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Bile salt sequestration induces hepatic de novo lipogenesis through farnesoid X receptor– and liver X receptorα–controlled metabolic pathways in mice
Author(s) -
Herrema Hilde,
Meissner Maxi,
van Dijk Theo H.,
Brufau Gemma,
Boverhof Renze,
Oosterveer Maaike H.,
Reijngoud DirkJan,
Müller Michael,
Stellaard Frans,
Groen Albert K.,
Kuipers Folkert
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23408
Subject(s) - farnesoid x receptor , medicine , endocrinology , liver x receptor , lipogenesis , chemistry , triglyceride , reabsorption , cholesterol 7 alpha hydroxylase , lipid metabolism , cholesterol , nuclear receptor , biology , biochemistry , kidney , transcription factor , gene
Diabetes is characterized by high blood glucose levels and dyslipidemia. Bile salt sequestration has been found to improve both plasma glycemic control and cholesterol profiles in diabetic patients. Yet bile salt sequestration is also known to affect triglyceride (TG) metabolism, possibly through signaling pathways involving farnesoid X receptor (FXR) and liver X receptor α (LXRα). We quantitatively assessed kinetic parameters of bile salt metabolism in lean C57Bl/6J and in obese, diabetic db/db mice upon bile salt sequestration using colesevelam HCl (2% wt/wt in diet) and related these to quantitative changes in hepatic lipid metabolism. As expected, bile salt sequestration reduced intestinal bile salt reabsorption. Importantly, bile salt pool size and biliary bile salt secretion remained unchanged upon sequestrant treatment due to compensation by de novo bile salt synthesis in both models. Nevertheless, lean and db/db mice showed increased, mainly periportally confined, hepatic TG contents, increased expression of lipogenic genes, and increased fractional contributions of newly synthesized fatty acids. Lipogenic gene expression was not induced in sequestrant‐treated Fxr −/− and Lxr α −/− mice compared with wild‐type littermates, in line with reports indicating a regulatory role of FXR and LXRα in bile salt–mediated regulation of hepatic lipid metabolism. Conclusion: Bile salt sequestration by colesevelam induces the lipogenic pathway in an FXR‐ and LXRα‐dependent manner without affecting the total pool size of bile salts in mice. We speculate that a shift from intestinal reabsorption to de novo synthesis as source of bile salts upon bile salt sequestration affects zonation of metabolic processes within the liver acinus. (H EPATOLOGY 2010.)