Kynurenine 3-hydroxylase Inhibitor RO 61-8048 Alleviates Nonalcoholic Fatty Liver Disease in High-Fat Diet-Induced Obese Mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) caused by childhood obesity has become an important public health problem, leading to hepatic fat accumulation, inflammation, hepatocyte apoptosis, and potential liver dysfunction. Kynurenine monooxygenase (KMO) is an enzyme of the kynurenine (Kyn) pathway, which is associated with various chronic diseases. Here, we investigated the effect of KMO inhibitor (RO 61-8048) via the kynurenine pathway for the treatment of NAFLD. In this study, C57BL/6 mice were fed with high-fat diet (HFD) and fructose/sucrose (55%:45%) for to simulate fatty degeneration in vivo. Hepatic lipid peroxidation, steatosis, inflammasome activation and apoptosis were examined. In vitro, AML12 cells was incubated with free fatty acids (FFAs) for 24 h to study the potential mechanism of RO 61-8048 treatment. Histopathological examination indicated that RO 61-8048 alleviated hepatic steatosis, lipid vacuolization, and inflammatory cell infiltration in HFD-fed mice. RO 61-8048 significantly reduced the body weights and liver weights, and ameliorated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), High-density lipoprotein cholesterol (HDL-C), Low density lipoprotein cholesterol (LDL-C) and produce quinolinic acid (QUIN) levels in C57BL/6 mice. Compared to HFD-fed mice, RO 61-8048 alleviated release of inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)−1β, IL-6) and hepatic apoptosis. A dual luciferase reporter assay suggested the interaction between SP3 and KMO promoter. Consistent with the in vivo results, RO 61-8048 alleviated lipid droplet accumulation and reduced lipid reactive oxygen species (ROS) levels and apoptosis in AML12 cells. Collectively, our study demonstrates that transcription factor specificity protein 3 (SP3) is able to bind with the promoter of KMO. The KMO inhibitor (RO 61-8048) ameliorates lipid metabolism, inflammatory injury and hepatocyte apoptosis in NAFLD through the tryptophan-kynurenine pathway, potentially serving as a promising candidate for alleviating NAFLD.