Effect Of Dual Activation Of PPARα/γ By Polyketide J2D From Marine Mud Fungi On NAFLD And Its Molecular Mechanism

PPAR α/γ as one of the important members of nuclear receptor family.It has been regarded as a good target for the treatment of NAFLD,but more and more PPARα/γClinical drugs for NAFLD are exposed to toxic and side effects such as hepatotoxicity,fracture and gallstone formation.Therefore,it is necessary to screen for PPARα/γ with specific,high efficiency and low toxicity There is still a wide range of research and application prospects in the treatment of NAFLD.Our group isolated two natural products J2D and J2B from marine mud fungi.J2D specifically activated PPARα/γ by reporter assay.In view of PPARα/γ,We tested the effects of J2D and J2B by adipocyte differentiation model and hepatocyte steatosis model.The results showed that J2D could significantly induce adipocyte differentiation and lipid accumulation,and reduce the content of lipid droplets in hepatocytes.At the same time,compared with the model group,J2D could significantly reduce the body weight,liver fat vacuoles,triglycerides,cholesterol and other pathological characteristics of C57BL mice fed with high-fat diet.PPARa in liver tissue is involved in many physiological processes,such as fatty acid transport,lipid droplet formation and oxidative metabolism.The results showed that J2D could significantly upregulate the mRNA levels of target genes of fatty acid metabolism,including slc27a2 and mitochondria.The expression level of β-oxidation enzyme acadl and so on.In addition,we found that PPARy is required for J2D to reduce oleic acid-induced lipid droplet accumulation in hepatocytes Not PPARγ The participation of the government.In conclusion,we have isolated a pair of novel PPARs from marine mud fungi and j2D has better pharmacological effect than J2B in the treatment of NAFLD.This may be helpful for the study of PPARα/γ.In the process of fatty acid metabolism,the molecular mechanism of action provides a new idea and is expected to find a new dual targeting compounds for the treatment of NAFLD.