Related Experiment Video
Updated: May 11, 2026
Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
Published on: July 18, 2025
Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling
Mikael Bjursell1, Marianne Wedin, Therése Admyre
1AstraZeneca R&D, Mölndal, Sweden. mikael.bjursell@astrazeneca.com
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.
Insights
Aging mice lacking the nuclear receptor FXR (Nr1h4) show late-onset leanness and improved glucose control. However, these mice develop severe non-alcoholic steatohepatitis (NASH)-like liver disease and cholestasis.
Area of Science:
- Metabolic research
- Hepatology
- Endocrinology
Background:
- Nuclear receptor subfamily 1, group H, member 4 (FXR) is activated by bile acids and regulates bile acid synthesis.
- FXR plays a key role in cholesterol and glucose homeostasis, primarily in the liver and intestine.
Purpose of the Study:
- To investigate the metabolic and liver function consequences of FXR deficiency in aging mice.
- To characterize the phenotype of a novel FXR-deficient mouse line fed a standard chow diet.
Main Methods:
- Generation and characterization of a novel FXR-deficient mouse line.
- Assessment of body weight, body composition, energy metabolism, glucose homeostasis, and liver function in aging mice.
- Histopathological analysis of liver tissues to evaluate steatosis, inflammation, and cell damage.
Main Results:
- FXR-deficient mice exhibited normal growth initially but developed late-onset leanness due to reduced body fat mass and increased energy expenditure.
- Improved glucose tolerance and lower fasting glucose/insulin levels were observed in aged FXR-deficient mice.
- Significant liver pathology, including increased liver weight, steatosis, hepatocyte ballooning, lobular inflammation, elevated ALT, bilirubin, and bile acids, indicative of NASH and cholestasis, was observed.
Conclusions:
- Aging FXR-deficient mice display a paradoxical phenotype of leanness with improved glucose control but develop severe, age-related liver disease resembling NASH and cholestasis.
- These findings highlight a critical role for FXR in maintaining liver health and metabolic balance during aging.
- The study provides a valuable model for investigating FXR-targeted therapies for metabolic and liver diseases.
