Insig Proteins Mediate Feedback Inhibition of Cholesterol Synthesis in the Intestine

Enterocytes are the only cell type that must balance the de novo synthesis and absorption of cholesterol, although the coordinate regulation of these processes is not well understood. Our previous studies demonstrated that enterocytes respond to the pharmacological blockade of cholesterol absorption by ramping up de novo sterol synthesis through activation of sterol regulatory element-binding protein-2 (SREBP-2). Here, we genetically disrupt both Insig1 and Insig2 in the intestine, two closely related proteins that are required for the feedback inhibition of SREBP and HMG-CoA reductase (HMGR). This double knock-out was achieved by generating mice with an intestine-specific deletion of Insig1 using Villin-Cre in combination with a germ line deletion of Insig2. Deficiency of both Insigs in enterocytes resulted in constitutive activation of SREBP and HMGR, leading to an 11-fold increase in sterol synthesis in the small intestine and producing lipidosis of the intestinal crypts. The intestine-derived cholesterol accumulated in plasma and liver, leading to secondary feedback inhibition of hepatic SREBP2 activity. Pharmacological blockade of cholesterol absorption was unable to further induce the already elevated activities of SREBP-2 or HMGR in Insig-deficient enterocytes. These studies confirm the essential role of Insig proteins in the sterol homeostasis of enterocytes.     

Combinational effects of farnesoid X receptor antagonist and statin on plasma lipid levels and low-density lipoprotein clearance in guinea pigs

Aims

We previously reported anti-dyslipidemic effects of a farnesoid X receptor antagonist in monkeys. In this study, we compared the cholesterol-lowering effects of single and combined administration of a farnesoid X receptor antagonist, compound-T8, and the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor atorvastatin in a guinea pig model.

Main methods

Plasma levels of 7α-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7α-hydroxylase activity, were measured after a single administration of compound-T8. The effects of compound-T8 or atorvastatin on plasma cholesterol levels and low-density lipoprotein (LDL) clearance were investigated after 14 or 16 days of repeated dosing, respectively. Fractional catabolic rate of plasma LDL was estimated by intravenous injection of DiI-labeled human LDL. The cholesterol-lowering effects of combination therapy were investigated after 7 days of repeated treatment.

Key findings

Compound-T8 (10 and 30 mg/kg) increased plasma 7α-hydroxy-4-cholesten-3-one levels in a dose-dependent manner. Single administration of compound-T8 (30 mg/kg) and atorvastatin (30 mg/kg) reduced plasma non-high-density lipoprotein (non-HDL) cholesterol levels by 48% and 46%, respectively, and increased clearance of plasma DiI-labeled LDL by 29% and 35%, respectively. Compound-T8 (10 mg/kg) or atorvastatin (10 mg/kg) reduced non-HDL cholesterol levels by 19% and 25%, respectively, and combination therapy showed an additive effect and lowered cholesterol levels by 48%.

Significance

Similar to atorvastatin, compound-T8 reduced plasma non-HDL cholesterol levels accompanied with accelerated LDL clearance in guinea pigs. Combination therapy additively decreased plasma non-HDL cholesterol levels. Therefore, monotherapy with a farnesoid X receptor antagonist and combination therapy of a farnesoid X receptor antagonist with atorvastatin would be attractive dyslipidemia treatment options.     

海军飞行员血脂异常现状调查与防治

目的:调查海军飞行员血脂异常的现状,探讨血脂异常类型分布及其特点。方法:对随机抽取的海军飞行员查体资料进行分析,获取飞行员年龄、身高、体重、飞行机种、吸烟、饮酒情况及血脂水平,进行统计学处理。结果:海军飞行员血脂异常者46.0%(184/400),其中HDL-C异常者19.0%(76/400),TG异常者16.0%(64/400),TC异常者16.0%(64/400),LDL-C异常者2%(8/400)。20-29岁组与40-49岁组相比,TG、TC、HDL-C、LDL-C均有统计学差异(P0.05);BMI24组与BMI≥24组相比,TG、HDL-C有统计学差别(P0.05);吸烟组与不吸烟组相比,TG、HDL-C有统计学差别(P0.05);饮酒组与不饮酒组相比,TG、TC有统计学差别(P0.05)。结论:海军飞行员血脂异常问题突出,以HDL-C降低、TG及TC升高为主要血脂异常类型,年龄、吸烟、饮酒、超重可能是影响其血脂异常的主要因素。     

Association of circulating selenium concentration with dyslipidemia: Results from the NHANES

BackgroundObservational studies have suggested that selenium levels might associate with the risk of cardio-metabolic diseases, but how circulating selenium is related to dyslipidemia remains inconclusive.ObjectivesTo investigate the association of circulating selenium levels with lipid profiles and dyslipidemia among US adults.MethodsUsing the data collected from the National Health and Nutrition Examination Survey (NHANES 1999–2006), we performed multivariate logistic regression to examine the association of circulating selenium levels (in quartiles) with total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and atherogenic index (AI).ResultsWe included 2903 adults (49.3 % male) (average age: 61.9) for analysis. Circulating selenium had non-linear association with TC, LDL-C, HDL-C, and AI (all p < 0.05). When comparing with the lowest quartile, subjects with the highest quartile of circulating selenium (>147.00 μg/L) had the higher odds of elevated TG (OR: 1.75, 95% CI = 1.14, 2.68), TC (OR: 2.47, 95% CI = 1.62, 3.76), LDL-C (OR: 2.52, 95% CI = 1.60, 3.96), non-HDL-C (OR: 2.17, 95% CI = 1.41, 3.33), AI (OR: 1.20, 95% CI = 0.73, 1.97) and low-HDL-C (OR: 2.10, 95% CI = 1.19, 3.72). Similar patterns were observed in subgroup analysis.ConclusionsHigher circulating selenium levels had non-linear association with lipid profiles and the increased odds of dyslipidemia.     

Identification of six novel susceptibility loci for dyslipidemia using longitudinal exome-wide association studies in a Japanese population

Recent genome-wide association studies have identified various dyslipidemia-related genetic variants. However, most studies were conducted in a cross-sectional manner. We thus performed longitudinal exome-wide association studies of dyslipidemia in a Japanese population. We used ~244,000 genetic variants and clinical data of 6022 Japanese individuals who had undergone annual health checkups for several years. After quality control, the association of dyslipidemia-related phenotypes with 24,691 single nucleotide polymorphisms (SNPs) was tested using the generalized estimating equation model. In total, 82 SNPs were significantly (P < 2.03 × 10^?6) associated with dyslipidemia phenotypes. Of these SNPs, four (rs74416240 of TCHP, rs925368 of GIT2, rs7969300 of ATXN2, and rs12231744 of NAA25) and two (rs34902660 of SLC17A3 and rs1042127 of CDSN) were identified as novel genetic determinants of hypo-HDL- and hyper-LDL-cholesterolemia, respectively. A replication study using the cross-sectional data of 8310 Japanese individuals showed the association of the six identified SNPs with dyslipidemia-related traits.     

血脂异常相关酶的研究进展

血脂异常在临床上最常见的是高脂蛋白血症。随着经济的发展和人民生活水平的提高,高脂血症作为心脑血管疾病的重要危险因素,更加威胁着人类健康,对脂质异常和相关酶的研究也在逐渐深入。本文综述了几种与脂质代谢异常相关的关键酶及其研究进展。     

Lipoic acid improves hypertriglyceridemia by stimulating triacylglycerol clearance and downregulating liver triacylglycerol secretion

Elevated blood triacylglycerol (TG) is a significant contributing factor to the current epidemic of obesity-related health disorders, including type-2 diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. The observation that mice lacking the enzyme sn-glycerol-3-phosphate acyltransferase are protected from insulin resistance suggests the possibility that the regulation of TG synthesis be a target for therapy. Five-week-old Zucker Diabetic Fatty (ZDF) rats were fed a diet containing (R)-α-lipoic acid (LA, ∼200 mg/kg body weight per day) for 5 weeks. LA offset the rise in blood and liver TG by inhibiting liver lipogenic gene expression (e.g. sn-glycerol-3-phosphate acyltransferase-1 and diacylglycerol O-acyltransferase-2), lowering hepatic TG secretion, and stimulating clearance of TG-rich lipoproteins. LA-induced TG lowering was not due to the anorectic properties of LA, as pair-fed rats developed hypertriglyceridemia. Livers from LA-treated rats exhibited elevated glycogen content, suggesting dietary carbohydrates were stored as glycogen rather than becoming lipogenic substrate. Although AMP-activated protein kinase (AMPK) reportedly mediates the metabolic effects of LA in rodents, no change in AMPK activity was observed, suggesting LA acted independently of this kinase. The hepatic expression of peroxisome proliferator activated receptor α (PPARα) target genes involved in fatty acid β-oxidation was either unchanged or decreased with LA, indicating a different mode of action than for fibrate drugs. Given its strong safety record, LA may have potential clinical applications for the treatment or prevention of hypertriglyceridemia and diabetic dyslipidemia.     

Synthesis and pharmacological characterization of 1-benzyl-4-aminoindole-based thyroid hormone receptor β agonists

A series of 1-benzylindole-based TRβ agonists were prepared and evaluated. Compounds 11b′ and 11c′ were found to have cholesterol-lowering in a rat model with marginal effects on cardiac function and HPT axis. The present work illustrates the potential use of indoles as inner ring isosteres.     

National differences in screening programmes for cardiovascular risks could obstruct understanding of cardiovascular prevention studies in Europe

Introduction

In North-West Europe, cardiovascular disease is still a major cause of death and despite several efforts (e.g. European guidelines and conferences) cardiovascular risk factors are still inconsistently diagnosed and treated.

Methods

We evaluated the first consultations of patients in two cardiovascular referral clinics in France and the Netherlands, while evaluating the differences in national guidelines and between the profiles of patients at their first consultation.

Results

Notable differences exist between the two locally used guidelines in their programmes of cardiovascular risk assessment and their definition of LDL-cholesterol target levels. With regard to the LDL-cholesterol levels, more patients are ‘on target’ when using the French guideline than when using the Dutch guideline. Evaluation of the patient’s profile at first presentation showed that the LDL-cholesterol levels were significantly lower in the Dutch patients (n = 77) compared with the French patients (n = 119). Dutch patients used significantly more statins than French patients.

Conclusion

Despite the small study population included in this study, we found that comparison of daily care (as part of a primary prevention programme) is rather difficult due to several national differences in the approach to patients. All these factors combined should be taken into account, when discussing and extrapolating results obtained from analysis of cardiovascular prevention programmes.     

High Density Lipoprotein Protects against Polymicrobe-induced Sepsis in Mice

HDL has been considered to be a protective factor in sepsis; however, most contributing studies were conducted using the endotoxic animal model, and evidence from clinically relevant septic animal models remains limited and controversial. Furthermore, little is known about the roles of HDL in sepsis other than LPS neutralization. In this study, we employed cecal ligation and puncture (CLP), a clinically relevant septic animal model, and utilized apoA-I knock-out (KO) and transgenic mice to elucidate the roles of HDL in sepsis. ApoA-I-KO mice were more susceptible to CLP-induced septic death as shown by the 47.1% survival of apoA-I-KO mice versus the 76.7% survival of C57BL/6J (B6) mice (p = 0.038). ApoA-I-KO mice had exacerbated inflammatory cytokine production during sepsis compared with B6 mice. Further study indicated that serum from apoA-I-KO mice displayed less capacity for LPS neutralization compared with serum from B6 mice. In addition, apoA-I-KO mice had less LPS clearance, reduced corticosterone generation, and impaired leukocyte recruitment in sepsis. In contrast to apoA-I-KO mice, apoA-I transgenic mice were moderately resistant to CLP-induced septic death compared with B6 mice. In conclusion, our findings reveal multiple protective roles of HDL in CLP-induced sepsis. In addition to its well established role in neutralization of LPS, HDL exerts its protection against sepsis through promoting LPS clearance and modulating corticosterone production and leukocyte recruitment. Our study supports efforts to raise HDL levels as a therapeutic approach for sepsis.