Abstract
Hepatic lipogenesis is normally tightly regulated but is aberrantly elevated in obesity. Fibroblast Growth Factor-15/19 (mouse FGF15, human FGF19) are bile acid-induced late fed-state gut hormones that decrease hepatic lipid levels by unclear mechanisms. We show that FGF15/19 and FGF15/19-activated Small Heterodimer Partner (SHP/NR0B2) have a role in transcriptional repression of lipogenesis. Comparative genomic analyses reveal that most of the SHP cistrome, including lipogenic genes repressed by FGF19, have overlapping CpG islands. FGF19 treatment or SHP overexpression in mice inhibits lipogenesis in a DNA methyltransferase-3a (DNMT3A)-dependent manner. FGF19-mediated activation of SHP via phosphorylation recruits DNMT3A to lipogenic genes, leading to epigenetic repression via DNA methylation. In non-alcoholic fatty liver disease (NAFLD) patients and obese mice, occupancy of SHP and DNMT3A and DNA methylation at lipogenic genes are low, with elevated gene expression. In conclusion, FGF15/19 represses hepatic lipogenesis by activating SHP and DNMT3A physiologically, which is likely dysregulated in NAFLD.
Highlights
Hepatic lipogenesis is normally tightly regulated but is aberrantly elevated in obesity
As a first step in determining whether the lipogenic gene program is actively repressed in the late fed state, we examined the temporal expression of key lipogenic genes, fatty acid synthase (Fasn), sterol-regulatory element binding protein-1 (Srebp1), and acetylcoA carboxylase-1 (Acc1), after refeeding C57BL/6 mice that had been fasted for 12 h
Similar to the results in FGF15-KO mice (Fig. 1c), the decrease in Fasn premRNA levels in the late fed state was blocked in SHP and AAV-Ctr (SHP)-KO mice and plateau levels of the mRNA were increased in these mice (Fig. 1d)
Summary
Hepatic lipogenesis is normally tightly regulated but is aberrantly elevated in obesity. FGF19-mediated activation of SHP via phosphorylation recruits DNMT3A to lipogenic genes, leading to epigenetic repression via DNA methylation. In non-alcoholic fatty liver disease (NAFLD) patients and obese mice, occupancy of SHP and DNMT3A and DNA methylation at lipogenic genes are low, with elevated gene expression. Hepatic lipogenesis is tightly regulated, mainly at the level of transcription, in response to nutritional states[1], but is elevated in obesity-induced non-alcoholic fatty liver disease (NAFLD) and diabetes[3,4]. We report that FGF15/19 represses hepatic lipogenesis by activating SHP and DNMT3A physiologically, but this regulation is defective in obese mice and possibly in NAFLD patients. In NAFLD patients and obese mice, occupancy of SHP and DNMT3A and DNA methylation at the lipogenic genes are aberrantly low, which is consistent with elevated expression of these genes
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