한빛사 논문
Sangwon Byun1,6,7, Sunmi Seok1,7, Young-Chae Kim1, Yang Zhang2, Peter Yau3, Naoki Iwamori4, H. Eric Xu5, Jian Ma2, Byron Kemper1 & Jongsook Kim Kemper1,*
1 Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
2 Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
3 Proteomics Center, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
4 Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka 812-85812, Japan.
5 Laboratory of Structure Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
6 Present address: Korea Research Institute of Bioscience and Biotechnology (KRIBB), Gwahak-ro, Yuseong-gu, Daejeon, South Korea.
7 Thease authors contributed equally: Sangwon Byun, Sunmi Seok.
*Correspondence to Jongsook Kim Kemper
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.
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