Blood glucose levels remained unchanged upon treatment KU-60019 molecular weight in

lean mice. Fasting insulin levels (not shown) were unchanged and decreased, respectively, in colesevelam-treated lean and db/db mice. Nonesterified fatty acid and very low-density lipoprotein TG levels (Supporting Fig. 1) were significantly reduced in colesevelam-treated db/db mice compared with untreated controls but remained unchanged in lean mice. Control db/db mice showed increased feces production and a higher fecal bile salt output, representing hepatic bile salt synthesis, compared with lean controls (Fig. 1A,B). As expected, colesevelam treatment led to massive increases in fecal bile salt output (Fig. 1B). Untreated lean and db/db mice had similar bile flow rates and biliary bile salt output rates (Fig. 1C,D) that remained unchanged in both models upon sequestrant treatment. Direct end products EPZ-6438 chemical structure of de novo bile salt synthesis are the primary bile salts cholate (CA) and chenodeoxycholate (CDCA). Modifications of these bile salts in the liver and intestine give rise to differentially structured primary and secondary bile salts, respectively.

Supporting Table 1 provides details on biliary and fecal bile salt compositions. In short, sequestrant treatment resulted in a strongly increased relative content of fecal deoxycholate in both groups. Cholate remained the major biliary bile salt species in both models upon sequestrant treatment. Next, we determined relevant kinetic parameters SDHB of CA,23 the major primary bile salt species in mice. Untreated db/db mice displayed a larger pool size and a higher synthesis rate of CA compared with untreated lean mice (Fig. 2). Importantly, CA pool size remained unchanged upon colesevelam treatment in both models. Synthesis rates of CA were massively increased upon sequestrant treatment (+375% and +172%, lean and db/db mice, respectively) and completely compensated for the increased fecal bile salt loss induced by colesevelam. The calculated amount of CA reabsorbed from intestines of colesevelam-treated lean

and db/db mice was reduced by about 30% compared with untreated controls (Fig. 2D). Decreased plasma bile salt levels further reflect a reduced flux of bile salts returning to the liver (Fig. 2E). To gain insight into colesevelam-induced changes in total bile salt pool composition and synthesis of bile salts derived from the primary bile salt species CA and CDCA, we calculated the amount of CA- and CDCA-derived bile salts in the pool as well as their synthesis rates (for details on calculation, see Supporting Materials and Methods). Upon sequestrant treatment, the total pools of bile salts remained unchanged in both models (Fig. 3A). Nevertheless, the pool size of CDCA-derived bile salts was decreased. The synthesis of CA-derived bile salts was massively increased, whereas synthesis of CDCA-derived bile salts remained unchanged in sequestrant-treated mice compared with untreated controls (Fig. 3B).