Ageing Fxr Deficient Mice Develop Increased Energy Expenditure, Improved Glucose Control and Liver Damage Resembling NASH
Open Access
- 20 May 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (5), e64721
- https://doi.org/10.1371/journal.pone.0064721
Abstract
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.This publication has 49 references indexed in Scilit:
- Loss of FXR Protects against Diet-Induced Obesity and Accelerates Liver Carcinogenesis in ob/ob MiceMolecular Endocrinology, 2012
- Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestineJournal of Lipid Research, 2007
- The Farnesoid X Receptor Modulates Adiposity and Peripheral Insulin Sensitivity in MiceJournal of Biological Chemistry, 2006
- Farnesoid X receptor is essential for normal glucose homeostasisJCI Insight, 2006
- Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasisCell Metabolism, 2005
- The Farnesoid X-receptor Is an Essential Regulator of Cholesterol HomeostasisJournal of Biological Chemistry, 2003
- A Regulatory Cascade of the Nuclear Receptors FXR, SHP-1, and LRH-1 Represses Bile Acid BiosynthesisMolecular Cell, 2000
- Targeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid HomeostasisCell, 2000
- Bile Acids: Natural Ligands for an Orphan Nuclear ReceptorScience, 1999
- Identification of a nuclear receptor that is activated by farnesol metabolitesCell, 1995