S1836 Glucagon Like Peptide 1 (GLP-1) Attenuates Hepatic Steatosis in Nonalcoholic Steatohepatitis in Diabetic Mice

Abstract

Background and aims: Metabolic syndrome-related NASH is one of the emerging healththreatening problems in industrialized countries worldwide. Despite of numerous experimental/clinical challenges, therapeutic strategies for NASH have not been well established. In this study, we investigated the therapeutic effect of ursolic acid, a pentacyclic triterpene acid, on high-fat diet (HFD)-induced steatohepatitis in obese, diabetic KK-Ay mice.Methods: Male, 8-week old KK-Aymice were fed a diet containing 32% fat for 4 weeks, and subsequently given daily intra-gastric injections of UA (100 mg/kg BW, suspended in 0.5% metyl-cellulose solution) or vehicle alone in combination with continuous HFD-feeding for up to 4 weeks. Liver histology was assessed by H-E staining. Serum aminotransferases and tissue triglyceride levels were determined colorimetrically by standard enzymatic methods. Steady state mRNA levels for SREBP-1c, fatty acid synthase (FAS), enoyl-CoA hydratase (ECHD) and acyl-CoA oxidase 1 (ACOX1) in the liver were analyzed quantitatively by real-time RT-PCR. Results: All KK-Ay mice gained body weight constantly during 4-week pre-feeding period, and the control mice continued gaining body weight over 10% during the subsequent 4-week treatment period; however, mice given UA lost body weight nearly 7% (P<0.001 vs. control group) despite of the equivalent dietary consumption. Except for body weight loss, mice treated with UA appeared to be healthy. KK-Ay mice developed remarkable steatohepatitis following 4-week pre-feeding with HFD as expected; however, treatment with UA dramatically improved liver pathology within 1 week, and the effect was sustained for 4-week treatment period. Indeed, serum transaminases levels, as well as hepatic triglyceride contents, were decreased significantly in mice treated with UA. Interestingly, mice treated with UA showed significantly decreased expression of hepatic SREBP-1c and FAS mRNA levels, indicating that fatty acid synthesis is down-regulated by UA. Further, hepatic mRNA levels of β-oxidation enzymes such as ECHD and ACOX1 were also significantly lower in UAtreated mice.Conclusions: These findings clearly demonstrated that ursolic acid significantly improves HFD-induced severe steatohepatitis in KK-Ay mice without dietary restriction. The mechanisms underlying this therapeutic effect of UA most likely involve decreased fatty acid synthesis and radical-generating β-oxidation in the liver. Since this chemical is an active ingredient of herbal medicine, it is postulated that UA is useful for a new preventive/ therapeutic reagent for NASH.