Applicability of non-cholesterol sterols in predicting response in cholesterol metabolism to simvastatin and fluvastatin treatment among hypercholesterolemic men

Background and aimsWe hypothesized that (I) certain features in cholesterol metabolism at baseline could predict a response to statins, (II) good and poor responders to statins have a differential profile of serum and fecal sterols and (III) serum non-cholesterol sterols reflect cholesterol metabolism on statins.Methods and resultsWe examined serum lipids, serum and fecal cholesterol, cholesterol precursors, cholestanol and phytosterols and cholesterol metabolism among 20 hypercholesterolemic men at baseline and on 16-wk simvastatin/fluvastatin treatment.At baseline, the mean of serum cholestanol/cholesterol was 11% lower but those of lathosterol/cholesterol, lathosterol/cholestanol, desmosterol/cholesterol, desmosterol/cholestanol were 36–65% higher among good than poor responders (p < 0.05 for each). On statins, reductions in ratios of serum precursor sterols and increases of absorption sterols were 1.8–2.9 times higher among good than poor responders (p < 0.05 for each). In the whole study group, changes from baseline values of lathosterol/cholestanol were related to those of cholesterol and LDL-C in serum (r = +0.513 and +0.451, p = 0.021 and 0.046, respectively). Serum lathosterol ratios to cholesterol, cholestanol and sitosterol consistently reflected a ratio of cholesterol synthesis (mg/d/kg)/fractional cholesterol absorption (%) (r-range +0.456 to +0.727, p < 0.05 for each).ConclusionsLow serum baseline ratios to cholesterol of lathosterol, cholestenol and desmosterol, but a high ratio of cholestanol predicted a poor response to statins. Good responders were characterized by more profound reductions of serum and fecal (lathosterol) precursor sterols and increases of serum absorption marker sterol ratios on statins. Serum surrogate sterol markers of cholesterol metabolism were applicable in evaluating cholesterol absorption and synthesis also on statins.     

Plasma proprotein convertase subtilisin kexin type 9 levels are related to markers of cholesterol synthesis in familial combined hyperlipidemia

Background and aimsTwo recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL.Methods and resultsMarkers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001).ConclusionsThe present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.     

Non-cholesterol sterols in different forms of primary hyperlipemias

Background and AimsWe investigated the behaviour of non-cholesterol sterols, surrogate markers of cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol), in primary hyperlipemias.Methods and resultsWe studied 53 patients with polygenic hypercholesterolemia (PH), 38 patients with familial combined hyperlipemia (FCH), and 19 age- and sex-matched healthy control subjects. In all participants, plasma sitosterol, campesterol and lathosterol were determined by gas chromatography coupled to mass spectrometry. To correct for the effect of plasma lipid levels, non-cholesterol sterol concentrations were adjusted for plasma cholesterol (10² μmol/mmol cholesterol). Patients with FCH were more frequently men, and had higher body mass index (BMI), fasting glucose, insulin and HOMA-IR. Lathosterol was higher in FCH than in pH or controls (p < 0.05). Campesterol was significantly lower in FCH (p < 0.05), while no differences were found between pH and controls. Sitosterol displayed higher values in pH compared to FCH (p < 0.001) and controls (p < 0.05). Spearman’s rank correlations showed positive correlations of lathosterol with BMI, waist circumference, HOMA-IR, triglycerides, apoprotein B, and a negative one with HDL-cholesterol. Sitosterol had a negative correlation with BMI, waist circumference, HOMA-IR, triglycerides, and a positive one with HDL-cholesterol and apoprotein AI. Multivariate regression analyses showed that cholesterol absorption markers predicted higher HDL-cholesterol levels, while HOMA-IR was a negative predictor of sitosterol and BMI a positive predictor of lathosterol.ConclusionsOur findings suggest the occurrence of an increased cholesterol synthesis in FCH, and an increased cholesterol absorption in pH. Markers of cholesterol synthesis cluster with clinical and laboratory markers of obesity and insulin resistance.     

Alterations of cholesterol synthesis and absorption in obstructive sleep apnea: Influence of obesity and disease severity

Background and aimsObstructive sleep apnea (OSA) is closely linked to obesity and related adverse metabolic changes, including dyslipidemia. However, it is not clear whether OSA is an independent contributing factor to dyslipidemia, or the observed association is a reflection of a concomitant presence of obesity. Additionally, dyslipidemia is usually evaluated through measurement of parameters of routine lipid status, while more precise evaluation of lipid homeostasis is rarely performed in OSA. In this study, we analyzed markers of cholesterol synthesis and absorption in patients with OSA with respect to the presence of obesity and the disease severity.Methods and resultsThis study enrolled 116 OSA patients. Concentrations of non-cholesterol sterols (NCS), measured by LC-MS/MS, were used as markers of cholesterol synthesis and absorption. Apnea-hypopnea index (AHI) and oxygen saturation (SaO₂) were utilized as markers of OSA severity. Serum lipid status parameters were determined by routine enzymatic methods. Markers of cholesterol synthesis were increased (P = 0.005), whilst markers of cholesterol absorption decreased (P = 0.001) in obese OSA patients. Cholesterol synthesis/absorption ratio was elevated in obese subjects (P < 0.001). Concentration of cholesterol synthesis marker lathosterol was significantly higher in subjects with severe OSA (P = 0.014) and we observed a trend of decreased cholesterol absorption in these patients. AHI was revealed as an independent determinant of lathosterol concentration (P = 0.022).ConclusionsOur results suggest that the presence of obesity and severe forms of OSA is characterized by elevated endogenous cholesterol synthesis. AHI was singled out as an independent determinant of the serum level of cholesterol synthesis marker lathosterol.     

Cholesterol,non-cholesterol sterols and bile acids in paediatric gallstones

BackgroundDepending on underlying aetiopathogenetic factors human gallstones contain various amounts of cholesterol, non-cholesterol sterols and bile acids, which have remained unexplored in paediatric gallstone patients.AimsTo evaluate sterol and bile acids compositions of paediatric gallstones.Patients and methodsStudy group included 21 consecutively cholecystectomised children. Gas–liquid chromatography was used to quantitate gallstone sterols and bile acids. Results were compared to adult gallstones (n = 194).ResultsCholesterol stones (n = 9) had higher proportions of cholestenol and lathosterol, but lower those of lanosterol and phytosterols than pigment stones (n = 12) (p < 0.05 for each). Patients with gallstone cholesterol content over 70% were female. Gallstone cholesterol positively reflected body mass index and, in cholesterol stones-group, age (r = ∼+0.700, p < 0.05). Three patients on parenteral nutrition had brown pigment stones consisting of high amounts of campesterol and sitosterol ranging 483–9303 μg/100 mg of stone. Pigment stones had 13-fold higher amount of bile acids than cholesterol stones (p < 0.05). Black pigment stones contained ∼3-fold higher phytosterol proportions, and pigment stones and cholesterol stones had ∼43% lower proportions of deoxycholic acid than adults (p < 0.05).ConclusionGallstones in patients on parenteral nutrition are rich in phytosterols. With respect to gallstone sterols, gallstone disease of adolescent girls resembles that of adults. Composition of bile acids in paediatric gallstones is different from adults.     

Impact of buttermilk consumption on plasma lipids and surrogate markers of cholesterol homeostasis in men and women

Background and aimsSphingolipids (SL) are important components of the milk fat globule membrane (MFGM) found in buttermilk. While studies in animal models suggest that dietary SL may have cholesterol-lowering properties, data in human are lacking. The aim of this study was to investigate the impact of buttermilk consumption on plasma lipids and surrogate markers of cholesterol (C) homeostasis in humans.Methods and resultsMen and women (n = 34) with serum LDL-C <5.0 mmol/L at screening (mean LDL-C = 3.8 mmol/L) were recruited in this double-blinded randomized crossover placebo controlled study. Their diets were supplemented with 45 g/d of buttermilk and with 45 g/d of a macro/micronutrient matched placebo (4 weeks each in random order). Serum lipid concentrations and surrogate markers of cholesterol homeostasis were measured post diet and compared using mixed models for repeated measures. Consumption of buttermilk led to reduction in serum cholesterol (?3.1%, P = 0.019), LDL-C (?3.1%, P = 0.057) and triacylglycerol (?10.7%, P = 0.007). Buttermilk consumption increased plasma lathosterol concentrations (+12.1%, P = 0.001), but multiple regression analysis indicated that variations in β-sitosterol concentrations (P = 0.002) were the only significant predictor of the LDL-C response to buttermilk consumption.ConclusionButtermilk consumption may be associated with reduced cholesterol concentrations in men and women, primarily through inhibition of intestinal absorption of cholesterol.Registration numberThis trial is registered at clinicaltrials.gov as NCT01248026.     

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.     

Enhanced cholesterol efflux to HDL through the ABCA1 transporter in hypertriglyceridemia of type 2 diabetes

ObjectiveOur objective was to examine the role of hypertriglyceridemia on the capacity of HDL to facilitate ABCA-1 mediated cholesterol efflux in type 2 diabetes (T2DM).MethodsHDL mediated cholesterol efflux through the ABCA-1 transporter was measured using BHK cell lines in samples of 71 participants with T2DM in the presence or absence of high triglyceride levels (TG). Additionally, HDL mediated efflux was measured in 13 diabetic and non-diabetic participants fasting and four hours after a high-fat test challenge.ResultsHDL mediated cholesterol efflux function was increased in participants with T2DM with hypertriglyceridemia when compared to participants with T2DM without hypertriglyceridemia (efflux ratio mean ± standard deviation (SD), T2DM + TG: 1.17 ± 0.25 vs. T2DM − TG: 1.03 ± 0.19, p = 0.0098). In the fat challenge study, we observed a significant increase in ABCA-1 mediated cholesterol efflux capacity following an ingestion of high-fat test meal by participants in both groups of T2DM (n = 6, efflux ratio, mean ± SD, pre: 0.86 ± 0.4 vs. post: 1.34 ± 0.6, p = 0.01) and non-diabetic participants (n = 7, efflux ratio mean ± SD pre: 1.24 ± 0.31 vs. post: 1.39 ± 0.42, p = 0.04) that was partly explained by the difference in CETP activity (r = 0.6, p = 0.03).ConclusionOur study suggests that high triglyceride levels facilitate ABCA-1 mediated efflux function of HDL in part by activating CETP.     

Insulin-induced glucose control improves HDL cholesterol levels but not reverse cholesterol transport in type 2 diabetic patients

Type 2 diabetes (T2D) is characterized by low HDL cholesterol (HDL-C) and HDL dysfunction. We herein tested whether lowering HbA1c affects HDL-C and reverse cholesterol transport (RCT). Forty-two uncontrolled T2D patients initiating basal insulin were included. HbA1c, HDL-C and RCT were assessed at baseline and after 6 months. At baseline, HDL-C and RCT were directly correlated (r = 0.50; p < 0.001). After 6 months of insulin therapy, HbA1c dropped from 8.8 ± 0.16% to 7.1 ± 0.1%, while average HDL-C and RCT did not change. Follow-up HDL-C and RCT were still correlated (r = 0.31; p = 0.033) and ΔHDL-C correlated with ΔRCT (r = 0.32; p = 0.029). ΔHbA1c correlated with ΔHDL-C (r = 0.43, p = 0.001), but not with ΔRCT. In patients with ΔHbA1c above the median value (1.3%), HDL-C (but not RCT) increased significantly. In conclusion, glucose control correlates with increased HDL-C, but not with improved RCT. Thus, persistent HDL dysfunction despite improved HbA1c and HDL-C can contribute to residual cardiovascular risk in T2D.     

Detection of defective 3β-hydroxysterol Δ7-reductase activity in cultured human fibroblasts: a method for the diagnosis of Smith-Lemli-Opitz syndrome

Summary Patients with the autosomal recessive disorder Smith-Lemli-Opitz syndrome (SLO) have recently been shown to have markedly increased tissue levels of certain cholesterol biosynthesis intermediates, most notably 7-dehydrocholesterol. The findings strongly suggest a block in the step that catalyses reduction of 7-dehydrocholesterol to cholesterol. The accumulation of 7-dehydrocholesterol can generally easily be detected in serum by gas chromatography-mass spectrometry. However, it could not be totally ruled out that SLO patients with less severe enzyme defects could escape detection by this method. A more direct way of diagnosing a defect in 7-dehydrocholesterol reduction would be to assay the conversion of 7-dehydrocholesterol to cholesterol in cultured fibroblasts from patients with suspected SLO.In the present work, an assay for the conversion of [³H]lathosterol to [³H]-cholesterol in cultured human fibroblasts is described. Lathosterol is the immediate precursor of 7-dehydrocholesterol in the cholesterol biosynthetic pathway and was chosen for the assay instead of 7-dehydrocholesterol owing to the difficulty in preparation and handling of the latter compound. Fibroblasts from control subjects converted [³H]lathosterol to [³H]cholesterol efficiently, whereas in fibroblasts from SLO patients the conversion did not go beyond 7-dehydrocholesterol. It is concluded that the present method is useful for the diagnosis of SLO.     

Cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male LDL receptor knockout mice

ObjectiveIt is generally assumed that hepatic inflammation in obesity is linked to the pathogenesis of insulin resistance. Several recent studies have shed doubt on this view, which questions the causality of this association. This study focuses on Kupffer cell-mediated hepatic inflammation as a possible driver of insulin resistance in the absence and presence of obesity.MethodsWe used male mice deficient for the low-density lipoprotein receptor (Ldlr^−/−) and susceptible to cholesterol-induced hepatic inflammation. Whole body and hepatic insulin resistance was measured in mice fed 4 diets for 2 and 15 weeks, i.e., chow, high-fat (HF), HF-cholesterol (HFC; 0.2% cholesterol) and HF without cholesterol (HFnC). Biochemical parameters in plasma and liver were measured and inflammation was determined using immunohistochemistry and RT-PCR.ResultsAt 2 weeks, we did not find significant metabolic effects in either diet group, except for the mice fed a HFC diet which showed pronounced hepatic inflammation (p < 0.05) but normal insulin sensitivity. At 15 weeks, a significant increase in insulin levels, HOMA-IR, and hepatic insulin resistance was observed in mice fed a HFC, HFnC, and HF diet compared to chow-fed mice (p < 0.05). Regardless of the level of hepatic inflammation (HFC > HF, HFnC; p < 0.05) insulin resistance in mice fed HFC was no worse compared to mice on a HFnC and HF diet.ConclusionThese data show that cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male Ldlr^−/− mice. This study suggests that Kupffer cell-driven hepatic inflammation is a consequence, not a cause, of metabolic dysfunction in obesity.     

Twenty-one year tracking of serum non-cholesterol sterols. The Cardiovascular Risk in Young Finns study

Background and aimTo show tracking of cholesterol metabolism, the ratios to cholesterol of e.g. serum cholestenol, desmosterol, and lathosterol, reflecting cholesterol synthesis, and cholestanol, campesterol, avenasterol and sitosterol, reflecting cholesterol absorption, were measured 21 years apart.Methods and resultsIn random population samples initially comprising 12- (n = 162), 15- (n = 158), and 18-year-old (n = 148) males participating in the Cardiovascular Risk in Young Finns Study, serum sterols and squalene were measured with gas–liquid chromatography in 1980 and 2001. Quartiles of cholestanol, indicating low to high cholesterol absorption, were defined from the cholestanol values in 1980.Serum cholesterol increased in the oldest age group only, but synthesis markers (except desmosterol) increased in all age groups after the follow-up (e.g. lathosterol, total population +47.3 ± 2.6% (SE), P < 0.001). Campesterol (+69.0 ± 3.0%, P < 0.001) and sitosterol increased, avenasterol was unchanged, and cholestanol decreased (−6.2 ± 0.7%, P < 0.001), respectively. The 1980 synthesis and absorption markers were interrelated with respective values 21 years later in all age groups and quartiles (e.g. lathosterol, total population 1980 vs. 2001 r = 0.460, cholestanol 1980 vs. 2001 r = 0.593, P < 0.001 for both). Synthesis markers were highest in the first and lowest in the fourth quartile both in 1980 and 2001 (e.g. 2001, desmosterol, quartile 1, 99 ± 9, quartile 4, 83 ± 2 μg/mg of cholesterol, P < 0.05).ConclusionsCholesterol metabolism is significantly tracked in adolescent males over the follow-up of 21 years. Thus, high cholesterol synthesis and low absorption characterize subjects with the lowest cholestanol quartile, while those with the highest quartile have low synthesis and high absorption in both adolescence and later in young adult life.     

Trends in total cholesterol control among American adults with hypercholesterolemia, 1988–2018

Background and aimsCholesterol control and management in patients with hypercholesterolemia are significant for the primary and secondary prevention of atherosclerotic cardiovascular disease. This study analyzed the trend of serum total cholesterol (TC) control (<240 mg/dL and <200 mg/dL) in American adults with hypercholesterolemia and thereby make some effective recommendations for the public health measures.Methods and resultsBasing on the National Health and Nutrition Examination Survey (NHANES) data from 1988 to 2018 (12 cycles), we calculated the weighted and representative rate of patients with hypercholesterolemia who had controlled TC, and then described the trend. Among the adults with hypercholesterolemia, the age-adjusted rate of those whose TC was less than 240 mg/dL increased from 7.67% (95%CI: 5.94%–9.40%) in 1988–1991 to 58.52% (95%CI: 55.89%–61.15%) in 2013–2014 and then remained stable; and the age-adjusted rate of those whose TC was less than 200 mg/dL increased from 2.49% (95%CI: 1.48%–3.50%) in 1988–1991 to 44.58% (95%CI: 40.00%–49.16%) in 2017–2018.ConclusionWe concluded that the rate of controlling TC below 200 mg/dL among all patients had shown an increasing trend from 1988 to 2018 in America, while the rate of controlling TC below 240 mg/dL remained stable in recent years after an increasing.     

Serum cholesterol predicts transplant-free survival in cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt

BackgroundMalnutrition is frequent in patients with cirrhosis and has been associated with poor prognosis. The Model for End-stage Liver Disease (MELD) score was created to predict survival after Transjugular Intrahepatic Porto-systemic Shunt (TIPS) but lacks a nutritional parameter.AimsTo evaluate the prognostic value of serum cholesterol in patients with cirrhosis undergoing TIPS and to develop a prognostic score to predict survival.MethodsAn explorative cross-sectional study was conducted of cirrhotic patients undergoing TIPS from 2008 until 2019. Exclusion criteria were liver transplantation or hepatocellular carcinoma before TIPS. Risk analysis was used to compare survival according to clinical and analytical data. The diagnostic performance of serum cholesterol added to MELD was evaluated and confirmed in an external validation cohort.ResultsThe final cohort of 100 patients had a mean MELD score of 14±5 and cholesterol of 122±51 mg/dL. MELD (p < 0,05) and both cholesterol (p < 0,05) and low-density lipoprotein levels (LDL-C) (p < 0,05) were independent predictors of post-TIPS transplant-free survival with an optimal cut-off of 106 mg/dL for serum cholesterol. The combined MELD-cholesterol risk score improved diagnostic accuracy of each parameter separately, and this was confirmed in the external cohort.ConclusionSerum cholesterol and LDL-C are independent predictors of transplant-free survival in cirrhotic patients undergoing TIPS. The MELD-cholesterol score slightly improved prognostic accuracy.Lay SummaryAs an objective and easily measured indicator of both nutritional status and hepatic function, serum cholesterol could be useful to predict transplant-free survival in patients with cirrhosis undergoing TIPS. It can enable health care providers to identify high-risk patients and to optimize nutritional status before TIPS.     

Cholesterol metabolism in pediatric short bowel syndrome after weaning off parenteral nutrition

BackgroundSmall intestine essentially regulates cholesterol homeostasis.AimsTo evaluate cholesterol metabolism in short bowel syndrome (SBS).MethodsCholesterol precursors (e.g., cholestenol, desmosterol and lathosterol) and plant sterols (campesterol and sitosterol), respective markers of cholesterol synthesis and absorption, were determined in SBS patients (n = 12) an average of 31 months after weaning off parenteral nutrition and in age-matched controls (n = 80).ResultsAmong patients, serum cholesterol precursor sterol to cholesterol ratios were 2–10 times higher (P < 0.0001 for each). Those without any remaining ileum had 1.2–2.8 times higher precursor sterol to cholesterol ratios than those with an ileal remnant (P < 0.05 for each). Serum cholesterol concentration, campesterol/cholesterol and campesterol/sitosterol were 34–39% lower (P < 0.05 for each) in relation to controls. Bile acid absorption was markedly impaired (2.4 (0.2–3.2)%). Plant sterol ratios reflected the absolute length of remaining jejunum (r = 0.625–0.663), and precursor sterol ratios inversely that of ileum (r = −0.589 to 0.750, P < 0.05 for all).ConclusionAfter weaning off parenteral nutrition, patients with pediatric onset SBS continue to have marked intestinal malabsorption of bile acids and moderate cholesterol malabsorption resulting in decreased serum cholesterol despite a marked compensatory increase in cholesterol synthesis.     

Blood glucose and cholesterol levels in adult population of Bangladesh: Results from STEPS 2006 survey

BackgroundA nationally representative survey was carried out to determine the distribution of blood glucose and cholesterol in adult population of Bangladesh in the absence of existing data.MethodsThe study adopted a multistage and geographically clustered sampling technique of households. A total of 2610 individuals (1444 men and 1166 women) aged 25–64 years were selected from rural and urban areas. Capillary blood glucose and total cholesterol levels were measured using an overnight fasting state.ResultsThe mean age of the participants was 41 years [standard deviation (SD), 11 years]. Half of them (49%) were from urban areas. Half of them (51%) had primary or higher education. Mean glucose was 74 mg/dL (SD 23 mg/dL). Men had higher mean glucose levels (79 mg/dL) than women (67 mg/dL). Age-standardized prevalence of diabetes (blood glucose level ≥126 mg/dL and/or use of anti-diabetic medication) was 5.5%. In men, it was almost two-and-half times (7.6%) compared with women (2.8%). It was also double in urban areas (7.8%) compared with rural areas (3.4%). Mean cholesterol level among all participants was 167 mg/dL (SD 26 mg/dL). Men and women had almost similar levels (169 mg/dL versus 166 mg/dL, respectively). Prevalence of high cholesterol level (≥240 mg/dL) was very low (1.3%) in both men (2.2%) and women (0.5%). However, the prevalence of borderline high cholesterol was substantial (5.8%) in this sample.ConclusionThe prevalence of high hypercholesterolemia is low, whereas there is a high prevalence of borderline high cholesterol and diabetes in the adult population of Bangladesh. This warrants population-based interventions to tackle this problem.     

Effects of plant stanol esters supplied in a fat free milieu by pastilles on cholesterol metabolism in colectomized human subjects

Background and aimNutritional products containing fat-soluble phytosterol esters for serum cholesterol lowering have traditionally been oil-based. Their cholesterol-lowering efficacy when provided by low-fat vehicles with a diet of normal fat content is questionable. The aims of the present study were to find out whether 1-week consumption of plant stanol esters in pastilles alters absorption percentage of labeled esterified and free cholesterol and fecal elimination of sterols, including phytosterols (n = 9), and to define the impact of dietary fat on intestinal sterol ester hydrolysis (n = 8) in colectomized human subjects.Methods and resultsLevels of lipoprotein cholesterol and triacylglycerols, non-cholesterol sterols and squalene in serum, neutral sterols, non-cholesterol sterols, fat and bile acids in feces, cholesterol absorption efficiency and cholesterol synthesis were analyzed at baseline and at the end of the treatment period. Analyses of esterified and free cholesterol and phytosterols were performed during diets with normal and low-fat content.Serum levels of total and low-density lipoprotein cholesterol decreased by 9% and 14%, respectively (P < 0.01 for both), and absorption of ³H-esterified and ¹⁴C-free cholesterol decreased in proportion to baseline values (r = −0.58, P < 0.05) by over 40% (P < 0.01) in colectomized patients with stanol ester pastilles. Fecal elimination of cholesterol was increased by about 35% and almost 60% of campestanol and sitostanol esters were hydrolyzed during their transit in gastrointestinal tract when consumed with a normal fat diet (mean daily fat 93 ± 13 g) for 1 week. The hydrolysis of plant stanol esters was more pronounced with a normal than with a low-fat diet (70% versus 40%, P < 0.001).ConclusionsWe conclude that plant stanol esters provided in fat free milieu exert favourable effects on serum lipid profile by decreasing absorption of cholesterol in colectomized human subjects, even though the intestinal hydrolysis of plant stanol esters is weaker on low than normal fat diet.     

The effect of a high fat meal on heart rate variability and arterial stiffness in adolescents with or without type 1 diabetes

AimType 1 diabetes (T1D) is associated with increased arterial stiffness and cardiac autonomic neuropathy. We tested whether those variables are acutely affected by a high fat meal (HFM).MethodsResponses to a HFM were measured in adolescents with T1D (N = 14) or without T1D (Control, N = 21). Heart rate variability (HRV), arterial stiffness, blood pressure (BP), and energy expenditure (EE) were measured before (baseline) and four times over 180 min postprandially.ResultsT1D had higher blood glucose and insulin, but the suppression of fatty acids (~40%) and rise in triglycerides (~60%) were similar between groups. T1D had 9% higher EE, but postprandial increase in EE was similar to Controls. T1D had ~7 to 24% lower baseline HRV but a similar postprandial decline of ~8 to 25% as Controls. Both groups had a similar 2 to 5% increase in BP after the meal. Rate pressure product increased postprandially in both groups and was higher in T1D. Pulsewave velocity and augmentation index did not differ between groups or change postprandially.ConclusionAdolescents with T1D have evidence of cardiac autonomic dysfunction and increased EE, but those variables, along with arterial stiffness, are not acutely made worse by a HFM.     

Genetic depletion of Soat2 diminishes hepatic steatosis via genes regulating de novo lipogenesis and by GLUT2 protein in female mice

Depletion of the cholesterol esterifying enzyme acyl-Coenzyme A: cholesterol acyltransferase 2 (ACAT2, encoded by Soat2) protects mice from atherosclerosis, diet-induced hypercholesterolemia, and hepatic steatosis when fed high-cholesterol diet. The glucose transporter 2 (GLUT2) represents the main gate of glucose uptake by the liver. Lipid synthesis from glucose (de novo lipogenesis; DNL) plays a pivotal role in the development of hepatic steatosis. Inhibition of DNL is a successful approach to reverse hepatic steatosis, as shown by different studies in mice and humans. Here we aimed to investigate whether depletion of Soat2 per se can reduce hepatic steatosis, also in the presence of very low levels of cholesterol in the diet, and the underlying mechanisms. Female Soat2?/? and wild type mice were either fed high-fat or high-carbohydrate diet and both contained <0.05% (w/w) cholesterol. Analysis in serum, liver, muscles and adipose tissues were performed. We found Soat2?/? mice fed high-fat, low-cholesterol diet to have less hepatic steatosis, decreased expression of genes involved in DNL and lower hepatic GLUT2. Similar findings were found in Soat2-/- mice fed high-carbohydrate, low-cholesterol diet.ConclusionDepletion of Soat2 reduces hepatic steatosis independently of the presence of high levels of cholesterol in the diet. Our study provides a link between hepatic cholesterol esterification, DNL, and GLUT2.     

Serum high-density lipoprotein cholesterol concentration and functional state: The Korean Urban Rural Elderly (KURE) Study

BackgroundFunctional state and cholesterol metabolism are important for older adults; however, this association has not been fully investigated among community-dwelling older adults. Thus, we investigated the association of HDL cholesterol with multiple functional state measures in an elderly Korean population.MethodsThis cross-sectional analysis included 3514 participants, aged 65 years or older, who participated in baseline health assessment for the Korean Urban Rural Elderly cohort study from 2012 to 2015. HDL cholesterol concentration was analyzed using both continuous and categorical variables. Functional state was assessed by the mini-mental state examination (MMSE), activities of daily living (ADL) scale, instrumental activities of daily living (IADL) scale, timed up-and go (TUG) test, and chair-rise test (CRT). Multiple logistic regression models were used to investigate independent association between HDL cholesterol and functional state, after adjusting for sex, age, body mass index, systolic blood pressure, fasting glucose, lipid-lowering drug, history of cancer and cardiovascular disease, and health behaviors.ResultsHDL cholesterol concentration was significantly associated with MMSE, ADL, IADL, TUG, and CRT in the unadjusted model. After adjustment for covariates, the association remained significant for MMSE (standardized β = 0.059, p = 0.001), ADL (standardized β = −0.053, p = 0.004), and CRT (standardized β = −0.037, p = 0.037). In fully-adjusted model, Participants who had a lower HDL concentration (<40 mg/dL) showed significantly increased odds for having MMSE decline (OR 1.451, 95% CI 1.119–1.883) and ADL dependency (OR 2.251, 95% CI 1.119–4.526), compared reference group (≥60 mg/dL).ConclusionsHigher HDL cholesterol concentration was associated with better functional state among Korean older adults.