Abstract
Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we report fasting-induced Fibroblast Growth Factor-21 (FGF21) signaling activates hepatic autophagy and lipid degradation via Jumonji-D3 (JMJD3/KDM6B) histone demethylase. Upon FGF21 signaling, JMJD3 epigenetically upregulates global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increases its nuclear localization and interaction with the nuclear receptor PPARα to transcriptionally activate autophagy. Administration of FGF21 in obese mice improves defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and ULK1 is substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.
Highlights
Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation
Expression of 846 genes was decreased by downregulation of JMJD3 (Fig. 1b, Supplementary Fig. 2a), which include genes involved in autophagy, Ulk1, Atg3, Atg7, and Lc3; a transcriptional activator of autophagy, Tfeb7; a lipase important for lipophagy, Atgl17; and a fasting-induced hepatokine promoting lipid catabolism, Fgf2118,19, and H3K27-me3 levels detected by ChIP-seq at most of these genes were increased (Fig. 1c, Supplementary Fig. 2c)
The present study shows that histone demethylase JMJD3 is a key epigenetic activator of hepatic autophagy as part of a fastinginduced Fibroblast Growth Factor-21 (FGF21)-JMJD3 signaling axis in mice
Summary
Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. We report fasting-induced Fibroblast Growth Factor-21 (FGF21) signaling activates hepatic autophagy and lipid degradation via Jumonji-D3 (JMJD3/KDM6B) histone demethylase. Upon FGF21 signaling, JMJD3 epigenetically upregulates global autophagy-network genes, including Tfeb, Atg, Atgl, and Fgf, through demethylation of histone H3K27-me, resulting in autophagy-mediated lipid degradation. In non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and ULK1 is substantially decreased These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals. Histone acetyltransferase hMOF has a role in determining whether autophagy induction leads to cellular survival or death, and the AMPK-SKP2-CARM1 signaling axis epigenetically activates transcription of autophagy-related genes after nutrient deprivation. JMJD3 is activated by the fasting-induced hepatokine, Fibroblast Growth Factor-21 (FGF21), and epigenetically upregulates global autophagy-network genes. We further show that FGF21-mediated autophagy induction and lowering lipids in obese mice are dependent on JMJD3 and that the hepatic FGF21JMJD3-autophagy axis is likely dysregulated in NAFLD patients
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