Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A

Young-Chae Kim, Sunmi Seok, Yang Zhang, Jian Ma, Bo Kong, Grace Guo, Byron Kemper and Jongsook Kim Kemper ()
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Young-Chae Kim: University of Illinois at Urbana-Champaign
Sunmi Seok: University of Illinois at Urbana-Champaign
Yang Zhang: School of Computer Science, Carnegie Mellon University
Jian Ma: School of Computer Science, Carnegie Mellon University
Bo Kong: Ernest Mario School of Pharmacy, Rutgers University
Grace Guo: Ernest Mario School of Pharmacy, Rutgers University
Byron Kemper: University of Illinois at Urbana-Champaign
Jongsook Kim Kemper: University of Illinois at Urbana-Champaign

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19803-9

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