Recent studies reported the positive association between exposure to insecticides and increased risks of obesity and type 2 diabetes, which is closely associated with non- alcoholic fatty liver disease (NAFLD). However, the effect of insecticide exposure on NAFLD remains unknown. Therefore, this project investigated the roles of insecticide exposure in the development of NAFLD using HepG2 hepatocytes. First, 12 insecticides were tested for their effects on triglycerides (TG) accumulation and interactions with palmitic acid (PA), which induces steatosis. Among tested insecticides, permethrin and ivermectin significantly altered TG accumulation and interacted with PA. Further mechanistic studies showed that permethrin promoted lipogenesis with or without PA and suppressed fatty acid oxidation with PA, while ivermectin suppressed lipogenesis with or without PA. Next, permethrin induces metabolic disease was further investigated. Permethrin is known to alter calcium homeostasis, which is critical for cellular functions. Thus, mechanisms of permethrin on calcium-mediated cellular signaling pathway was examined particularly on activation of the extracellular signal-related kinase (ERK1/2 or 42/p44). Permethrin induced oxidative stress and phosphorylation of ERK1/2 dependent to membrane depolarization. It was further determined that permethrin-induced ERK1/2 activation was mediated by the metabotropic glutamate receptors (mGluRs)- phosphoinositide phospholipase C (PLC)-protein kinase C (PKC) pathways, but not by changes of intracellular calcium or endoplasmic reticulum (ER) stress-mediated mechanism. Last, the potential therapeutic effect of piceatannol on NAFLD using steatosis- induced HepG2 hepatocytes was determined. Piceatannol reduced fat accumulation by suppressing lipogenesis genes (SREBP1 and ACC) and FA uptake (CD36) and promoting FA oxidation genes (FXR, PPARα, and CPT1α) in steatosis-induced HepG2 cells. Additionally, it was identified that piceatannol could exert its ameliorating effect on steatosis via anti-oxidative mediated. The findings indicated the efficacy of piceatannol mitigating the development of NAFLD and the potential involving mechanisms, which also expanded the current knowledge of developing future NAFLD treatment using plants originated phytochemicals as therapeutic agents.