生物
磷酸化
视黄醇X受体
过氧化物酶体增殖物激活受体
信号转导
细胞生物学
基因表达
FGF21型
肝细胞
激酶
核受体
受体
成纤维细胞生长因子
转录因子
生物化学
基因
体外
作者
Santiago Vernia,Alexandra Lee,Norman J. Kennedy,Myoung Sook Han,Marta Isasa,Julie Cavanagh-Kyros,Armanda Roy,Aafreen Syed,Shanzah Chaudhry,Yvonne J. K. Edwards,Steven P. Gygi,Guangping Gao,Roger J. Davis
标识
DOI:10.1073/pnas.2210434119
摘要
The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating peroxisome proliferator-activated receptor α (PPARα)-dependent expression of the hepatokine fibroblast growth factor 21 (FGF21). Hepatocyte-specific gene ablation studies demonstrated that the Mapk9 gene (encoding JNK2) plays a key mechanistic role. Mutually exclusive inclusion of exons 7a and 7b yields expression of the isoforms JNK2α and JNK2β. Here we demonstrate that Fgf21 gene expression and metabolic regulation are primarily regulated by the JNK2α isoform. To identify relevant substrates of JNK2α, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK deficiency in hepatocytes, and mice that express only JNK2α or JNK2β in hepatocytes. We identified the JNK substrate retinoid X receptor α (RXRα) as a protein that exhibited JNK2α-promoted phosphorylation in vivo. RXRα functions as a heterodimeric partner of PPARα and may therefore mediate the effects of JNK2α signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXRα proteins. We found that the RXRα phosphorylation site Ser260 was required for suppression of Fgf21 gene expression. Collectively, these data establish a JNK-mediated signaling pathway that regulates hepatic Fgf21 expression.
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