Expression levels of established LXRα target genes,

however, were unaffected in sequestrant-treated lean and db/db mice, suggestive of unchanged LXRα signaling. Yet, investigation in sequestrant-treated Lxrα−/− mice revealed that lipogenic gene expression was not increased in these mice compared with untreated wild-type littermates. Our results from colesevelam-treated Fxr−/− and Lxrα−/− mice confirm earlier findings that FXR and LXRα are both involved in regulation of bile salt–mediated changes in lipogenic pathways.17 The exact molecular mechanisms through which these nuclear receptors signal regulate the lipogenic response to bile salt sequestration exceed the scope of this report. At a physiological level, bile salt–mediated signaling pathways are dependent on the concentration of bile salts Ku-0059436 cell line in the liver acinus. We speculate Osimertinib mw that the concept of metabolic zonation43 might

add to the understanding of the observed hepatic effects upon bile salt sequestration. Hepatocytes localized around the portal vein display different metabolic activities than those lining the central vein; for example, bile salt and fat synthesis are pericentrally localized processes, whereas cholesterol synthesis is performed mainly by portal hepatocytes.43 As we show in the current report, the amount of bile salt molecules reabsorbed in the ilea of colesevelam-treated mice was decreased by ≈30% with a subsequent reduction in plasma bile salt levels and, hence, reduced bile salt signaling in periportal hepatocytes. Newly synthesized bile salts, which accommodate a much larger fraction of the bile salt pool of colesevelam-treated mice compared with controls, are primarily secreted by pericentrally localized cells and possibly exert differential signaling functions.

Selective periportal fat accumulation and differentially affected expression levels of hepatic FXR target genes support this hypothesis. Additionally, it was shown that Cyp7a1, which is exclusively expressed in pericentral hepatocytes,44 translocates to a larger area of the liver lobulus with more involvement of periportally localized cells in sequestrant-treated rats.45 Our working model is summarized in Supporting Fig. 5. It should be stressed that this hypothesis requires dedicated investigation. In conclusion, we show that colesevelam Thiamet G treatment increases lipogenesis and chain elongation in mice that, at least at the level of gene expression, is dependent on FXR and LXRα. A shift from reabsorption to de novo synthesis as the source of biliary bile salts affects the sinusoidal gradient of bile salts.46 This shift modifies the regulation of genes and proteins involved in bile salt synthesis and bile salt–mediated regulation of metabolism and possibly underlies the phenotypical response to colesevelam treatment in mice. We are indebted to Rick Havinga for excellent contributions to the mouse studies performed.