HFD-inducued metabolic syndrome is promoted by JNK7b isoform

The JUN NH2-terminal kinase (JNK) signal transduction pathway is activated during the hepatic metabolic stress response. The pre-mRNAs expressed by the Mapk8 and Mapk9 genes (encode JNK1 and JNK2) in hepatocytes exhibit mutually exclusive inclusion exons 7a or 7b that encode a segment of the substrate binding site that is required for selective protein phosphorylation. We established mice with conditional inclusion of exons 7a / 7b to test the function of JNK spliceoforms. We report that the JNK27b spliceoform plays a key role in the hepatic metabolic stress response by suppressing signaling by the nuclear hormone receptor PPARa. This function of JNK27b is mediated by an integrated mechanism involving circadian dysfunction and the phosphorylation of the PPARa partner protein RXRa on Ser265. Our analysis identifies a key role for a specific JNK spliceoform in the hepatic adaptive response to metabolic stress.