Phosphorylation of RXRa mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome

The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating peroxisome proliferator-activated receptor a (PPAR alpha)-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 JNK2 alpha and JNK2 beta. Here we demonstrate that Fgf21 gene expression and metabolic regulation are primarily regulated by the JNK2a isoform. To identify relevant substrates of JNK2 alpha, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK deficiency in hepatocytes, and mice that express only JNK2 alpha or JNK2 beta in hepatocytes. We identified the JNK substrate retinoid X receptor a (RXRa) as a protein that exhibited JNK2 alpha-promoted phosphorylation in vivo. RXRa functions as a heterodimeric partner of PPARa and may therefore mediate the effects of JNK2 alpha signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXR alpha proteins. We found that the RXR alpha phosphorylation site Ser(260) was required for suppression of Fgf21 gene expression. Collectively, these data establish a JNK-mediated signaling pathway that regulates hepatic Fgf21 expression.