Liver receptor homolog-1 is critical for adequate up-regulation of Cyp7a1 gene transcription and bile salt synthesis during bile salt sequestration
✍ Scribed by Carolien Out; Jurre Hageman; Vincent W. Bloks; Han Gerrits; Maarten D. Sollewijn Gelpke; Trijnie Bos; Rick Havinga; Martin J. Smit; Folkert Kuipers; Albert K. Groen
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 700 KB
- Volume
- 53
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
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 chowfed 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 (1593% in wildtype versus 19% in LRH-1-KD). This translated into an increase in bile salt synthesis of 1272% in wildtype versus 121% 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. (