TY - JOUR
T1 - Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase
AU - Byun, Sangwon
AU - Seok, Sunmi
AU - Kim, Young Chae
AU - Zhang, Yang
AU - Yau, Peter
AU - Iwamori, Naoki
AU - Xu, H. Eric
AU - Ma, Jian
AU - Kemper, Byron
AU - Kemper, Jongsook Kim
N1 - Funding Information:
We thank Matthew J. Potthoff at the University of Iowa for providing liver samples from FGF21-LKO mice. We also thank Giyeong Kim for constructing the Tfeb and Atg7 luciferase reporter plasmids containing PPARα cistrome. Liver tissues of normal subjects and NAFLD patients were obtained through the Liver Tissue Cell Distribution System, University of Minnesota, which was funded by NIH Contract # HHSN276201200017C. Petri dish, mouse, and liver images in the figures are unmodified images provided by Servier Medical Art, licensed under a Creative Commons License [https:// creativecommons.org/licenses/by/3.0/legalcode]. This study was supported by an American Heart Association post-doctoral fellowship to SB (17POST33410223), an American Heart Association scientist development award (16SDG27570006) to Y.C.K., and by grants from the American Diabetes Association (1-16-IBS-156) and National Institutes of Health (DK062777 and DK095842) to J.K.K.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-14384-z
DO - 10.1038/s41467-020-14384-z
M3 - Article
C2 - 32042044
AN - SCOPUS:85079239775
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 807
ER -