TY - JOUR
T1 - Liver Receptor Homolog-1 Is Critical for Adequate Up-regulation of Cyp7a1 Gene Transcription and Bile Salt Synthesis During Bile Salt Sequestration
AU - Out, Carolien
AU - Hageman, Jurre
AU - Bloks, Vincent W.
AU - Gerrits, Han
AU - Sollewijn Gelpke, Maarten D.
AU - Bos, Trijnie
AU - Havinga, Rick
AU - Smit, Martin J.
AU - Kuipers, Folkert
AU - Groen, Albert K.
PY - 2011
Y1 - 2011
N2 - Liver receptor homolog-1 (LRH-1) is a nuclear receptor that controls a variety of metabolic pathways. In cultured cells, LRH-1 induces the expression of CYP7A1 and CYP8B1, key enzymes in bile salt synthesis. However, hepatic Cyp7a1 mRNA levels were not reduced upon hepatocyte-specific Lrh-1 deletion in mice. The reason for this apparent paradox has remained elusive. We describe a novel conditional whole-body Lrh-1 knockdown (LRH-1-KD) mouse model to evaluate the dependency of bile salt synthesis and composition on LRH-1. Surprisingly, Cyp7a1 expression was increased rather than decreased under chow-fed conditions in LRH-1-KD mice. This coincided with a significant reduction in expression of intestinal Fgf15, a suppressor of Cyp7a1 expression, and a 58% increase in bile salt synthesis. However, when fecal bile salt loss was stimulated by feeding the bile salt sequestrant colesevelam, Cyp7a1 expression was up-regulated in wildtype mice but not in LRH-1-KD mice (+593% in wildtype versus 19% in LRH-1-KD). This translated into an increase in bile salt synthesis of +272% in wildtype versus +21% in LRH-1-KD mice. Conclusion: Our data provide mechanistic insight into a missing link in the maintenance of bile salt homeostasis during enhanced fecal loss and support the view that LRH-1 controls Cyp7a1 expression from two distinct sites, i.e., liver and ileum, in the enterohepatic circulation. (HEPATOLOGY 2011;53:2075-2085)
AB - Liver receptor homolog-1 (LRH-1) is a nuclear receptor that controls a variety of metabolic pathways. In cultured cells, LRH-1 induces the expression of CYP7A1 and CYP8B1, key enzymes in bile salt synthesis. However, hepatic Cyp7a1 mRNA levels were not reduced upon hepatocyte-specific Lrh-1 deletion in mice. The reason for this apparent paradox has remained elusive. We describe a novel conditional whole-body Lrh-1 knockdown (LRH-1-KD) mouse model to evaluate the dependency of bile salt synthesis and composition on LRH-1. Surprisingly, Cyp7a1 expression was increased rather than decreased under chow-fed conditions in LRH-1-KD mice. This coincided with a significant reduction in expression of intestinal Fgf15, a suppressor of Cyp7a1 expression, and a 58% increase in bile salt synthesis. However, when fecal bile salt loss was stimulated by feeding the bile salt sequestrant colesevelam, Cyp7a1 expression was up-regulated in wildtype mice but not in LRH-1-KD mice (+593% in wildtype versus 19% in LRH-1-KD). This translated into an increase in bile salt synthesis of +272% in wildtype versus +21% in LRH-1-KD mice. Conclusion: Our data provide mechanistic insight into a missing link in the maintenance of bile salt homeostasis during enhanced fecal loss and support the view that LRH-1 controls Cyp7a1 expression from two distinct sites, i.e., liver and ileum, in the enterohepatic circulation. (HEPATOLOGY 2011;53:2075-2085)
U2 - https://doi.org/10.1002/hep.24286
DO - https://doi.org/10.1002/hep.24286
M3 - Article
C2 - 21391220
SN - 0270-9139
VL - 53
SP - 2075
EP - 2085
JO - Hepatology (Baltimore, Md.)
JF - Hepatology (Baltimore, Md.)
IS - 6
ER -