| First Author | Vernia S | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 44 | Pages | e2210434119 |
| PubMed ID | 36282921 | Mgi Jnum | J:351526 |
| Mgi Id | MGI:7384242 | Doi | 10.1073/pnas.2210434119 |
| Citation | Vernia S, et al. (2022) Phosphorylation of RXRalpha mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome. Proc Natl Acad Sci U S A 119(44):e2210434119 |
| abstractText | The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating peroxisome proliferator-activated receptor alpha (PPARalpha)-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 JNK2alpha and JNK2beta. Here we demonstrate that Fgf21 gene expression and metabolic regulation are primarily regulated by the JNK2alpha isoform. To identify relevant substrates of JNK2alpha, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK deficiency in hepatocytes, and mice that express only JNK2alpha or JNK2beta in hepatocytes. We identified the JNK substrate retinoid X receptor alpha (RXRalpha) as a protein that exhibited JNK2alpha-promoted phosphorylation in vivo. RXRalpha functions as a heterodimeric partner of PPARalpha and may therefore mediate the effects of JNK2alpha signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXRalpha proteins. We found that the RXRalpha 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. |
