AstraZeneca R&D, Mölndal, Sweden.
PLoS One. 2013 May 20;8(5):e64721. doi: 10.1371/journal.pone.0064721. Print 2013.
Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH) and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.
核受体亚家族 1，组 H，成员 4（Nr1h4，FXR）是一种胆汁酸激活的核受体，主要在肝脏、肠道、肾脏和肾上腺中表达。激活后，主要功能是抑制胆固醇 7α-羟化酶（Cyp7a1），这是经典或中性胆汁酸合成途径中的限速酶。在本研究中，创建了一种新型的 Fxr 缺陷小鼠品系，并研究了其在给予普通饮食的老化小鼠中的代谢和肝功能。在年轻时期，Fxr 缺陷小鼠在体重、体成分、能量摄入和支出以及行为方面与野生型小鼠相似。然而，从 15 周龄开始，Fxr 缺陷小鼠的体重几乎没有增加，直到 39 周龄，主要是因为体脂肪量减少。体重增加减少与能量消耗增加有关，而能量消耗增加并没有通过增加食物摄入来补偿。老年和瘦的 Fxr 缺陷小鼠的空腹血糖和胰岛素水平较低，葡萄糖耐量改善。然而，Fxr 缺陷小鼠表现出明显增加的肝重、脂肪变性、肝细胞气球样变性和肝小叶炎症，以及升高的血浆丙氨酸氨基转移酶（ALT）、胆红素和胆汁酸水平，这些发现与非酒精性脂肪性肝炎（NASH）和胆汁淤积相符。总之，老化的 Fxr 缺陷小鼠表现出迟发性消瘦，伴有能量消耗增加和葡萄糖控制改善，但发展出严重的 NASH 样肝病理。
