Liver receptor homolog-1 is critical for adequate up-regulation of Cyp7a1 gene transcription and bile salt synthesis during bile salt sequestration

Hepatology. 2011 Jun;53(6):2075-85. doi: 10.1002/hep.24286.


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 +9% 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allylamine / analogs & derivatives
  • Allylamine / pharmacology
  • Animals
  • Anticholesteremic Agents / pharmacology
  • Bile Acids and Salts / metabolism*
  • Cholesterol 7-alpha-Hydroxylase / metabolism*
  • Colesevelam Hydrochloride
  • Female
  • Gene Expression Regulation / drug effects
  • Homeostasis / physiology
  • Ileum / metabolism
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • Receptors, Cytoplasmic and Nuclear / deficiency
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Up-Regulation / physiology*


  • Anticholesteremic Agents
  • Bile Acids and Salts
  • Nr5a2 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Allylamine
  • Cholesterol 7-alpha-Hydroxylase
  • Cyp7a1 protein, mouse
  • Colesevelam Hydrochloride