Dipeptidyl Peptidase-4 Inhibition Ameliorates Western Diet-Induced Hepatic Steatosis and Insulin Resistance Through Hepatic Lipid Remodeling and Modulation of Hepatic Mitochondrial Function

作者：Aroor Annayya R; Habibi Javad; Ford David A; Nistala Ravi; Lastra Guido; Manrique Camila; Dunham Merlow M; Ford Kaitlin D; Thyfault John P; Parks Elizabeth J; Sowers James R; Rector R Scott^*

来源：Diabetes, 2015, 64(6): 1988-2001.

DOI：10.2337/db14-0804

Novel therapies are needed for treating the increasing prevalence of hepatic steatosis in Western populations. In this regard, dipeptidyl peptidase-4 (DPP-4) inhibitors have recently been reported to attenuate the development of hepatic steatosis, but the potential mechanisms remain poorly defined. In the current study, 4-week-old C57BI/6 mice were fed a high-fat/high-fructose Western diet (WD) or a WD containing the DPP-4 inhibitor, MK0626, for 16 weeks. The DPP-4 inhibitor prevented WD-induced hepatic steatosis and reduced hepatic insulin resistance by enhancing insulin suppression of hepatic glucose output. WD-induced accumulation of hepatic triacylglycerol (TAG) and diacylglycerol (DAG) content was significantly attenuated with DPP-4 inhibitor treatment. In addition, MK0626 significantly reduced mitochondrial incomplete palmitate oxidation and increased indices of pyruvate dehydrogenase activity, TCA cycle flux, and hepatic TAG secretion. Furthermore, DPP-4 inhibition rescued WD-induced decreases in hepatic PGC-1 alpha and CPT-1 mRNA expression and hepatic Sirt1 protein content. Moreover, plasma uric acid levels in mice fed the WD were decreased after MK0626 treatment. These studies suggest that DPP-4 inhibition ameliorates hepatic steatosis and insulin resistance by suppressing hepatic TAG and DAG accumulation through enhanced mitochondrial carbohydrate utilization and hepatic TAG secretion/export with a concomitant reduction of uric acid production.

• 出版日期2015-6