Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase

Sangwon Byun, Sunmi Seok, Young-Chae Kim, Yang Zhang, Peter Yau, Naoki Iwamori, H. Eric Xu, Jian Ma, Byron Kemper and Jongsook Kim Kemper ()
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Sangwon Byun: University of Illinois at Urbana-Champaign
Sunmi Seok: University of Illinois at Urbana-Champaign
Young-Chae Kim: University of Illinois at Urbana-Champaign
Yang Zhang: Carnegie Mellon University
Peter Yau: University of Illinois at Urbana-Champaign
Naoki Iwamori: Kyushu University
H. Eric Xu: Van Andel Research Institute
Jian Ma: Carnegie Mellon University
Byron Kemper: University of Illinois at Urbana-Champaign
Jongsook Kim Kemper: University of Illinois at Urbana-Champaign

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14384-z

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