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Published on: September 9, 2021
MK-0626, a selective DPP-4 inhibitor, attenuates hepatic steatosis in ob/ob mice
Tatsuya Ohyama1, Ken Sato1, Yuichi Yamazaki1
1Tatsuya 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.
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.
Insights
MK-0626, a dipeptidyl peptidase-4 inhibitor, reduced hepatic steatosis in obese mice by enhancing AMP-activated protein kinase (AMPK) activity. This treatment also improved lipid accumulation, liver enzymes, and glucose/insulin levels, offering a potential therapeutic strategy.
Area of Science:
- Metabolic Diseases
- Pharmacology
- Hepatology
Background:
- Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern.
- Dipeptidyl peptidase-4 (DPP-4) inhibitors are primarily used for type 2 diabetes management.
- The potential of DPP-4 inhibitors in treating hepatic steatosis requires further investigation.
Purpose of the Study:
- To elucidate the mechanism of action of MK-0626, a DPP-4 inhibitor, on hepatic steatosis.
- To evaluate the in vivo efficacy of MK-0626 in a preclinical model of obesity and fatty liver.
Main Methods:
- Obese (ob/ob) mice were treated with MK-0626 (1.5 or 3 mg/kg) or vehicle for 4 or 8 weeks.
- Control groups included untreated ob/ob mice and lean littermates.
- Biochemical analyses of serum markers and hepatic gene expression, along with AMP-activated protein kinase (AMPK) activity assays, were performed.
Main Results:
- MK-0626 treatment significantly ameliorated hepatic lipid accumulation in a dose-dependent manner.
- Reductions in serum alanine aminotransferase, glucose, insulin, and HOMA scores were observed.
- Increased serum adiponectin levels and enhanced hepatic AMPK activity were noted, alongside modulation of key lipogenic and triglyceride transport genes.
Conclusions:
- MK-0626 effectively attenuates hepatic steatosis in diet-induced obese mice.
- The mechanism involves enhanced AMPK activity, inhibition of lipogenic gene expression, and increased hepatic triglyceride secretion.
- MK-0626 demonstrates potential as a therapeutic agent for managing non-alcoholic fatty liver disease.
