Substituting sitostanol-ester margarine for part of the daily fat intake in subjects with mild hypercholesterolemia was effective in lowering serum total cholesterol and LDL cholesterol.

Carbohydrate overfeeding for 3 wk induced a >10-fold greater relative change in liver fat (27%) than in body weight (2%). The increase in liver fat was proportional to that in DNL. Weight loss restores liver fat to normal. These data indicate that the human fatty liver avidly accumulates fat during carbohydrate overfeeding and support a role for DNL in the pathogenesis of NAFLD. This trial was registered at www.hus.fi as 235780.

Objectives: To investigate whether baseline serum cholestanol:cholesterol ratio, which is negatively related to cholesterol synthesis, could predict reduction of coronary events in the Scandinavian simvastatin survival study. Design: Follow up of patients with coronary heart disease in whom baseline ratios were related to major coronary events. Setting: Four universities in Finland. Subjects: A subgroup of 868 patients with coronary heart disease selected from the Scandinavian simvastatin survival study. Intervention: Treatment with simvastatin or placebo. Main outcome measures: Serum concentrations of low density lipoprotein and high density lipoprotein cholesterol, total triglyceride concentration, and cholesterol:cholestanol ratio. Major coronary events. Results: With increasing baseline quarter of cholestanol distribution the reduction in relative risk increased gradually from 0.623 (95% confidence interval 0.395 to 0.982) to 1.166 (0.791 to 1.72). The risk of recurrence of major coronary events increased 2.2-fold (P < 0.01) by multiple logistic regression analysis between the lowest and highest quarter of cholestanol. The ratio of cholestanol was related inversely to the body mass index and directly to high density lipoprotein cholesterol and triglyceride concentrations but their quarters of distribution were not related to risk reduction. Conclusions: Measurement of serum cholestanol concentration revealed a subgroup of patients with coronary heart disease in whom coronary events were not reduced by simvastatin treatment. Thus, patients with high baseline synthesis of cholesterol seem to be responders whereas those with low synthesis of cholesterol are non-responders.

The roles of polymorphisms of the sitosterolemia genes ABCG5 and ABCG8 in the regulation of cholesterol metabolism and insulin sensitivity were studied in mildly hypercholesterolemic noncoronary subjects (n ‫؍‬ 263, 144 men and 119 women) divided into tertiles by baseline serum cholestanol-to-cholesterol ratio ( Յ 118.3 and Ն 147.7 10 2 ؋ mmol/mol cholesterol), a surrogate marker of cholesterol absorption efficiency. The lowest cholestanol tertile was associated with high body mass index (BMI), plasma glucose, serum insulin and triglycerides, and cholesterol synthesis markers (cholestenol, desmosterol, lathosterol) and low HDL cholesterol and cholesterol absorption markers (campesterol, sitosterol) ( P Ͻ 0.01 for all). The 19H allele of the ABCG8 gene accumulated in the lowest cholestanol tertile ( P Ͻ 0.001) and was associated with low total and LDL cholesterol and absorption markers and with high synthesis markers ( P Ͻ 0.05 for all). The 604E allele of the ABCG5 gene in men was associated with high BMI, plasma insulin, low serum sitosterol, and high serum cholestenol levels ( P Ͻ 0.05 for all). In a subgroup of 71 men, the 604E allele was associated with insulin resistance measured with the hyperinsulinemic euglycemic clamp. In conclusion, low cholesterol absorption efficiency was associated with characteristics of the metabolic syndrome. Low serum cholesterol and cholesterol absorption were linked to the D19H polymorphism of the ABCG8 gene, and characteristics of the insulin resistance syndrome in men were linked with the Q604E polymorphism of the ABCG5 gene. Serum cholesterol level is regulated by cholesterol absorption and synthesis. In different study populations (1-3), serum total and LDL cholesterol levels are associated positively with cholesterol absorption efficiency and negatively with cholesterol synthesis, suggesting that the higher the cholesterol absorption level, the higher the serum cholesterol level and the lower cholesterol synthesis. Cholesterol absorption efficiency and cholesterol synthesis are inversely related, and they can reliably be depicted by serum noncholesterol sterol levels (2). However, it is not known which of these variables, cholesterol absorption or synthesis, is the one primarily regulated. It has been shown that both absorption efficiency and synthesis of cholesterol are genetically determined (4, 5), such that in coronary families, the heredity of cholesterol metabolism can be predicted by serum cholestanol-to-cholesterol ratio, a surrogate marker of cholesterol absorption efficiency (4). We have recently shown that cholesterol absorption correlates positively and cholesterol synthesis correlates negatively with insulin sensitivity (6), but the link between insulin action and cholesterol metabolism has remained unknown. Phytosterolemia, an inherited disease with high absorption and low biliary secretion of cholesterol and plant sterols, is caused by a mutation in genes regulating ABCG5 (G5) or ABCG8 (G8) transporter proteins (7,8). Two sequence variations (D19H a...

Type 2 diabetes has been associated with high synthesis and low absorption of cholesterol independent of weight, indicating that insulin resistance may be a link between glucose and cholesterol metabolism. Therefore, we investigated the relationship of serum cholesterol precursors, reflecting cholesterol synthesis, and serum plant sterols and cholestanol, reflecting cholesterol absorption efficiency, with insulin sensitivity measured with the hyperinsulinemic euglycemic clamp in 72 healthy normoglycemic men. Men in the most insulin-resistant tertile had higher serum cholesterol precursor ratios ( P Ͻ 0.05), whereas no significant differences in serum absorption sterols were observed. In bivariate analysis, cholesterol synthesis markers correlated with fasting insulin ( r ‫؍‬ 0.36-0.46, P Ͻ 0.01) and the rates of insulin-stimulated whole-body glucose uptake (WBGU; r ‫؍‬ ؊ 0.37-0.40, P Ͻ 0.01). Also, cholesterol absorption markers correlated with fasting insulin and WBGU ( P Ͻ 0.05). Fasting insulin correlated with desmosterol ( r ‫؍‬ 0.286, P ‫؍‬ 0.015) and lathosterol ( r ‫؍‬ 0.248, P ‫؍‬ 0.037) even when the rates of WBGU and body mass index (BMI) were controlled for. We conclude that insulin resistance is linked to high cholesterol synthesis and decreased cholesterol absorption. Because fasting insulin correlated with cholesterol synthesis independent of the rates of BMI and WBGU, it is possible that regulation of cholesterol synthesis by hyperinsulinemia may be a link between insulin resistance and cholesterol metabolism. Insulin resistance and type 2 diabetes (T2DM) have been constantly associated with high triglyceride and low HDL-cholesterol levels. Increased synthesis of VLDL particles in the liver has been proposed to be the main cause of increased concentrations of triglyceride-rich lipoproteins. This overproduction of VLDL and triglycerides in the liver has been proposed to be driven by high levels of serum FFAs in patients with insulin resistance. In T2DM, high levels of VLDL cholesterol have also been observed, and because of that, mildly increased levels of LDL cholesterol may occur [for review, see refs. (1, 2)]. These observations are in agreement with the findings that increased cholesterol synthesis has been observed in obese subjects (3) and in patients with the metabolic syndrome (4). Because similar findings have been observed in patients with T2DM independent of weight (5), insulin resistance could explain the increase in cholesterol synthesis in patients with obesity and T2DM. This hypothesis is supported by the finding that in subjects with normal glucose tolerance, high glucose is linked to increased synthesis of cholesterol (6). Increase in cholesterol synthesis is always accompanied by low rates of cholesterol absorption; therefore, it has been difficult to determine which of these two is primarily affected in subjects with obesity or T2DM.In this study, we tried to answer the following questions. 1 ) Is directly measured insulin sensitivity linked to cholesterol metabolism in ...

Background Laparoscopic Roux-en-Y gastric bypass (RYGB) induces a more favorable metabolic profile than expected by weight loss alone. In this study, we investigated the effect of RYGB on serum bile acid levels and their relation to clinical outcomes. Methods We included 30 obese patients who underwent RYGB (BMI=46.1±5.9 kg/m2). Clinical measurements and laboratory determinations were performed before surgery and 1 year after surgery. Fasting serum bile acids were measured by an enzymatic method and individual bile acids were quantified by HLPC-tandem mass spectrometry. Indirect calorimetry was performed to measure the rates of energy expenditure and substrate oxidation. Results Fasting total serum bile acid levels increased twofold after RYGB (pre, 3.68±2.03 vs. post, 7.06± 9.65 μmol/l, +92 %, p=0.002). This increase in total bile acids was accompanied by a decrease in conjugated bile acids, which correlated with decreased glucose oxidation (r=0.571, p=0.002) and with increased lipid oxidation (r=−0.626, p=0.0004). The change in taurineconjugated bile acids correlated with altered DIO2 mRNA expression in adipose tissue (r=−0.498, p=0.013) potentially linking bile acid conjugation to substrate oxidation through DIO2. Conclusions Fasting serum bile acid levels increase after RYGB. More specifically, changes in bile acid conjugation after RYGB associate with altered energy metabolism.

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OBJECTIVE -To investigate cholesterol metabolism in obesity with and without diabetes.RESEARCH DESIGN AND METHODS -We performed cross-sectional metabolic studies in obese individuals with and without type 2 diabetes. The study population consisted of 16 obese (BMI Ͼ30 kg/m 2 ) diabetic subjects with a mean age of 52 Ϯ 2 years (SE) and 16 nondiabetic control subjects of similar age and weight. Cholesterol absorption efficiency was measured with peroral dual isotopes and cholesterol synthesis with sterol balance.RESULTS -Serum total cholesterol did not differ between the groups, but LDL and HDL cholesterol were significantly lower and VLDL cholesterol and serum total and VLDL triglycerides were higher in the diabetic group than in the control group. Cholesterol absorption efficiency was 29 Ϯ 1% in diabetic subjects vs. 42 Ϯ 2% in the control subjects (P Ͻ 0.01). Cholesterol synthesis was higher (17 Ϯ 1 vs. 14 Ϯ 1 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ; P Ͻ 0.05) and neutral sterol and bile acid excretion and cholesterol turnover tended to be higher in the diabetic group than in the control group. Blood glucose was positively related to cholesterol synthesis in the diabetic group (r ϭ ϩ0.663, P Ͻ 0.01) and in the control group (r ϭ ϩ0.590, P Ͻ 0.05), suggesting that the higher blood glucose level, the higher the cholesterol synthesis. In addition, blood glucose was significantly positively related to fecal neutral sterol excretion in both groups.CONCLUSIONS -Cholesterol absorption efficiency was lower and cholesterol synthesis was higher in obese subjects with diabetes than in those without diabetes, suggesting that diabetes modulates cholesterol metabolism more than obesity alone. Diabetes Care 25:1511-1515, 2002