Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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.
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.
肝受体同源物-1（LRH-1）是一种核受体，可控制多种代谢途径。在培养的细胞中，LRH-1诱导CYP7A1 和 CYP8B1 的表达，这是胆汁盐合成的关键酶。然而，在小鼠中，肝细胞特异性 Lrh-1 缺失并未降低肝 Cyp7a1 mRNA 水平。造成这种明显矛盾的原因一直难以捉摸。我们描述了一种新的条件性全身 Lrh-1 敲低（LRH-1-KD）小鼠模型，以评估胆汁盐合成和组成对 LRH-1 的依赖性。令人惊讶的是，在 LRH-1-KD 小鼠中，即使在正常饮食条件下，Cyp7a1 的表达也增加而不是减少。这与肠道 Fgf15 表达的显著降低相吻合，Fgf15 是 Cyp7a1 表达的抑制剂，胆汁盐合成增加了 58%。然而，当用胆汁盐螯合剂考来烯胺刺激粪便胆汁盐丢失时，野生型小鼠中的 Cyp7a1 表达上调，但 LRH-1-KD 小鼠中则没有（野生型增加 593%，LRH-1-KD 增加 9%）。这转化为野生型小鼠胆汁盐合成增加了+272%，而 LRH-1-KD 小鼠增加了+21%。
我们的数据为在增强的粪便丢失期间维持胆汁盐动态平衡的缺失环节提供了机制上的见解，并支持了 LRH-1 从两个不同部位控制 Cyp7a1 表达的观点，即肠肝循环中的肝脏和回肠。
