Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function.

Autor:	Aroor AR; Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, MO Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO., Habibi J; Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, MO Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO., Ford DA; Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO Center for Cardiovascular Research, Saint Louis University, St. Louis, MO., Nistala R; Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, MO Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO., Lastra G; Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, MO Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO., Manrique C; Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, MO Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO., Dunham MM; Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO Center for Cardiovascular Research, Saint Louis University, St. Louis, MO., Ford KD; Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO Center for Cardiovascular Research, Saint Louis University, St. Louis, MO., Thyfault JP; Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO., Parks EJ; Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO., Sowers JR; Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, MO Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO., Rector RS; Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO rectors@health.missouri.edu.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2015 Jun; Vol. 64 (6), pp. 1988-2001. Date of Electronic Publication: 2015 Jan 20.
DOI:	10.2337/db14-0804
Abstrakt:	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 C57Bl/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-1α 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. (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
Databáze:	MEDLINE
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