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.