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

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.

An FGF15/19-TFEB regulatory loop controls hepatic cholesterol and bile acid homeostasis

“…Therefore, FGF15/19 inhibition of TFEB function is consistent with TFEB being a catabolic pathway activator in response to fasting signals 24,40,41 . Studies so far have attributed the cyto-protective effects of TFEB largely to activation of the autophagy-lysosome clearance pathway in various cell types and organ systems, and activation of TFEB has been thought to hold promise for treating lysosomal storage disorders and neurodegenerative diseases [20][21][22][23] .…”

“…Furthermore, many studies have also shown that FGF15/19 acts as an insulin-independent postprandial hormone to stimulate hepatic protein and glycogen synthesis and repress gluconeogenesis and autophagy 30 , 37 , 39 . Therefore, FGF15/19 inhibition of TFEB function is consistent with TFEB being a catabolic pathway activator in response to fasting signals 24 , 40 , 41 .

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BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination

“…Brd4 -floxed mice have been described previously and were generated and maintained in-house ( 22 ). For LKD of BRD4, 8-week-old Brd4 -floxed male mice were injected with 3 × 10 11 genome copies/body weight of AAV8-TBG-Cre as a control or AAV8-TBG-GFP via the tail vein as described previously ( 5 , 34 , 50 ). To examine the protective effects of FXR activation or BRD4 inhibition on drug-induced intrahepatic cholestasis, C57BL/6 mice or BRD4-LKD mice were treated daily for 7 days by oral gavage with 10 mg/kg OCA or i.p.…”

“…Chromatin IP (ChIP). ChIP assays were done as described previously (37,50). Briefly, minced mouse liver or PMH were washed twice with PBS, then incubated with 1% formaldehyde for 10 min at 37°C.…”

The therapeutic effects of FGF21 on diabetic nephropathy are realized by augmenting autophagy via AMPK/mTOR signaling pathway

“…Zhu et al found out that FGF21 significantly increased autophagy-related gene expression both in MSG mice and fatloaded HepG2 cells [22]. In addition, FGF21 also activates hepatic autophagy via JMJD3/KDM6B histone demethylase [23]. Recently, it is well known that FGF21 augments auophagy in random-pattern skin flaps via AMPK/mTOR signaling pathway and improves tissue survival [24].…”