Effects of plant stanol esters on serum cholesterol concentrations, relative markers of cholesterol metabolism and endothelial function in type 1 diabetes

We investigated the effect of plant stanol esters (STAEST) on serum total and LDL cholesterol concentrations and endothelial function in subjects with type 1 diabetes (T1D). In addition, the changes in the relative serum markers of cholesterol metabolism were recorded. In a parallel, randomized, double-blind study the intervention group (n = 11) consumed STAEST spread (2 g/day stanols) and the control group (n = 8) the same spread containing no added stanols for 12 weeks. At baseline, brachial artery diameter was negatively correlated with serum HDL cholesterol concentration (r = −0.476, P < 0.05), but not with total or LDL cholesterol concentrations or serum non-cholesterol sterol ratios to cholesterol. Flow-mediated dilatation was positively associated with serum absorption marker ratios to cholesterol, significantly so with the sitosterol ratio (r = 0.467, P < 0.05). During the intervention, serum total and LDL cholesterol concentrations were reduced by 4.9 and 6.9% from baseline in the STAEST group, and by 10.8 and 16.1% from controls, respectively (P < 0.05 for all). No significant changes in HDL cholesterol and serum triglyceride concentrations were found. The STAEST consumption reduced serum campesterol and sitosterol ratios by 17–21% (P < 0.05) from baseline, but the relative serum synthesis markers were not changed. Brachial artery diameter and flow-mediated dilatation did not change during the investigation. In conclusion, STAEST significantly reduced serum total and LDL cholesterol concentrations and serum plant sterol ratios without affecting HDL and triglyceride concentrations in subjects with T1D. STAEST had no effect on endothelial function.     

Comparison of the effects of dietary plant sterol and stanol esters on lipid metabolism

BACKGROUND AND AIM: To compare the cholesterol-lowering efficacy and other metabolic effects of plant sterol and stanol esters, both of which are commonly used in the dietary management of hypercholesterolaemia. METHODS AND RESULTS: The cholesterol-lowering efficacy of equivalent intakes of sterol and stanol esters and of different intakes of stanol esters were compared at 1 and 2 months, both in normal subjects and treated patients with familial hypercholesterolaemia. Systemic effects were assessed by measuring serum levels of plant sterols and of lathosterol and 7alpha-hydroxy-cholestenone, indices of sterol absorption and of cholesterol and bile acid synthesis respectively. There were no significant differences during the study between 1.6g daily of sterol and stanol esters in reducing total cholesterol (by 3-7%) or low density lipoprotein cholesterol (by 4-8%), nor between 1.6 and 2.6 g daily of stanol. However, the cholesterol-lowering effect of plant sterol esters was attenuated between 1 and 2 months. This was accompanied by increased serum plant sterols and decreased levels of 7alpha-hydroxy-cholestenone, especially in statin-treated hypercholesterolaemic patients not taking bile acid sequestrants. CONCLUSIONS: These findings suggest that absorption of dietary plant sterols suppressed bile acid synthesis, thereby diminishing their cholesterol-lowering efficacy. In contrast, plant stanols reduced plant sterol absorption and maintained their cholesterol-lowering efficacy.     

Effects of plant stanol esters supplied in low-fat yoghurt on serum lipids and lipoproteins, non-cholesterol sterols and fat soluble antioxidant concentrations.

Oil-based products enriched with plant stanol esters can lower low-density lipoprotein (LDL) cholesterol concentrations by 10-14%. Effectiveness of low-fat products, however, has never been evaluated, although such products fit into a healthy diet. We therefore examined the effects of plant stanol esters emulsified into low-fat yoghurt (0.7% fat) on fasting concentrations of plasma lipids and lipid-soluble antioxidants, which may also change by plant stanol consumption. Sixty non-hypercholesterolemic subjects first consumed daily three cups (3 x 150 ml) of placebo yoghurt for 3 weeks. For the next 4 weeks, 30 subjects continued with the placebo yoghurt, while the other 30 subjects received three cups of experimental yoghurt. Each cup provided 1 g of plant stanols (0.71 g sitostanol plus 0.29 g campestanol) as its fatty acid ester. LDL cholesterol (mean+/-S.D.) increased by 0.06+/-0.21 mmol/l in the placebo group, but decreased by -0.34+/-0.30 mmol/l in the experimental group. The difference in changes between the two groups of 0.40 mmol or 13.7% was highly significant (P<0.001; 95% confidence interval for the difference, (-)0.26 -(-)0.53 mmol/l). Effects were already maximal after 1 week. HDL cholesterol and triacylglycerol concentrations did not change. Total tocopherol levels increased by 1.43 micromol/mmol LDL cholesterol (14.0%, P=0.015). beta-carotene levels, however, decreased by -0.02 micromol/mmol LDL cholesterol (-14.4%, P=0.038). Decreases in absolute beta-carotene concentrations were found in all apoB-containing lipoproteins. LDL-cholesterol standardised phytofluene levels decreased by 21.4+/-25.7% (P<0.001), while other plasma carotenoid (lutein/zeaxanthin, beta-cryptoxanthin, lycopene and alpha-carotene) levels did not change significantly. We conclude that low-fat yoghurt enriched with plant stanol esters lowers within 1 week LDL cholesterol to the same extent as oil-based products. LDL-cholesterol standardised concentrations of tocopherol increased. The observed decrease in beta-carotene levels, as found in many other studies, appears not to be limited to the LDL fraction.     

Effects of growth hormone on glucose and fat metabolism in human subjects.

This article focuses on in vivo data from tests performed in normal subjects and in patients who had abnormal growth hormone (GH) status. Experimental data in human subjects demonstrate that GH acutely inhibits glucose disposal in skeletal muscle. At the same time GH stimulates the turnover and oxidation of free fatty acid (FFA), and experimental evidence suggests a causal link between elevated FFA levels and insulin resistance in skeletal muscle. Observational data in GH-deficient adults do not indicate that GH replacement is associated with significant impairment of glucose tolerance, but it is recommended that overdosing be avoided and glycemic control be monitored.     

Effects of cigarette smoking and dietary lipids on rat lipoprotein metabolism

The effects of cigarette smoke inhalation on rat lipoprotein metabolism have been examined. Rats were subjected to cigarette smoke exposure over a 3-week period (two 1-h sessions/day) using a Bat-Mason inhalation machine. Rats exposed to cigarette smoke showed a decrease in total serum triglyceride and an increase in very low density lipoprotein cholesterol (VLDL-C). Administration of cigarette smoke to rats fed a saturated fat and cholesterol enriched diet also led to an increase in VLDL-C and a decrease in total serum triglycerides compared to controls. In addition, cigarette smoke exposure to animals fed the lipid enriched diet caused a decrease in high density lipoprotein cholesterol (HDL-C). Pair-feeding experiments indicated that the increase in VLDL-C and the decrease in HDL-C could not be solely attributed to the reduction in food intake and the small decrease in growth rate observed following cigarette smoke exposure. The changes observed in VLDL-C and HDL-C are at least qualitatively similar to the changes seen in human smokers compared to non-smokers.     

Influence of menopause on blood cholesterol levels in women: the role of body composition, fat distribution and hormonal milieu

Objectives. In this study we investigated the relationships between blood lipids and menopausal status. Setting and subjects. All data were obtained from the first cross-sectional examination of the Virgilio Menopause Health Project in a large cohort of middle-aged women in pre, peri-, and postmenopausal age. The data refer to 426 women without metabolic or endocrine diseases, relevant hepatic, renal and cardiovascular abnormalities, none were dieting or taking medications. Main outcome measures. A precoded questionnaire including full clinical history, socio-economic and personal information, habitual diet, physical activity, drug use and smoking habits, careful recording of gynaecological events and family history for disease was completed. Several anthropometric parameters and the bioelectrical impedance analysis was used to measure free fatty mass. Blood samples for hormones and biochemistry were also obtained. Results. There were no significant differences on body mass index, fatty mass, free fatty mass and parameters of body fat distribution between the three groups. Again, there were no differences in smoking habits, dietary intake or indices of physical activity amongst the groups. There was a significant increase from pre to postmenopause of LH and FSH and a decrease of oestradiol and testosterone, whereas no difference was found in sex hormone-binding globulin. Age-adjusted values of glucose, triglycerides and high density lipoprotein (HDL-) cholesterol were similar in all groups, whereas postmenopausal women had significantly higher values of total and low density lipoprotein (LDL-) cholesterol. On the contrary, there was a significant fall in insulin levels passing from pre to postmenopause. In multiple regression models, total and LDL-cholesterol correlated positively with body mass index, waist-to-hip ratio and age, and negatively with free fatty mass and oestradiol blood levels. Conclusions. These results are consistent with the hypothesis that menopausal status may have a significant and independent effect in determining increased total and LDL-cholesterol concentrations in postmenopausal women.     

Effects of fat mass reduction by dieting and by lipectomy on carbohydrate metabolism in obese patients

Summary The interrelation of enlarged body fat mass (BFM) with reduced carbohydrate tolerance and hyperinsulinemia was studied in obese subjects with chemical diabetes. These patients were subjected to lipectomy following weight loss induced by a low-calorie, low-carbohydrate diet. An improvement in glucose tolerance and in insulin sensitivity and a reduction in insulin release during OGTT was observed after a diet-induced BFM loss of 9.9 ± 1.2 kg. Subsequent surgical reduction of BFM by 6.0 ± 0.5 kg had no further effect upon carbohydrate tolerance, insulin release or insulin sensitivity though a marked decrease in basal plasma FFA values was observed. These findings suggest that fat mass enlargementper se has no effect on blood glucose homeostasis after oral or i.v. loading. The improvement in carbohydrate tolerance and in insulin resistance usually observed following diet-induced loss of BFM seems to be due to the reduction in calorie and carbohydrate intake rather than to decrease of BFM. Preliminary results of this study were presented at the 9th Congress of the International Diabetes Federation, held in New Delhi in 1976 (abstract ≠ 333).     

利拉鲁肽对低脂联素血症小鼠胆固醇代谢相关基因的影响

目的 探讨利拉鲁肽(liraglutide)对脂联素基因表达缺陷ApoE基因敲除(ApoE-/-)小鼠胆固醇代谢相关基因的影响.方法 雄性ApoE-/-小鼠36只按随机数字表法随机分为单纯高脂喂养组(HF组,n=10)、空载腺病毒组(GFP组,n=6)、高脂+脂联素RNAi腺病毒组(ADI组,n=10)、利拉鲁肽治疗的高脂+脂联素RNAi腺病毒组(HEA组,n=10).采用扩展胰岛素钳夹术评价其胰岛素敏感性,酶联免疫法测定血浆脂联素水平,实时荧光定量PCR方法 检测肝脏组织胰岛素诱导基因1和2(INSIG1,INSIG2)、固醇调节元件结合蛋白1和2(SREBP-1,SREBP-2)、羟甲基戊二酸单酰辅酶A还原酶(HMGCR)和低密度脂蛋白受体(LDLR)mRNA表达.结果 ADI组血浆总胆固醇、甘油三酯、低密度脂蛋白胆固醇、空腹胰岛素和游离脂肪酸水平较其他3组显著升高(P＜0.01);而高密度脂蛋白胆固醇水平则显著降低(P＜0.05).ADI组血浆脂联素水平显著低于HEA、HF和GF组(P＜0.01).ADI组肝组织INSIG2和LDLR mRNA表达水平较其他3组显著降低(P＜0.01或P＜0.05);HEA组肝组织HMGCR 和SREBP-2 mRNA表达水平较其他3组明显升高(P＜0.01或P＜0.05);ADI、HF和GFP组HMGCR和SREBP-2 mRNA表达水平无明显差异.结论 利拉鲁肽可能通过上调脂联素水平调节胆固醇代谢相关基因的表达,从而改善胆固醇代谢紊乱.

Abstract：

Objective To investigate the effects of liraglutide on gene expression related to cholesterol metabolism in ApoE-/-mice with adiponectin deficiency. Methods Thirty six ApoE-/-mice fed with the high-fat diet were subdivided into four groups. One group was given 100 μl(1×109PFU) of adenoviral pAd-U6-GFP(GFP group, n=6). The second group received 100 μl of adenoviral pAd-U6-Acrp30(ADI group, n=10). The third group was given 100 μl of adenoviral pAd-U6-Acrp30 and liraglutide(HEA group, n=10) and the fourth group was given only 100 μl sterile saline(HF group, n=10). Insulin sensitivity and glucose metabolism were assessed by the hyperinsulinemic-euglycemic clamp technique using 3-[3H] glucose as a tracer. Plasma adiponectin level was evaluated using a commercially available ELISA kit. The mRNA expressions of genes involved in cholesterol metabolism were measured by quantitative realtime PCR. Results Fasting blood glucose(FBG), free fatty acids(FFA), total cholesterol, triglyceride, low density lipoprotein cholesterol, adiponectin, and fasting plasma insulin(FINS) in ADI mice were significantly higher than those in the other groups(P＜0.01), while high density lipoprotein cholesterol was significantly lower(P＜0.05). During the clamp, glucose infusion rate(GIR) in ADI group was significantly lower than the other groups(P＜0.01), and hepatic glucose production(HGP) significantly higher in ADI group(P＜0.01). The mRNA expressions of INSIG2 and LDLR in ADI group were significantly down-regulated in HEA group(P＜0.01 or P＜0.05), while HMGCR and SREBP-2 were significantly up-regulated in HEA group(P＜0.01 or P＜0.05). Conclusions Liraglutide regulates a number of genes involved in cholesterol metabolism and ameliorates hypercholesterolemia by elevating plasma adiponectin level.     

Effect of dalcetrapib, a CETP modulator, on non-cholesterol sterol markers of cholesterol homeostasis in healthy subjects

Objective

Subjects with high HDL-C show elevated plasma markers of cholesterol absorption and reduced markers of cholesterol synthesis. We evaluated the effect of dalcetrapib, a cholesteryl ester transfer protein modulator, on markers of cholesterol homeostasis in healthy subjects.

Methods

Dalcetrapib was administered daily with or without ezetimibe in a randomized, open-label, crossover study in 22 healthy subjects over three 7-day periods: dalcetrapib 900 mg, ezetimibe 10 mg, dalcetrapib 900 mg plus ezetimibe 10 mg. Plasma non-cholesterol sterols lathosterol and desmosterol (cholesterol synthesis markers) and campesterol, β-sitosterol and cholestanol (intestinal cholesterol absorption markers) were measured. A hamster model was used to compare the effect of dalcetrapib and torcetrapib with or without ezetimibe on these markers and determine the effect of dalcetrapib on cholesterol absorption.

Results

Dalcetrapib increased campesterol, β-sitosterol, and cholestanol by 27% (p = 0.001), 32% (p < 0.001), and 12% (p = 0.03), respectively, in man (non-cholesterol sterol/cholesterol ratio). Dalcetrapib + ezetimibe reduced campesterol by 11% (p = 0.02); β-sitosterol and cholestanol were unaffected. Lathosterol and desmosterol were unchanged with dalcetrapib, but both increased with ezetimibe alone (56–148%, p < 0.001) and with dalcetrapib + ezetimibe (32–38%, p < 0.001). In hamsters, dalcetrapib and torcetrapib increased HDL-C by 49% (p = 0.04) and 72% (p = 0.003), respectively. Unlike torcetrapib, dalcetrapib altered cholesterol homeostasis towards increased markers of cholesterol absorption; cholesterol synthesis markers were unaffected by either treatment. Dalcetrapib did not change plasma ³H-cholesterol level but increased ³H-cholesterol in plasma HDL vs non-HDL, after oral dosing of labeled cholesterol.

Conclusion

Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis.     

Action of insulin and glucose on the re-esterification rate of free fatty acids in isolated human fat cells

Summary In isolated human fat cells of the greater omentum and the mammary gland, the effect of glucose, fructose, and/or insulin was tested on the re-esterification rate of FFA measured by the balance method. It could be shown that in the absence of glucose no re-esterification activity was demonstrable. Glucose alone or fructose alone stimulated the re-esterification of FFA dose-dependently in isolated fat cells of the greater omentum, and to a minor degree in fat cells of the mammary gland. Insulin had no effect on the re-esterification rate of FFA in the presence or absence of glucose or fructose, whereas it significantly stimulated the incorporation of glucose-C into CO₂ and lipids. It is concluded that the re-esterification of FFA in human adipose tissue, at least in vitro, is mainly controlled by glucose without need for insulin.Preliminary results of this investigation were presented at the 6th Annual Meeting of the EASD, Warsaw, 1970.     

Role of central and peripheral aminopeptidase activities in the control of blood pressure: a working hypothesis

Although there is a large body of knowledge on protein synthesis, the available data on protein catabolism, although quite substantial, are still inadequate. This is due to the marked differences in the activity of proteolytic enzymes, compounded by different substrate specificities and multiple environmental factors. Understanding enzyme behavior under physiological and pathological conditions requires the identification of specific proteolytic activities, such as aminopeptidases, as able to degrade certain peptidergic hormones or neuropeptides. Another requirement is the isolation, purification and characterization of the enzymes involved. In addition, systematic studies are needed to determine each enzyme’s subcellular location, tissue distribution, and the influence of environmental factors such as diurnal rhythm, age, gender, diet, cholesterol, or steroids. Central and peripheral aminopeptidases may play a role in the control of blood pressure by coordinating the effect of the different peptides of the renin–angiotensin system cascade, acting through the AT₁, AT₂, and AT₄ receptors. Our review of the available data suggests the hypothesis that cholesterol or steroids, particularly testosterone, significantly influence aminopeptidase activities, their substrate availability and consequently their functions. These observations may have relevant clinical implications for a better understanding of the pathophysiology of cardiovascular diseases, and thus for their treatment with aminopeptidase inhibitors.     

不对称二甲基精氨酸对THP-1巨噬细胞源性泡沫细胞内胆固醇含量的影响

目的 观察不对称二甲基精氨酸（ADMA）对THP-1巨噬细胞源性泡沫细胞内胆固醇含量的影响.方法 THP-1单核细胞给予160nmol/L佛波酯（PMA）孵育48h,诱导分化成巨噬细胞,与80mg/L氧化型低密度脂蛋白（ox-LDL）孵育24h,使巨噬细胞转化为泡沫细胞,用油红O染色在光镜下鉴定泡沫细胞形态及变化.再以不同浓度ADMA（1μmol/L、5μmol/L、10μmol/L、20μmol/L、30μmol/L）作用泡沫细胞24h,以20μmol/L ADMA作用泡沫细胞不同时间（0h,6h,12h,24h,48h）,酶比色法检测泡沫细胞内胆固醇的含量.结果 ①单核细胞加人PMA诱导48h后,分化为巨噬细胞,再经ox-LDL诱导24h后转化为泡沫细胞.②与对照组相比,5μmol/L、10μmol/L、20μmol/L,30μmol/L的ADMA作用于,THP-1巨噬细胞源性泡沫细胞24h后,细胞内胆固醇含量均明显增加（P＜0.01）,③与对照组相比,20μmol/L的ADMA作用于THP-1巨噬细胞源性泡沫细胞12h,24h,48h,细胞内胆固醇含量均明显增加（P＜0.01）.结论 ①单核细胞株THP-1经PMA诱导后,可分化为巨噬细胞,再经ox-LDL诱导后,可转化为泡沫细胞.②ADMA可以增加THP-1巨噬细胞源性泡沫细胞内胆固醇的含量.     

高脂喂养对ApoE基因敲除小鼠胆固醇代谢相关基因表达的影响

建立高脂诱导载脂蛋白E基因敲除(ApoE-/-)小鼠胰岛素抵抗模型,探讨其对胆固醇代谢相关基因表达的影响.结果 显示高脂喂养组ApoE-/-小鼠空腹血糖、游离脂防酸、总胆固醇、甘油三酯、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)和空腹血浆胰岛素水平明显高于对照组(均P＜0.01);肝组织中INSIG2和SCAP mRNA明显升高(P＜0.05或P＜0.01),肝INSIG2蛋白水平也明显增高(P＜0.05);而SREBP1 mRNA表达明显降低(P＜0.05).这些改变可能在该小鼠模型胆固醇代谢紊乱和胰岛素抵抗的发生中具有一定的作用.

Abstract：

To investigate the effect on gene expression related cholesterol metabolism in ApoE-/- mice with high-fat-induced insulin resistance(IR). In high-fat fed mice, FBG, FFA, TC, TG, LDL-C, HDL-C, and fasting plasma insulin were significantly higher than those of controls(P＜0.01). The INSIG2 and SCAP mRNA expressions in liver were significantly increased in high-fat fed mice compared with controls(P＜0. 05 or P＜0.01), and INSIG2 protein levels also increased(P＜0. 05). But SREBP1 mRNA expression in liver of high-fat fed mice was significantly reduced(P＜0. 05). These changes might contribute to IR and disorder of cholesterol metabolism in high-fat fed ApoE-/- mice.     

Effects of a high fat diet on intestinal microbiota and gastrointestinal diseases

Along with the rapid development of society, lifestyles and diets have gradually changed. Due to overwhelming material abundance, high fat, high sugar and high protein diets are common. Numerous studies have determined that diet and its impact on gut microbiota are closely related to obesity and metabolic diseases. Different dietary components affect gut microbiota, thus impacting gastrointestinal disease occurrence and development. A large number of related studies are progressing rapidly. Gut microbiota may be an important intermediate link, causing gastrointestinal diseases under the influence of changes in diet and genetic predisposition. To promote healthy gut microbiota and to prevent and cure gastrointestinal diseases, diets should be improved and supplemented with probiotics.     

Effects of sucrose polyester on cholesterol metabolism in man

Sucrose polyester (SPE) is a nonabsorbable, fat-like material that has been shown to lower plasma cholesterol levels in man and that has a high degree of patient acceptability. This study was carried out to examine further its effects on lipid metabolism. We have investigated the action of feeding SPE on plasma levels of cholesterol, triglycerides, and fatsoluble vitamins, on cholesterol absorption, excretion and synthesis, and on biliary lipid composition. Eleven normolipidemic, overweight subjects were studied on the metabolic ward. The design consisted of a 6-wk control period (weight loss at 1000 cal/day) and a 6-wk period of SPE supplementation (also with 1000 cal/day). SPE was tolerated well by all patients; although each patient experienced some degree of increased frequency of stools during the test period, none averaged more than one stool per day during SPE treatment. SPE feeding caused an overall mean reduction in plasma cholesterol of 6.8% beyond the 20% reduction caused by weight loss and low-cholesterol diet alone. Of the 11 patients, 6 had a mean decrease in plasma cholesterol of 12.5%, while 5 did not show a reduction on SPE. Plasma triglyceride levels were reduced initially by 13% during weight loss, and the addition of SPE caused no further reduction. There was no consistent effect on plasma levels of Vitamin A; Vitamin E levels were reduced by 24%. SPE diminished percent cholesterol absorption in every patient tested (control = 38%; SPE feeding = 17%), and there was an overall net increase in neutral sterol excretion (control = 506 mg/day, SPE feeding = 724 mg/day). Bile acid excretion similarly increased (control = 225 mg/day, SPE feeding = 376 mg/day). Percent saturation of gallbladder bile was not adversely affected by sucrose polyester feeding during weight loss.     

Effects of total fat content and fatty acid composition in diet on factor VII coagulant activity and blood lipids

In a strictly controlled cross-over study (twice 2 weeks) of 11 healthy adults, the effects of a low-fat diet (32% of total energy from fat) with a low or a high ratio of polyunsaturated to saturated fatty acids (0.28 and 0.89, respectively) were observed. Factor VII activity and antigen levels, serum cholesterol, HDL-cholesterol and triglycerides were measured. Factor VII activity was determined in clotting assays using human and bovine thromboplastin (interacting primarily with activated factor VII, F VIIa), allowing differentiation between F VIIc and F VIIa. A significant decrease of F VII levels (median 11.0–14.5%, P < 0.05) and triglycerides (median 0.22–0.27 mmol/1, P < 0.05) was observed on both diets, while only the highly unsaturated diet reduced serum cholesterol levels (median 0.65 mmol/1, P < 0.001). There were no significant correlations between changes in blood lipids and F VIIc. Low fat diets may reduce the risk for ischemic heart disease without lowering of cholesterol levels by eliminating states of hypercoagulability such as elevated factor VII coagulant activity.