Mechanism Of Nuclear Receptor Nur77 Regulating Lipid Metabolism In Nonalcoholic Fatty Liver Disease

With the improvement of living standards,non-alcoholic fatty liver Disease(NAFLD)develops into a chronic metabolic disease that plagues the world.However,there is no effective treatment for this type of disease,and targeted therapy is urgently needed.Non-alcoholic fatty liver disease is a prevalent liver disease associated with lipotoxicity,lipid peroxidation,oxdative stress,and inflammation.The nuclear orphan receptor Nur77 is one member of the NR4A family,a transcriptional regulator and a lipotoxicity sensor.Nur77 plays a critical role in the glucose and lipid metabolism.However,the physiological function of Nur77 in lipid metabolism of NAFLD is unclear.Therefore,this project aims to explore the role of nuclear receptor Nur77 in NAFLD and its potential molecular mechanism.We treated human hepatocytes with oleic acid or high glucose/insulin to establish an in vitro fat infiltration model,and used zebrafish to construct NAFLD anminal model.Then detected the expression of Nur77 and lipogenesis related enzymes under various models.In the current study,we discovered that the expression level of Nur77 and transcription factor SREBP1,which regulates lipogenesis,were higher in the liver tissue of NAFLD patients and diet-induced NAFLD zebrafish than in the matched control groups.The same phenomenon could be observed in cell experiments.Moreover,when Nur77 was knocked out or its expression was inhibited,the process of de novo lipogenesis mediated by SREBP1 was also inhibited.Melatonin inhibited steatosis by regulating the function of Nur77,thereby improving lipid accumulation in the liver.Further studies showed that Nur77 bound to the promoter region of SREBP cleavage activating protein(SCAP),and regulated the activation of SREBP1 at the protein activation level,promoting the expression of SREBP 1 downstream target genes.Our findings demonstrated that Nur77 is an important regulator of hepatic lipid metabolism,which provides a line of evidence for taking Nur77 as a drug target in lipid metabolism disorder-associated diseases,such as NAFLD.