Nonalcoholic fatty liver disease (NAFLD) occurs when excess fat is stored in the liver and it is strongly linked with metabolic syndrome and oxidative stress. Selenium (Se) is an essential micronutrient in animals, which has a variety of biological functions, including antioxidant and anti-inflammatory. However, the exact effect of dietary selenium on NAFLD and the underlying molecular mechanism are not yet clear. Herein, we fed a high-fat diet (HFD) to C57BL/6 mice to construct an in vivo NAFLD model, treated AML-12 cells with palmitic acid (PA) to construct an in vitro NAFLD model, and AML-12 cells were stimulated with H2O2 to induce hepatocyte oxidative stress and then treated with adequate selenium. We observed that adequate selenium significantly improved the hepatic injury and insulin resistance in HFD mice, and decreased the fat accumulation and the expression of lipogenic genes in PA-induced AML-12 cells. Meanwhile, selenium significantly inhibited the production of reactive oxygen species (ROS), inhibited apoptosis, and restored mitochondrial number and membrane potential in PA- induced AML-12 cells. In addition, selenium can promote selenoproteinP1 (SEPP1) synthesis to regulate the Kelch-like ECH-associated protein 1 (KEAP1)/NF-E2-related factor 2 (NRF2) pathway, so as to defend against hepatocyte oxidative stress. These findings suggest that dietary selenium supplementation can effectively resist hepatic injury and insulin resistance during NAFLD development, and regulate the KEAP1/NRF2 pathway to resist oxidative stress by promoting SEPP1 synthesis.

Twist‐related protein 2 (TWIST2) is identified as a basic helix‐loop‐helix (b‐HLH) transcription repressor by dimerizing with other b‐HLH proteins. The significance of TWIST2 has been emphasized in various tumors; however, few studies report its functions in metabolism and metabolic diseases. Here we aimed to explore the novel role and regulation mechanism of TWIST2 in hepatic steatosis. Our results showed that Twist2 knockdown caused mice obesity, insulin resistance, and hepatic steatosis, which were accompanied with inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction. In vitro , TWIST2 overexpression ameliorated hepatocellular steatosis, inhibited inflammation, and improved mitochondrial content and function with a fibroblast growth factor 21 (FGF21)‐dependent pattern. NF‐κB negatively regulated FGF21 transcription by directly binding to FGF21 promoter DNA, which was eliminated by TWIST2 overexpression by inhibiting NF‐κB expression and translocation to nucleus. TWIST2 overexpression decreased intracellular reactive oxygen species level, increased mitochondrial DNA and biogenesis, and enhanced ATP production and antioxidation ability. Additionally, TWIST2 expression was repressed by insulin‐targeting sterol regulatory element‐binding protein 1c (SREBP1c) and forkhead box protein O1 and was enhanced by dexamethasone targeting Krüppel‐like factor 15, which directly interacted with Twist2 promoter DNA. Together, our studies identify an important role and regulation mechanism of TWIST2 in maintaining hepatic homeostasis by ameliorating steatosis, inflammation, and oxidative stress via the NF‐κB‐FGF21 or SREBP1c‐FGF21 pathway, which may provide a new therapeutic scheme for nonalcoholic fatty liver disease.—Zhou, L., Li, Q., Chen, A., Liu, N., Chen, N., Chen, X., Zhu, L., Xia, B., Gong, Y., Chen, X. KLF15‐activating Twist2 ameliorated hepatic steatosis by inhibiting inflammation and improving mitochondrial dysfunction via NF‐κB‐FGF21 or SREBP1c‐FGF21 pathway. FASEB J. 33, 14254‐14269 (2019). www.fasebj.org