小肠成纤维细胞生长因子15/19通过调控PPARα延缓非酒精性脂肪肝病的机制研究

非酒精性脂肪性肝病NAFLD发病率在我国急剧上升。肝细胞脂肪不断累积是推动NAFLD向NASH转变的主要风险因素。核受体PPARα调控肝脏脂代谢。在肠道成纤维细胞生长因子15（FGF15）转基因小鼠肝脏中，PPARα及其靶基因水平显著上调，表明FGF15在RNA和蛋白多个水平调控PPARα表达。本项目对两种可能的调控机制进行研究：1）FGF15/19直接结合于其受体FGFR4，并激活下游JNK/ERK通路，进而磷酸化PPARα的结构域并调节其蛋白活性。同时，激活的MAPK通路作用于PPARα的5’UTR，直接影响其基因转录；2）FGF15/19激活FGFR4后，抑制胆汁酸的合成，降低胆汁酸通过EGFR/GSK3β介导的PPARα蛋白降解，从而间接地上调PPARα蛋白。此外，利用高脂诱导小鼠模型验证FGF15通过上调PPARα加速肝脏脂肪酸β氧化，延缓或阻止NAFLD疾病发展。

The prevalence of nonalcoholic fatty liver disease (NAFLD) in China has been increased dramatically in the past decade, and will continue to increase in the next ten to twenty years. Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. The pathologensis is unclear. NAFLD starts with the simple steatosis, and might develop to NASH in twenty years with the continuous accumulation of fat. Our preliminary RNA-seq data on tissue specific inducible Fibroblast growth factor FGF15 （FGF15） transgenic mice (TG) showed that mRNA levels of PPARα and its target genes are significantly increased compared to those in Wild-type mice, indicating the intestinal FGF15 regulates PPARα in both RNA and protein levels. Based on these preliminary data and the findings in the lab, two mechanisms are proposed for this project: 1) FGF15/19, secreted into blood and transfered to liver, binds to its receptor of FGFR4 in the liver, which further activates its downstream JNK1/2 and ERK1/2 signaling pathways. Activation of JNK/ERK might activate the phosphorylation sites in PPARα domains, thus affects its transcriptional activity and up-regulates its target gene expression. 2) FGF15/19 binds to its receptor FGFR4, then activates its downstream pathways to suppress bile acid biosynthesis, which greatly decreases the bile acid (BA) level in serum and intestine, as well as the whole-body bile acid pool size. Decreased BAs inhibit the BA/EGFR/GSK3β mediated ubiquitin (Ub)-proteasome degradation of PPARα protein. In turn, the overall PPARα protein level is increased with the decreased BA levels. We propose that the increase of PPARα and PPARα-mediated fatty acid β-oxidation, would decrease the fat deposit in the liver of FGF15 TG mice, and thus prevent the NAFLD development and NASH progression under high-fat feeding,which will bring a novel strategy or approach for NASH prevention or treatment.