Hepatic cholesterol and bile acid synthesis in Japanese patients with cholesterol gallstones

In Japan the composition of gallstones is changing rapidly from the once-predominant brownpigment stones to cholesterol ones. The present work was undertaken to clarify the mechanism of cholesterol supersaturated bile production in Japanese patients with cholesterol gallstones. In 26 non-obese and normolipidemic patients (11 with cholesterol gallstones, 8 with black- or brown-pigment gallstones, 7 without gallstones) a liver biopsy and hepatic bile were surgically obtained under standardized conditions. The cholesterol saturation of hepatic bile was significantly higher in cholesterol gallstone patients than in gallstone-free controls (195 ±10 vs. 146 ±8%, respectively; P < 0.01). The microsomal activities of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol synthesis, cholesterol 7 α-hydroxylase, the rate-limiting enzyme for bile acid synthesis, and 7 α-hydroxy-4-cholesten-3-one 12 α-hydroxylase (12 α-hydroxylase), the rate-limiting enzyme for cholic acid synthesis, were assayed simultaneously in the same subjects. There were positive correlations between HMG-CoA reductase and cholesterol 7 α-hydroxylase activities (Rs = 0.62, P < 0.005), and between cholesterol 7 α-hydroxylase and 12 α-hydroxylase activities (Rs = 0.44, P < 0.05) in all subjects, irrespective of the existence of gallstones. The activities of the three rate-limiting enzymes did not differ significantly among the three groups (cholesterol stone, pigment stone and stone-free). In conclusion, the cholesterol supersaturation of hepatic bile in nonobese and normolipidemic Japanese patients with cholesterol gallstones does not result from an increased hepatic cholesterol synthesis or a decreased bile acid synthesis. This study was supported in part by a Grant-in-Aid for Scientific Research (No. 02454226) from the Ministry of Education, Science and Culture of Japan, and a grant from University of Tsukuba Project Research.     

中国9省/自治区成年居民膳食胆固醇摄入与高胆固醇血症关系的前瞻性研究

目的 探讨成年居民膳食胆固醇摄入与高胆固醇血症的关系. 方法 利用“中国健康与营养调查”数据,本研究中纳入的研究对象为同时参加2004年和2009年2轮调查、且在2009年调查时年龄为25～65岁、血样检测和膳食调查数据完整的成年居民,共4 244人.以《中国成人血脂异常防治指南2007》为标准,血清TC≥6.22 mmol/L时,判定为高胆固醇血症.采用非条件logistic回归方法,研究膳食胆固醇摄入与高胆固醇血症的关系.结果 2009年成年居民平均血清TC水平为4.9 mmol/L,高胆固醇血症患病率为9.6%.2004－2009年膳食胆固醇摄入量总体呈大幅增长,尤其是低摄入量组的增幅最大.男性成年居民中2004年膳食胆固醇摄入中低水平者和2009年膳食胆固醇摄入高水平者,高胆固醇血症患病风险增加.女性膳食胆固醇摄入与高胆固醇血症之间未见统计学关联.结论 膳食胆固醇摄入与高胆固醇血症的关系具有性别差异.膳食胆固醇摄入水平升高,可增加男性居民发生高胆固醇血症的危险性.     

Search for familial hypercholesterolemia patients in an Italian community: A real-life retrospective study

Background and aimsFamilial hypercholesterolemia (FH) is a common inherited disorder of low-density lipoprotein (LDL) catabolism that causes elevated LDL-cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease (ASCVD). Despite the availability of effective treatments, FH remains underdiagnosed and undertreated. The aims of the study were to identify putative FH subjects using data from laboratory and cardiology databases, genetically characterize suspected FH patients referred to the Lipid Clinic and monitor attainment of treatment goals in identified patients.Methods and resultsWe retrieved the electronic health records of 221,644 individuals referred to laboratory for routine assessment and of 583 ASCVD patients (age ≤65) who underwent percutaneous transluminal coronary angioplasty (PTCA). We monitored the lipid profiles of subjects with LDL-C ≥ 250 mg/dl identified by laboratory survey (LS-P), PTCA patients and patients from the Lipid Clinic (LC-P). The laboratory survey identified 1.46% of subjects with LDL-C ≥ 190 mg/dl and 0.08% with LDL-C ≥ 250 mg/dl. Probable/definite FH was suspected in 3% of PTCA patients. Molecularly-confirmed FH was found in 44% of LC-P subjects. Five new LDLR mutations were identified. The 50% LDL-C reduction target was achieved by 70.6% of LC-P patients. Only 18.5% of PTCA patients reached the LDL-C < 55 mg/dl target.ConclusionBy using a combined approach based on laboratory lipid profiles, documented ASCVD and Lipid Clinic data, we were able to identify subjects with a high probability of being FH. Attainment of LDL-C goals was largely suboptimal. Efforts are needed to improve FH detection and achievement of lipid targets.     

Effect of dietary macronutrients on intestinal cholesterol absorption and endogenous cholesterol synthesis: a randomized crossover trial

Background and aimsExtensive research showed a diurnal rhythm of endogenous cholesterol synthesis, whereas recent research reported no diurnal rhythm of intestinal cholesterol absorption in males who consumed low-fat meals. Little is known about the acute effect of macronutrient consumption on cholesterol metabolism, and hence if meal composition may explain this absence of rhythmicity in cholesterol absorption. Therefore, we examined the effect of a high-fat, high-carbohydrate, and high-protein meal on postprandial intestinal cholesterol absorption and endogenous cholesterol synthesis in apparently healthy overweight and slightly obese males.Methods and resultsEighteen males consumed in random order an isoenergetic high-fat, high-carbohydrate, and high-protein meal on three occasions. Serum total cholesterol concentrations, cholesterol absorption markers (campesterol, cholestanol, and sitosterol), and cholesterol synthesis intermediates (7-dehydrocholesterol, 7-dehydrodesmosterol, desmosterol, dihydrolanosterol, lanosterol, lathosterol, zymostenol, and zymosterol) were measured at baseline (T0) and 240 min postprandially (T240). Meal consumption did not significantly change total cholesterol concentrations and cholesterol absorption marker levels (all p > 0.05). Serum levels of 7-dehydrocholesterol, lanosterol, lathosterol, zymostenol, and zymosterol decreased significantly between T0 and T240 (all p < 0.05). These decreases were not significantly different between the three meals (all p > 0.05), except for a larger decrease in dihydrolanosterol levels after the high-fat versus the high-carbohydrate meal (p = 0.009).ConclusionThe high-fat, high-carbohydrate, and high-protein meal did not significantly influence postprandial intestinal cholesterol absorption. Several cholesterol synthesis intermediates decreased postprandially, but the individual macronutrients did not differentially affect these intermediates, except for a possible effect on dihydrolanosterol.Trial registrationClinicalTrials.gov, NCT03139890.     

高密度脂蛋白胆固醇对行根治性治疗的酒精相关性肝细胞癌患者预后的影响

目的探索高密度脂蛋白胆固醇(HDL-C)与根治性治疗后酒精相关性肝细胞癌(HCC)患者预后的关系。方法回顾性分析2008年1月—2015年7月解放军总医院第五医学中心收治的43例接受根治性治疗的酒精相关性HCC患者临床资料,根据HDL-C水平分为正常组(n=26)及异常组(n=17)。比较2组间基本信息、实验室检验指标、影像学相关指标、肿瘤BCLC分期和肝功能Child-Pugh分级的差异。符合正态分布的计量资料2组间比较采用t检验,不符合正态分布的计量资料2组间比较采用Mann-Whithey U检验;计数资料2组间比较采用χ2检验。Kaplan-Meier法绘制生存曲线,组间比较采用log-rank检验。采用单因素和多因素Cox比例风险模型探索预后相关的独立危险因素。结果2组间前白蛋白比较差异有统计学意义[(162.38±60.86)mg/L vs(120.06±64.08)mg/L,t=2.184,P=0.035];肿瘤数目(HR=2.839,95%CI:1.120~7.200,P=0.028)、肿瘤大小(HR=2.634,95%CI:1.062~6.529,P=0.037)及HDL-C水平(HR=2.400,95%CI:1.040~5.537,P=0.040)是影响酒精相关性HCC患者总生存期的独立危险因素。HDL-C正常组的1、3、5年累积生存率分别为88.5%、72.4%、55.7%,HDL-C异常组分别为70.6%、43.7%、17.5%,2组累积生存率差异有统计学意义(χ2=5.881,P=0.015)。结论HDL-C水平的降低可能预示酒精相关性HCC患者预后较差。     

替米沙坦诱导大鼠肝细胞自噬促进肝脏胆固醇代谢的机制研究

目的探讨替米沙坦诱导大鼠肝细胞自噬对肝脏胆固醇代谢的影响及作用机制。方法将肝脏原代细胞分为正常对照组(Con)、替米沙坦1μmol/L组(Tel 1组)、替米沙坦3μmol/L组(Tel 3组)、替米沙坦10μmol/L组(Tel 10组)、替米沙坦10μmol/L联合PPARγ抑制剂GW 9662组(Tel+G组)。Tel 1、Tel 3、Tel 10组分别按1、3、10μmol/L浓度加入替米沙坦,Tel+G组加入10μmol/L替米沙坦及PPARγ抑制剂GW9662,培养24 h。检测肝细胞胆固醇浓度,Western blot法检测微管相关蛋白轻链3(LC3)、自噬蛋白区域(Beclin-1)、腺苷酸活化蛋白激酶(AMPK)、雷帕霉素靶分子(mTOR)表达水平。结果 Tel 3、Tel 10组胆固醇水平低于Con、Tel 1组(P<0.05)。Tel 1、Tel 3、Tel 10组LC3Ⅱ/Ⅰ比值、Beclin-1蛋白水平依次升高(P<0.05)。与Con、Tel 1组比较,Tel 3、Tel 10组p-AMPK/AMPK蛋白比值升高(P<0.05),p-mTOR/mTOR蛋白比值降低(P<0.05)。与Tel 10组比较,Tel+G组胆固醇水平、p-mTOR/mTOR蛋白比值升高(P<0.05),LC3II/I比值、p-AMPK/AMPK蛋白水平降低(P<0.05)。结论替米沙坦可通过诱导大鼠肝细胞自噬影响肝脏细胞胆固醇代谢,其机制可能与激活AMPK/mTOR途径和上调PPARγ有关。     

近交系NJS小鼠红细胞变形能力及其与血清胆固醇水平的关系

本文观察近交系NJS小鼠红细胞变形能力及其与血清胆固醇的关系。以DXC—300型核孔膜红细胞变形能力测定仪测定小鼠的红细胞变形指数（EFI），同时以日立7150型血液自动生化分析仪测定血清胆固醇（CHO）含量，并以C57BL／6J正常小鼠作对照。结果表明：NJS／小鼠EFI（0．29±0．06）显著高于C57BL／6J小鼠（0．20±0．10，P＜0．01），小鼠EFI与CHO水平呈正相关（r＝0．785，P＜0．01）。提示：红细胞变形能力受损可能在高胆固醇血症小鼠动脉粥样硬化的发病过程中起重要作用。     

Functional pasta consumption in healthy volunteers modulates ABCG1-mediated cholesterol efflux capacity of HDL

Backgrounds and aimsPrevention of cardiovascular (CV) disease is considered a central issue in public health and great attention is payed to nutritional approaches, including consumption of functional foods to reduce CV risk in individuals without indications for anti-atherosclerotic drugs. Cholesterol efflux capacity (CEC) is an important anti-atherogenic property of HDL and a marker of CV risk. We evaluated the effect of a daily consumption of an innovative whole-wheat synbiotic pasta, compared to a control whole-wheat pasta, on serum ATP binding cassette G1 (ABCG1)-mediated CEC in healthy overweight or obese individuals.Methods and resultsStudy participants (n = 41) were randomly allocated to either innovative or control pasta, consumed daily for twelve weeks. Serum CEC was measured before and after the dietary intervention, by a well-established radioisotopic technique on Chinese Hamster Ovary Cells transfected with human ABCG1. The innovative synbiotic pasta consumption was associated to a significantly higher post treatment/baseline ratio of ABCG1-mediated CEC values with respect to control pasta (mean ratio 1.05 ± 0.037 and 0.95 ± 0.042 respectively, p < 0.05). Analysis of the relationship between ABCG1-mediated CEC and glycemia, homocysteine, total folates and interleukin-6 showed specific changes in the correlations between HDL function and glycemia, oxidative and inflammatory markers only after synbiotic pasta consumption.ConclusionThis is the first report on serum CEC improvement obtained by a new synbiotic functional pasta consumption, in absence of lipid profile modifications, in overweight/obese participants. This pilot study suggests that a simple dietary intervention can be a promising approach to CV preservation through improving of athero-protective HDL function.     

Lowering cholesterol: effects on trauma death, cancer death and total mortality

Randomised trials of cholesterol reduction (26 trials, 50 000 patients, net cholesterol reduction ～10%) have demonstrated a clear reduction in the incidence of coronary heart disease (CHD) after just a few years of treatment. Overall, the reduction in CHD death was only half as large as the reduction in non-fatal myocardial infarction (MI), although both were statistically significant (2P < 0.005). In these trials, 60% of all deaths were from CHD, and since treatment reduced these by about 10%, the expected reduction in total deaths was about 6%. This expected reduction falls within the 95% confidence interval of the observed effect of cholesterol reduction on total mortality in these trials. There were small excesses of deaths from cancer and deaths from trauma among patients allocated active treatment. However, in no single trial, nor in the trials collectively, were these increases statistically significant. Furthermore, the increases did not appear to be specific to any one agent nor were the increases consistent between trials of the same agent. These observations are consistent with the hypothesis that the small excesses of cancer and trauma deaths observed in the cholesterol reduction trials occurred by chance.