A postprandial FGF 19‐ SHP ‐ LSD 1 regulatory axis mediates epigenetic repression of hepatic autophagy

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.

LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62

“…LSD1 as an epigenetic regulator of the autophagic pathway is pivotal in protecting oocytes from massive loss. Studies including ours have proved that LSD1 localizes to the nucleus of cells (Kahl et al, ; Lim et al, ) and is critical for the negative regulation of genes essential for the autophagic process by recruiting to the promoters of genes like Atg3 , Atg10 , transcription factor EB ( Tfeb) , sestrin 2 ( Sesn2 ), and p62 (Ambrosio, Ballabio, & Majello, ; Ambrosio & Majello, ; Ambrosio et al, ; Byun et al, ; Periz et al, ; Sardiello et al, ; Settembre et al, ; Wang, Long, et al, ). LSD1 importing to the nucleus is related to its N‐terminal nuclear localization signal motifs (Jin et al, ).…”

“…In most mammals, programmed loss of oocytes occurs briefly around the time of birth (Byun et al, ; Wang, et al, ; Wang, et al, ), but the reasons and the mechanisms remain uncertain. Several processes take effort to the oocyte loss and different PCDs may have various effects on oocyte PCD under specific situations before the pool of PFs is established.…”

“…However, only a handful of studies have indicated that epigenetic modification plays an important role in controlling oocyte PCD during PF pool establishment (Sun et al, , ). Most recent studies uncovered the potential role of LSD1, in mediating autophagy in various cell types (Ambrosio et al, ; Byun et al, ; Periz et al, ). LSD1 is the first identified lysine‐specific demethylase that specifically marks H3K4me1/2 and/or H3K9me1/2 via a FAD‐dependent oxidative reaction (Shi et al, ).…”

Endocrine Adiponectin‐FGF15/19 Axis in Ethanol-Induced Inflammation and Alcoholic Liver Injury

“…Both adiponectin and FGF15/19 are involved in regulating circadian rhythms, 83,84 autophagy 85,86 and ER stress 87,88 . Therefore, it is worthwhile to explore whether and how adiponectin-FGF15/19 signaling ameliorates these disturbed processes, and subsequently attenuates inflammatory responses and alleviates liver injury in response to ethanol challenge.…”

Classical and alternative roles for autophagy in lipid metabolism

“…3A). Small heterodimer partner or LSD1 knockout both markedly increase hepatic autophagy and reduce lipid accumulation [43 ▪ ]. Taken together, these transcriptional and signal transduction mechanisms construct an intricate regulatory network controlling lipophagy.…”