Regardless of sex, the combination of rs3764261 (CC genotype) and rs708272 (GG or GA genotypes) showed a stronger association with atherogenic dyslipidemia, including features of decreased HDL-C, elevated triglycerides, and LDL subclass pattern B (odds ratio [OR] = 2.99, 95% confidence interval [CI]: 1.78-5.02) compared with the single variant rs3764261 (OR = 2.11, 95% CI: 1.27-3.50) or rs708272 (OR = 2.12, 95% CI: 1.29-3.49).ConclusionThe polymorphisms of CETP rs3764261 (CC genotype) and rs708272 (GG and GA genotypes) may have a higher susceptibility to atherogenic dyslipidemia. Testing for CETP rs3764261 and rs708272 may serve as a surrogate marker for lipid management in statin-treated patients, which may help individualize treatment for reducing the residual risk of ASCVD.
| S-EPMC7802592 | biostudies-literature
Project description:Approaches to manage nonalcoholic fatty liver disease (NAFLD) are limited by an incomplete understanding of disease pathogenesis. The aim of this study was to identify hepatic gene-expression patterns associated with different patterns of liver injury in a high-risk cohort of adults with obesity. Using the NanoString Technologies (Seattle, WA) nCounter assay, we quantified expression of 795 genes, hypothesized to be involved in hepatic fibrosis, inflammation, and steatosis, in liver tissue from 318 adults with obesity. Liver specimens were categorized into four distinct NAFLD phenotypes: normal liver histology (NLH), steatosis only (steatosis), nonalcoholic steatohepatitis without fibrosis (NASH F0), and NASH with fibrosis stage 1-4 (NASH F1-F4). One hundred twenty-five genes were significantly increasing or decreasing as NAFLD pathology progressed. Compared with NLH, NASH F0 was characterized by increased inflammatory gene expression, such as gamma-interferon-inducible lysosomal thiol reductase (IFI30) and chemokine (C-X-C motif) ligand 9 (CXCL9), while complement and coagulation related genes, such as C9 and complement component 4 binding protein beta (C4BPB), were reduced. In the presence of NASH F1-F4, extracellular matrix degrading proteinases and profibrotic/scar deposition genes, such as collagens and transforming growth factor beta 1 (TGFB1), were simultaneously increased, suggesting a dynamic state of tissue remodeling. Conclusion: In adults with obesity, distinct states of NAFLD are associated with intrahepatic perturbations in genes related to inflammation, complement and coagulation pathways, and tissue remodeling. These data provide insights into the dynamic pathogenesis of NAFLD in high-risk individuals.
| S-EPMC8710788 | biostudies-literature
Project description:To investigate mechanisms by which hibernators avoid atherogenic hyperlipidemia during hibernation, we assessed lipoprotein and cholesterol metabolisms of free-ranging Scandinavian brown bears (Ursus arctos). In winter- and summer-captured bears, we measured lipoprotein sizes and sub-classes, triglyceride-related plasma-enzyme activities, and muscle lipid composition along with plasma-levels of antioxidant capacities and inflammatory markers. Although hibernating bears increased nearly all lipid levels, a 36%-higher cholesteryl-ester transfer-protein activity allowed to stabilize lipid composition of high-density lipoproteins (HDL). Levels of inflammatory metabolites, i.e., 7-ketocholesterol and 11ß-prostaglandin F2α, declined in winter and correlated inversely with cardioprotective HDL2b-proportions and HDL-sizes that increased during hibernation. Lower muscle-cholesterol concentrations and lecithin-cholesterol acyltransferase activity in winter suggest that hibernating bears tightly controlled peripheral-cholesterol synthesis and/or release. Finally, greater plasma-antioxidant capacities prevented excessive lipid-specific oxidative damages in plasma and muscles of hibernating bears. Hence, the brown bear manages large lipid fluxes during hibernation, without developing adverse atherogenic effects that occur in humans and non-hibernators.
| S-EPMC8455566 | biostudies-literature
Project description:Dyslipidemia is one of the common risk factors for NAFLD and is associated with cardiovascular (CV) mortality, which is the most common cause of death in NAFLD. Lipid-lowering agents (LLAs) are used to reduce CV events in the general population. Our aim was to assess whether the use of LLAs in patients with NAFLD can reduce the risk of CV mortality. We used the third National Health and Nutrition Examination Survey mortality linked files. Mortality was determined from the National Death Index records through 2011. NAFLD was diagnosed by ultrasound after exclusion of other causes of liver disease. After inclusion and exclusion, the cohort consisted of 2,566 patients with NAFLD (45.8% < 45 years of age, 52.8% male, 75.4% white). Those who were taking LLAs were more likely to be older, non-Hispanic white, and had significantly higher rates of diabetes mellitus (DM), hyperlipidemia, hypertension, metabolic syndrome, and history of CV disease (CVD) (all P< 0.01). In our multivariate analysis, DM was an independent predictor of overall mortality (adjusted hazard ratio [aHR]: 1.79 [95% confidence interval (CI): 1.40-2.30]) and CV mortality (aHR: 1.89 [95% CI: 1.08-3.30]). History of CVD was associated with both overall (aHR: 2.03 [95% CI: 1.57-2.63]) and CV mortality (aHR: 3.69 [95% CI: 2.23-6.08]). In contrast, the use of statins and other LLAs was not associated with reduction in overall (aHR = 0.95 [95% CI: 0.37-2.44] and aHR = 1.43 [95% CI: 0.99-2.07]) and CV mortality (aHR = 1.20 [95% CI: 0.26-5.54] and aHR = 1.63 [95% CI: 0.70-3.76]). Conclusion: The use of statins and other LLAs did not reduce the increased risk of overall or CV mortality in NAFLD.
| S-EPMC6167074 | biostudies-literature
Project description:Patients with type 2 diabetes (T2D) are at a markedly increased risk of cardiovascular disease (CVD). Dyslipidemia is a common risk factor and a strong predictor of CVD in T2D patients. Although statins decrease the incidence of CVD in T2D, residual cardiovascular risk remains high despite the achievement of optimal or near-optimal plasma low-density lipoprotein (LDL) cholesterol concentrations. This may, in part, be due to uncorrected atherogenic dyslipidemia. Hypertriglyceridemia, the driving force behind diabetic dyslipidemia, results from hepatic overproduction and/or delayed clearance of triglyceride-rich lipoproteins. In patients treated with a statin to LDL-cholesterol goals, the addition of ezetimibe, fenofibrate, niacin, or n-3 fatty acid ethyl esters may be required to correct the persistent atherogenic dyslipidemia. Clinical trial evidence describing best practice is limited, but recent data supports the strategy of adding fenofibrate to a statin, and suggests specific benefits in dyslipidemic patients and in the improvement of diabetic retinopathy. However, based on results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled LDL-cholesterol. Further evidence is required to support the role of ezetimibe and n-3 fatty acids in treating residual CVD risk in statin-treated T2D patients.
| S-EPMC4063096 | biostudies-other
Project description:Diets high in fat and cholesterol are associated with increased obesity and metabolic disease in mice and humans. To study the molecular basis of the metabolic response to dietary fat, 10 inbred strains of mice were fed atherogenic high-fat and control low-fat diets. Liver gene expression and whole animal phenotypes were measured and analyzed in both sexes. The effects of diet, strain, and sex on gene expression were determined irrespective of complex processes, such as feedback mechanisms, that could have mediated the genomic responses. Global gene expression analyses demonstrated that animals of the same strain and sex have similar transcriptional profiles on a low-fat diet, but strains may show considerable variability in response to high-fat diet. Functional profiling indicated that high-fat feeding induced genes in the immune response, indicating liver damage, and repressed cholesterol biosynthesis. The physiological significance of the transcriptional changes was confirmed by a correlation analysis of transcript levels with whole animal phenotypes. The results found here were used to confirm a previously identified quantitative trait locus on chromosome 17 identified in males fed a high-fat diet in two crosses, PERA x DBA/2 and PERA x I/Ln. The gene expression data and phenotype data have been made publicly available as an online tool for exploring the effects of atherogenic diet in inbred mouse strains (http://cgd-array.jax.org/DietStrainSurvey).
| S-EPMC2789673 | biostudies-literature
Project description:BackgroundThe atherogenic effects of hypothyroidism on lipid metabolism could result, in part, from the reduced clearance of remnant lipoproteins. In this study, we investigated the expression of hepatic low-density lipoprotein receptor-related protein 1 (LRP1), a receptor for remnant lipoproteins, in hypothyroidism and the effect of 3,3',5-triiodo-L-thyronine (T3) treatment on hepatic LRP1 expression.MethodsC57BL/6 mice were fed a normal diet (control group) or a low-iodine diet supplemented with 0.15% propylthiouracil (PTU/LI group) for 4 weeks. Mice in the PTU/LI group were injected intraperitoneally with T3 (0, 30, and 150 ?g/kg of body weight) for 7 days. HepG2 cells were incubated in fetal bovine serum or charcoal-stripped fetal bovine serum with various concentrations of T3. The expression and function of LRP1 in liver samples and cells were analyzed.ResultsHypothyroidism was successfully induced in PTU/LI mice. Hepatic LRP1 protein expression was lower in the PTU/LI group than in the control group. T3 treatment upregulated hepatic LRP1 protein expression in PTU/LI mice. LRP1 expression in HepG2 cells was reduced after incubation in the medium containing charcoal-stripped fetal bovine serum, which mimics hypothyroidism in vitro, and was recovered by T3 treatment. The protein expression of LRP1 in HepG2 cells was increased by T3 treatment in a dose-dependent manner up to 2.0 nM T3. However, LRP1 mRNA transcription was not affected by hypothyroidism conditions or T3 treatment, either in liver samples or in HepG2 cells. T3 treatment on HepG2 cells increased cellular uptake of lipid-conjugated apolipoprotein E through LRP1.ConclusionsOur data demonstrate that hepatic LRP1 expression and function decrease in hypothyroidism and are regulated by the thyroid hormone. These results suggest that in hypothyroidism, decreased expression of hepatic LRP1 may be associated with reduced clearance of circulating remnant lipoproteins.
| S-EPMC3770248 | biostudies-literature
Project description:Dyslipidemia and inflammation play key roles in the pathogenesis of both nonalcoholic fatty liver disease (NAFLD) and atherosclerosis. NAFLD, particularly its severe form nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular disease (CVD) risk. HDL (high density lipoprotein- also a CVD risk) are decreased in NAFLD but whether HDL function is abnormal in NAFLD is unknown. Furthermore, it is unknown whether dyslipidemia contributes to reduced HDL function in NAFLD and whether hepatic inflammation further impairs HDL function in patients with NASH. Therefore, the aim of this study was to investigate HDL function and to examine the effect of dyslipidemia and inflammation on HDL metabolism in patients with biopsy-proven simple steatosis (SS) and NASH. RESULTS: Compared to controls, SS and NASH subjects had significantly higher levels of plasma triglyceride, insulin, and were more insulin resistant (HOMA, P<0.05) with no differences in total cholesterol, HDL cholesterol, ApoB100 and ApoAI levels. NAFLD patients had increased production and degradation rates of both HDLc and ApoAI that resulted in their levels remaining stable. The degradation rates also were increased of other HDL proteins, including ApoAII, ApoAIV, vitamin D-binding protein, and complement 3 (all P<0.05). NAFLD patients had increased activities of LCAT and CETP, indicating altered HDL lipidation. NAFLD induced alterations in HDL metabolism were associated with reduced anti-oxidant but increased pro-inflammatory activity of HDL. However, no differences were observed in either HDL function or the kinetics of HDLc and HDL proteins between SS and NASH subjects.
2019-08-12 | PXD010199 | Pride
Project description:The precursors of atherogenic dyslipidemia (AD) are not well defined. Therefore, we investigated 62 non-obese, non-diabetic AD and 221 normolipemic children. Anthropometric parameters, blood pressure and biochemical measures were obtained in index children, their parents and all available siblings. The heritability (h(2)) of anthropometric and biochemical traits was estimated by SOLAR. Rare and common variants in APOA1 and LPL genes were screened by re-sequencing. Compared to normolipemic, AD children showed increased body mass index, waist circumference, plasma glucose, insulin, ApoB, HOMA-IR, hs-CRP and lower adiponectin (p<0.001 for all). Metabolic syndrome was present in 40% of AD while absent in controls. All traits (except adiponectin and hs-CRP) showed a strong familial aggregation, with plasma glucose having the highest heritability (89%). Overall, 4 LPL loss-of-function mutations were detected (p.Asp9Asn, p.Ser45Asn, p.Asn291Ser, p.Leu365Val) and their cumulative prevalence was higher in AD than in control children (0.073 vs. 0.026; P=0.038). The LPL p.S447* gain-of-function mutation, resulted to be less frequent in AD than in control children (0.064 vs. 0.126; P=0.082). No variant in the APOA1 gene was found. Our data indicate that AD is a rather common dyslipidemia in childhood; it associates with metabolic abnormalities typical of insulin resistant state and shows a strong familial aggregation. LPL variants may contribute to the development of AD phenotype.
| S-EPMC4405441 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) has become one of the most common diseases and severe problems worldwide because of the global increase in obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus. NAFLD includes a wide spectrum of liver diseases, the histological forms of which range from non-alcoholic fatty liver (NAFL), which is generally nonprogressive, to non-alcoholic steatohepatitis (NASH), which can progress to chronic hepatitis, liver cirrhosis (LC), and sometimes hepatocellular carcinoma (HCC). Unlike NAFL, as the progressive form of NAFLD, NASH is characterized by the presence of inflammation with or without fibrosis in addition to hepatic steatosis. Although it is widely known and proved that persistent hepatic injury and chronic inflammation in the liver activate quiescent hepatic stellate cells (HSCs) and lead to hepatic fibrosis, the three-step process of "inflammation-fibrosis-carcinoma" in NAFLD has not been investigated and clarified clearly. In this process, the initiation of inflammation in the liver and the function of various liver inflammatory cells have been discussed regularly, while the activated HSCs, which constitute the principal cells responsible for fibrosis and their cross-talk with inflammation, seem not to be investigated specifically and frequently. Also, accumulated evidence suggests that HSCs can not only be activated by inflammation but also participate in the regulation of liver inflammation. Therefore, it is necessary to investigate the unique roles of HSCs in NAFLD from the perspective of inflammation and fibrosis. Here, we review the pivotal effects and mechanisms of HSCs and highlight the potential value of HSC-targeted treatment methods in NAFLD.
| S-EPMC9606692 | biostudies-literature