Original Article
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World J Gastroenterol. Nov 21, 2014; 20(43): 16227-16235
Published online Nov 21, 2014. doi: 10.3748/wjg.v20.i43.16227
MK-0626, a selective DPP-4 inhibitor, attenuates hepatic steatosis in ob/ob mice
Tatsuya Ohyama, Ken Sato, Yuichi Yamazaki, Hiroaki Hashizume, Norio Horiguchi, Satoru Kakizaki, Masatomo Mori, Motoyasu Kusano, Masanobu Yamada
Tatsuya Ohyama, Ken Sato, Yuichi Yamazaki, Hiroaki Hashizume, Norio Horiguchi, Satoru Kakizaki, Masatomo Mori, Masanobu Yamada, Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
Motoyasu Kusano, Department of Endoscopy and Endoscopic Surgery, Gunma University Hospital, Gunma 371-8511, Japan
Author contributions: Sato K designed the research, wrote the paper, and analyzed the data; Ohyama T and Yamazaki Y performed the experiment; Hashizume H, Horiguchi N and Kakizaki S analyzed the data; Mori M and Kusano M revised the draft critically for important intellectual content; Yamada M gave final approval of the version to be published.
Supported by Merck Sharp and Dohme
Correspondence to: Ken Sato, MD, PhD, Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. satoken@gunma-u.ac.jp
Telephone: +81-27-2208127 Fax: +81-27-2208136
Received: November 13, 2013
Revised: January 6, 2014
Accepted: June 14, 2014
Published online: November 21, 2014
Abstract

AIM: To investigate the mechanism and in vivo effects of MK-0626, a dipeptidyl peptidase-4 inhibitor, on hepatic steatosis using ob/ob mice.

METHODS: We analyzed obese (ob/ob) 8-wk-old male mice that had been randomly divided into two groups of ob/ob mice (n = 16 each) and were treated with 1.5 or 3 mg/kg MK-0626 and two control groups of untreated ob/ob mice and lean littermates (n = 16 each). All mice were fed a normal chow diet with or without MK-0626 for either four or eight weeks. Blood samples were collected, and total hepatectomy was performed.

RESULTS: The administration of dietary MK-0626 ameliorated the hepatic lipid accumulation in ob/ob mice treated with 3 mg/kg MK-0626 (3 MK), P < 0.05, vs untreated ob/ob mice (ob/ob). The MK-0626 treatment reduced the serum alanine aminotransferase levels (both treatment groups, P < 0.05 vs ob/ob) and glucoses/insulin levels/calculated HOMA scores (1.5 MK, P < 0.05 vs ob/ob; 3 MK, P < 0.01 vs ob/ob) and increased the serum adiponectin levels (3 MK, P < 0.05 vs ob/ob) in a dose-dependent manner. The MK-0626 treatment increased the mRNA expression of peroxisome proliferator-activated receptor α/microsomal triglyceride transfer protein (1.5 MK, P < 0.05 vs ob/ob; 3 MK, P < 0.01 vs ob/ob) but reduced the sterol regulatory element binding transcription factor-1c/fatty acid synthase/stearoyl-CoA desaturase-1 (both treatment groups, P < 0.01 vs ob/ob). The MK-0626 treatment increased the activity of AMP-activated protein kinase (AMPK) (both treatment groups, P < 0.01 vs ob/ob).

CONCLUSION: MK-0626 could attenuate hepatic steatosis through enhancing AMPK activity, inhibiting hepatic lipogenic gene expression, enhancing triglyceride secretion from liver and increasing serum adiponectin levels.

Keywords: Dipeptidyl peptidase-4 inhibitor, Hepatic steatosis, ob/ob mice, AMP-activated protein kinase, Microsomal triglyceride transfer protein, Adiponectin

Core tip: Administration of MK-0626, a dipeptidyl peptidase-4 inhibitor, ameliorated hepatic steatosis; reduced serum alanine aminotransferase, glucose, and insulin levels; reduced HOMA scores; and increased serum adiponectin levels in ob/ob mice. MK-0626 treatment significantly increased the mRNA expression of peroxisome proliferator-activated receptor α and microsomal triglyceride transfer protein but significantly reduced sterol regulatory element binding transcription factor-1c, fatty acid synthase and stearoyl-CoA desaturase-1. AMP-activated protein kinase (AMPK) activity was significantly increased. These results suggest that MK-0626 could attenuate hepatic steatosis by enhancing AMPK activity, inhibiting hepatic lipogenic gene expression, enhancing triglyceride secretion from the liver and increasing serum adiponectin levels.