Pharmacological evaluation of pioglitazone and candesartan cilexetil in a novel mouse model of non-alcoholic steatohepatitis, modified choline-deficient, amino acid-defined diet fed low-density lipoprotein receptor knockout mice.

Abstract Low-density lipoprotein receptor knockout (LDLR-KO) mouse fed with modified choline-deficient and amino acid-defined (mCDAA) diet exhibits non-alcoholic steatohepatitis (NASH)-like pathophysiology. In order to pharmacologically benchmark this model, effects of pioglitazone, a thiazolidinedione and candesartan cilexetil, an angiotensin II type 1 receptor blocker (ARB) on steatosis and liver fibrosis were examined. Pioglitazone (10 mg/kg) and candesartan cilexetil (3 mg/kg) were orally administered once daily to LDLR-KO mice under mCDAA diet for 7 weeks. Blood biochemistry and hepatic histology were assessed, and hepatic gene expression levels and triglyceride content were measured. Pioglitazone suppressed hepatic collagen-1 gene expression by 43% and attenuated hepatic fibrosis areas by 49%. Pioglitazone also decreased plasma alanine aminotransferase (ALT) levels, liver weight, hepatic triglyceride content and hepatic expression of other fibrosis-related genes such as transforming growth factor β, osteopontin, and tissue inhibitor of metalloproteinase 1, and interleukin-6. Candesartan cilexetil suppressed hepatic collagen-1 gene expression by 33%, while the other endpoints including hepatic fibrosis areas were not affected. Pioglitazone exhibited anti-fibrotic effects accompanied by improving hepatic transaminase activity and hepatic lipid accumulation, but the effect of candesartan cilexetil was only limited unlike previous reports for ARBs. Since the pharmacological effects of pioglitazone in the current animal model are similar to those reported in patients with NASH, this model may represent some aspects of the pathophysiology of NASH. Further profiling using other agents or mechanisms that have been tested in the clinic will better clarify the utility of the animal model.