Cyp27a1 directs bile salt synthesis toward CDCA. Although expression of Cyp27a1 was

increased check details in colesevelam-treated mice, this was not reflected in increased CDCA synthesis (Fig. 3C). Despite the fact that bile salt reabsorption was not completely abolished, expression levels of the FXR target gene Fgf15 were undetectable in distal ilea of colesevelam-treated lean and db/db mice (Fig. 3D). Cholesterol synthesis is massively increased in colesevelam-treated lean and db/db mice, and colesevelam treatment increased fecal cholesterol excretion (Fig. 4A). Together with a strongly increased synthesis of bile salts, this finding translates into an increased turnover of cholesterol. However, this did not result in reduced plasma concentrations or hepatic contents of cholesterol (Fig. 4B,C). Increased hepatic expression of HmgCoAr, encoding the rate-controlling enzyme in cholesterol synthesis, and of Ldlr (Fig. 4D) indicated the anticipated hepatic compensatory response in cholesterol metabolism after colesevelam treatment. To

quantify this, the fraction of newly synthesized cholesterol was determined by analysis of the incorporation of [1-13C]-acetate into plasma cholesterol. Fractional learn more cholesterol synthesis was indeed robustly increased in colesevelam-treated mice (Fig. 4E). Both colesevelam-treated lean and

db/db mice had modestly increased (lean +50%, db/db +23%) hepatic TG contents compared with untreated controls (Table 1). Remarkably, fat accumulated primarily in periportal areas upon bile salt sequestration (Fig. 5A,B). Increased hepatic expression of key lipogenic genes (Srebp1c, Acc1, Fas, and Scd1) (Fig. 5C) was highly suggestive of enhanced synthesis of fatty acids. Indeed, the total fractions of newly synthesized C16:0, C18:0, and C18:1, as determined by incorporation of [1-13C]-acetate followed by mass isotopomer distribution analysis, confirmed that synthesis of these major hepatic fatty acid species was increased. Additionally, we calculated the contribution of de novo synthesis and chain elongation to the total fractional C18:0 and C18:1 this website synthesis.28 The increased total fraction of newly synthesized fatty acids was mainly attributable to increased chain elongation in colesevelam-treated lean and db/db mice (Fig. 5D). Bile salt–mediated changes in expression of one of the major regulators of lipogenesis, Srebp1c, have been reported to be regulated by both FXR- and LXRα-regulated pathways.17 Surprisingly, expression levels of well-defined FXR and LXRα target genes were differentially or not at all affected in colesevelam-treated lean and db/db mice (Supporting Figs. 3 and 4).