Z Gastroenterol 2015; 53 - P86
DOI: 10.1055/s-0035-1551774

NorUDCA improves liver injury and glucose sensitivity in a mouse model of obesity and steatosis

D Steinacher 1, T Claudel 1, T Stojakovic 2, M Trauner 1
  • 1Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
  • 2Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria

Background:

Non-alcoholic fatty liver disease ranges from simple benign steatosis to the more severe forms of non-alcoholic steatohepatitis (NASH), cirrhosis and ultimately hepatocellular carcinoma. The leptin deficient mouse (ob/ob) mimics metabolic syndrome and suffers from hyperinsulinemia, insulin resistance, hyperlipidemia, hepatic steatosis and inflammation. Bile acids (BA) operate via nuclear and G protein-coupled receptors. Currently, ursodeoxycholic acid (UDCA) is the only BA used as therapeutic in humans, but showed only limited efficacy in NASH. NorUDCA is a side-chained shortened derivative of UDCA improving liver injury in mouse models of cholestatic liver and bile duct injury. Therefore, we aim to explore whether NorUDCA improves hepatic steatosis and insulin resistance in ob/ob mice.

Material & Methods:

ob/ob mice received either a diet supplemented with 0.5% NorUDCA or chow diet for 6 weeks. Intraperitoneal glucose and insulin tolerance tests (IPGTT, IPITT) were performed at week 5 and 6. Serum biochemistry and liver histology were analyzed, gene and protein expressions of key markers of inflammation, lipid and glucose metabolism were assessed by RT-PCR and Western Blotting.

Results:

Mice treated with NorUDCA showed a significant reduction in AST, ALT and AP serum levels (p < 0,001). Serum triglycerides (TG) levels increased (1.4-fold induction), whereas non esterified fatty acids decreased (0.7-fold decrease), dilly hepatic TG content did not differ in NorUDCA treated mice. IPGTT uncovered a significant faster blood glucose clearance at 60 and 90 min under NorUDCA treatment. De novo lipogenesis was reduced as reflected by repressed Srebp1c and Scd1 mRNA levels (p < 0.05). mRNA expression of inflammatory marker (F4/80) was reduced by 2.2-fold and spleen weight was lower in NorUDCA treatment too.

Conclusion:

Our data suggest that NorUDCA treatment improves NASH features such as inflammation, glucose sensitivity and liver cell injury. NorUDCA may open a new avenue of pharmacological treatment for fatty liver disease and clinical studies appear warranted.