Published online Nov 21, 2014. doi: 10.3748/wjg.v20.i43.16227
Revised: January 6, 2014
Accepted: June 14, 2014
Published online: November 21, 2014
Processing time: 372 Days and 2.8 Hours
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.
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.