title: Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.
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.
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden. mikael.bjursell@astrazeneca.com
authors.forename: Mikael
authors.initials: M
authors.lastname: Bjursell
authors.forename: Marianne
authors.initials: M
authors.lastname: Wedin
authors.forename: Therése
authors.initials: T
authors.lastname: Admyre
authors.forename: Majlis
authors.initials: M
authors.lastname: Hermansson
authors.forename: Gerhard
authors.initials: G
authors.lastname: Böttcher
authors.forename: Melker
authors.initials: M
authors.lastname: Göransson
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindén
authors.forename: Krister
authors.initials: K
authors.lastname: Bamberg
authors.forename: Jan
authors.initials: J
authors.lastname: Oscarsson
authors.forename: Mohammad
authors.initials: M
authors.lastname: Bohlooly-Y
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D000375:Aging; D000818:Animals; D001786:Blood Glucose; D001823:Body Composition; D001835:Body Weight; D048429:Cell Size; D002149:Energy Intake; D004734:Energy Metabolism; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D065626:Non-alcoholic Fatty Liver Disease; D009929:Organ Size; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics; D012867:Skin / Q000473:pathology; D014280:Triglycerides / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001786:Blood Glucose; D005947:Glucose; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated