title: Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function.
abstract: 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.
authors.affiliation: Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, MO Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO.
authors.forename: Annayya R
authors.initials: AR
authors.lastname: Aroor
authors.affiliation: Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, MO Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO.
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.affiliation: Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO Center for Cardiovascular Research, Saint Louis University, St. Louis, MO.
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
authors.affiliation: Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, MO Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO.
authors.forename: Ravi
authors.initials: R
authors.lastname: Nistala
authors.affiliation: Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, MO Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO.
authors.forename: Guido
authors.initials: G
authors.lastname: Lastra
authors.affiliation: Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Missouri, Columbia, MO Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO.
authors.forename: Camila
authors.initials: C
authors.lastname: Manrique
authors.affiliation: Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO Center for Cardiovascular Research, Saint Louis University, St. Louis, MO.
authors.forename: Merlow M
authors.initials: MM
authors.lastname: Dunham
authors.affiliation: Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO Center for Cardiovascular Research, Saint Louis University, St. Louis, MO.
authors.forename: Kaitlin D
authors.initials: KD
authors.lastname: Ford
authors.affiliation: 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.
authors.forename: John P
authors.initials: JP
authors.lastname: Thyfault
authors.affiliation: 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.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Parks
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
authors.affiliation: 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.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Rector
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001823:Body Composition / Q000187:drug effects; D002518:Ceramides / Q000097:blood; D066273:Diet, Western / Q000009:adverse effects*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D010168:Palmitates / Q000097:blood; D019289:Pyruvic Acid / Q000097:blood; D014230:Triazoles / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood
chemical_list: D002518:Ceramides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C570834:MK0626; D010168:Palmitates; D014230:Triazoles; D014280:Triglycerides; D019289:Pyruvic Acid