Development Of A Therapeutic ApoJ Antagonist Peptide To Against Non-alcoholic Fatty Liver Disease

Metabolic syndromes(MS),such as non-alcoholic fatty liver disease(NAFLD)and typeⅡ diabetes mellitus(T2DM)are emerging as global public health issues.NAFLD has grown the most common cause of chronic liver disease in the world and becomes one of the three major liver disease that endanger human health.Despite the underlying mechanism of NAFLD progression is complicated,the "second-hit" hypothesis is the most prevailing model for its pathogenesis.Lipid deposition is considered as the "first hit" leading to increase the vulnerability of the liver to the followed "second hit" which promotes liver injury and metabolic syndromes.Hepatic lipid deposition represents not only the central manifestation of MS,but also one of underlying causes of NAFLD.Therefore,controlling general hepatic lipid accumulation is an essential way to prevent or reverse the progression of NAFLD.Apolipoprotein J(ApoJ)is a stress-induced chaperon and exerts multiple cellular function,including autophagy and apoptosis.ApoJ participates in the regulation of fat metabolism by inhibiting the expression of sterol regulatory component-binding protein(SREBP)-lc,regulating the expression of genes related to fat synthesis and glucose metabolism.Sterol O-Acyltransferase(SOAT)also plays an important role in maintaining intracellular fat metabolism through promoting the synthesis of intracellular cholesterol esters in lipid droplets(LDs).Previously,our group has shown that under lipid stress,ApoJ interacts with SOAT2 IDR(intrinsically disordered region,IDR)with,and induces it enzymatic activity,leading to lipid deposition.The result implies that IDR of SOAT2 might be functioned as a potential peptide substrate for ApoJ chaperone.By researching relevant literatures,a proof-of-concept ApoJ antagonist peptide will be designed based on amino acid sequence of SOAT2 IDR.ApoJ antagonist peptide will be applied to compete with the interaction of ApoJ and its client protein,thus blocks client proteins-mediated signaling pathways,alleviating the accumulation of LDs in the liver.In present study,we showed that ApoJ antagonist peptide alleviates lipid accumulation in hepatoma cell lines and improves lipid and glucose homeostasis in the mouse model of NAFLD.This study showed that ApoJ is a new target for relieving hepatic lipid deposition,and a therapeutic ApoJ antagonist peptide improves the disease progression of NAFLD...