A Postprandial FGF19-SHP-LSD1 Regulatory Axis mediates Epigenetic Repression of Hepatic autophagy

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2017 Apr 28

PMID 28446510

Citations 36

Authors

Sangwon Byun

Young-Chae Kim

Yang Zhang

Bo Kong

Grace Guo

Junichi Sadoshima

Jian Ma

Byron Kemper

Jongsook Kim Kemper

Affiliations

Soon will be listed here.

Abstract

Lysosome-mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient-sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed-state hormone, FGF19 (hFGF19, mFGF15). FGF19 treatment or feeding inhibits macroautophagy, including lipophagy, but these effects are blunted in SHP-null mice or LSD1-depleted mice. In addition, feeding-mediated autophagy inhibition is attenuated in FGF15-null mice. Upon FGF19 treatment or feeding, SHP recruits LSD1 to CREB-bound autophagy genes, including Tfeb, resulting in dissociation of CRTC2, LSD1-mediated demethylation of gene-activation histone marks H3K4-me2/3, and subsequent accumulation of repressive histone modifications. Both FXR and SHP inhibit hepatic autophagy interdependently, but while FXR acts early, SHP acts relatively late after feeding, which effectively sustains postprandial inhibition of autophagy. This study demonstrates that the FGF19-SHP-LSD1 axis maintains homeostasis by suppressing unnecessary autophagic breakdown of cellular components, including lipids, under nutrient-rich postprandial conditions.

Citing Articles

Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer.

Yuan J, Gu G, Jin B, Han Q, Li B, Zhang L Cell Death Dis. 2025; 16(1):163.

PMID: 40057469 PMC: 11890858. DOI: 10.1038/s41419-025-07489-0.

Autophagy modulates physiologic and adaptive response in the liver.

Le T, Truong N, Holterman A Liver Res. 2025; 7(4):304-320.

PMID: 39958781 PMC: 11792069. DOI: 10.1016/j.livres.2023.12.001.

FGF-based drug discovery: advances and challenges.

Chen G, Chen L, Li X, Mohammadi M Nat Rev Drug Discov. 2025; .

PMID: 39875570 DOI: 10.1038/s41573-024-01125-w.

Histone demethylases in autophagy and inflammation.

Ma Y, Lv W, Guo Y, Yin T, Bai Y, Liu Z Cell Commun Signal. 2025; 23(1):24.

PMID: 39806430 PMC: 11727796. DOI: 10.1186/s12964-024-02006-w.

Identification of chikusetsusaponin IVa as a novel lysine-specific demethylase 1 inhibitor that ameliorates high fat diet-induced MASLD in mice.

Liu Y, Luo R, Liu A, Wang J, Hu N, Li W Acta Pharmacol Sin. 2024; 46(3):632-652.

PMID: 39567752 PMC: 11845606. DOI: 10.1038/s41401-024-01412-7.

References

Kerr T, Saeki S, Schneider M, Schaefer K, Berdy S, Redder T . Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev Cell. 2002; 2(6):713-20. PMC: 4010195. DOI: 10.1016/s1534-5807(02)00154-5. View

Kim Y, Fang S, Byun S, Seok S, Kemper B, Kemper J . Farnesoid X receptor-induced lysine-specific histone demethylase reduces hepatic bile acid levels and protects the liver against bile acid toxicity. Hepatology. 2014; 62(1):220-31. PMC: 4480214. DOI: 10.1002/hep.27677. View

Rabinowitz J, White E . Autophagy and metabolism. Science. 2010; 330(6009):1344-8. PMC: 3010857. DOI: 10.1126/science.1193497. View

Byun S, Kim Y, Zhang Y, Kong B, Guo G, Sadoshima J . A postprandial FGF19-SHP-LSD1 regulatory axis mediates epigenetic repression of hepatic autophagy. EMBO J. 2017; 36(12):1755-1769. PMC: 5470039. DOI: 10.15252/embj.201695500. View

Lee J, Wagner M, Xiao R, Kim K, Feng D, Lazar M . Nutrient-sensing nuclear receptors coordinate autophagy. Nature. 2014; 516(7529):112-5. PMC: 4267857. DOI: 10.1038/nature13961. View

Singh R, Cuervo A . Lipophagy: connecting autophagy and lipid metabolism. Int J Cell Biol. 2012; 2012:282041. PMC: 3320019. DOI: 10.1155/2012/282041. View

Inagaki T, Choi M, Moschetta A, Peng L, Cummins C, McDonald J . Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005; 2(4):217-25. DOI: 10.1016/j.cmet.2005.09.001. View

Seok S, Fu T, Choi S, Li Y, Zhu R, Kumar S . Transcriptional regulation of autophagy by an FXR-CREB axis. Nature. 2014; 516(7529):108-11. PMC: 4257899. DOI: 10.1038/nature13949. View

Dentin R, Liu Y, Koo S, Hedrick S, Vargas T, Heredia J . Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature. 2007; 449(7160):366-9. DOI: 10.1038/nature06128. View

10.

Wang L, Lee Y, Bundman D, Han Y, Thevananther S, Kim C . Redundant pathways for negative feedback regulation of bile acid production. Dev Cell. 2002; 2(6):721-31. DOI: 10.1016/s1534-5807(02)00187-9. View

11.

Ong K, Mashek M, Bu S, Greenberg A, Mashek D . Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning. Hepatology. 2010; 53(1):116-26. PMC: 3025059. DOI: 10.1002/hep.24006. View

12.

Kim D, Kwon S, Byun S, Xiao Z, Park S, Wu S . Critical role of RanBP2-mediated SUMOylation of Small Heterodimer Partner in maintaining bile acid homeostasis. Nat Commun. 2016; 7:12179. PMC: 4947186. DOI: 10.1038/ncomms12179. View

13.

He C, Klionsky D . Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009; 43:67-93. PMC: 2831538. DOI: 10.1146/annurev-genet-102808-114910. View

14.

Kemper J, Kim H, Miao J, Bhalla S, Bae Y . Role of an mSin3A-Swi/Snf chromatin remodeling complex in the feedback repression of bile acid biosynthesis by SHP. Mol Cell Biol. 2004; 24(17):7707-19. PMC: 506991. DOI: 10.1128/MCB.24.17.7707-7719.2004. View

15.

Teperino R, Schoonjans K, Auwerx J . Histone methyl transferases and demethylases; can they link metabolism and transcription?. Cell Metab. 2010; 12(4):321-327. PMC: 3642811. DOI: 10.1016/j.cmet.2010.09.004. View

16.

Fang S, Miao J, Xiang L, Ponugoti B, Treuter E, Kemper J . Coordinated recruitment of histone methyltransferase G9a and other chromatin-modifying enzymes in SHP-mediated regulation of hepatic bile acid metabolism. Mol Cell Biol. 2006; 27(4):1407-24. PMC: 1800717. DOI: 10.1128/MCB.00944-06. View

17.

Grant C, Bailey T, Noble W . FIMO: scanning for occurrences of a given motif. Bioinformatics. 2011; 27(7):1017-8. PMC: 3065696. DOI: 10.1093/bioinformatics/btr064. View

18.

Artal-Martinez de Narvajas A, Gomez T, Zhang J, Mann A, Taoda Y, Gorman J . Epigenetic regulation of autophagy by the methyltransferase G9a. Mol Cell Biol. 2013; 33(20):3983-93. PMC: 3811684. DOI: 10.1128/MCB.00813-13. View

19.

Kemper J, Xiao Z, Ponugoti B, Miao J, Fang S, Kanamaluru D . FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab. 2009; 10(5):392-404. PMC: 2785075. DOI: 10.1016/j.cmet.2009.09.009. View

20.

Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell. 2008; 132(1):27-42. PMC: 2696814. DOI: 10.1016/j.cell.2007.12.018. View