Dipeptidyl peptidase-4 (DPP4) is a serine protease that degrades glucagon-like peptide-1 (GLP-1), an incretin hormone that stimulates insulin secretion from pancreatic

Dipeptidyl peptidase-4 (DPP4) is a serine protease that degrades glucagon-like peptide-1 (GLP-1), an incretin hormone that stimulates insulin secretion from pancreatic β-cells. DPP4 is also involved in the regulation of T cellmediated inflammatory processes. These properties of DPP4 suggest that it may play a role in the progression of nonalcoholic fatty liver disease (NAFLD). Hepatic DPP4 mRNA expression levels were analyzed by real-time PCR using liver biopsy samples from 17 NAFLD patients and 10 healthy subjects. In NAFLD patients, we also examined correlations between DPP4 expression levels and metabolic factors, including homeostasis model assessment-insulin resistance (HOMA-IR), body mass index (BMI), and serum cholesterol and triglyceride levels. To examine the potential effects of nutritional factors, DPP4 expression levels were analyzed in HepG2 cells subjected to various culture conditions. Hepatic DPP4 mRNA expression was significantly greater in NAFLD patients than in control subjects. DPP4 expression levels were negatively correlated with HOMA-IR and positively correlated with serum cholesterol levels. In HepG2 cells, high glucose significantly enhanced DPP4 expression, whereas insulin, fatty acids and cholesterol did not. Increased hepatic expression of DPP4 in NAFLD may be associated with metabolic factors, including insulin resistance, and may adversely affect glucose metabolism in this liver disease. Introduction Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological disorder characterized by the accumulation of triglycerides in hepatocytes. The incidence of NAFLD has increased markedly in recent years, accompanying the increased prevalence of obesity and type 2 diabetes mellitus (T2DM) (1). More than 10% of patients with NAFLD progress to non-alcoholic steatohepatitis (NASH), which is characterized by inflammatory cell infiltration and ballooning of hepatocytes in the liver. Liver cirrhosis and hepatocellular carcinoma occur in several patients with NASH (2). Obesity and insulin resistance (IR) are believed to be involved in the pathogenesis of NAFLD (3). Increased hepatic uptake of fatty acids as a result of elevated triglyceride degradation in adipose tissue causes hepatic fat accumulation. Reactive oxygen species (ROS) produced during lipid oxidation may induce hepatocyte death and inflammatory reactions. IR also reduces glucose uptake in muscles and diminishes insulin-dependent suppression of gluconeogenesis, ultimately progressing to T2DM (4). Dipeptidyl peptidase-4 (DPP4) inhibitors were recently introduced for the treatment of T2DM (5). DPP4 degrades glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion from pancreatic β-cells. DPP4 inhibitors enhance glucose-dependent insulin secretion by suppressing GLP-1 degradation. However, the physiological functions of DPP4 are not fully understood. In addition to its effect on GLP-1, multiple activities of DPP4 have been reported in various cellular processes. Of note, DPP4 seems to influence inflammation by regulating T cell proliferation and the cell cycle of NK cells (6,7). In addition, the enhanced tissue mRNA expression of DPP4 in diseases such as asthma or ulcerative colitis implies that DPP4 may play a role in the pathogenesis of several inflammatory diseases (8,9). Prolonged intrahepatic inflammation as a result of elevated generation of ROS is a significant process underlying the progression of liver disease from NAFLD to NASH (10). Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism MASAYUKI MIYAZAKI1, MASAKI KATO1, KOSUKE TANAKA1, MASATAKE TANAKA1, MOTOYUKI KOHJIMA1, KAZUHIKO NAKAMURA1, MUNECHIKA ENJOJI2, MAKOTO NAKAMUTA3, KAZUHIRO KOTOH1 and RYOICHI TAKAYANAGI1 1Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582; 2Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180; 3Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan Received August 29, 2011; Accepted December 6, 2011 DOI: 10.3892/mmr.2011.707 Correspondence to: Dr Masayuki Miyazaki, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka