TY - JOUR
T1 - Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A
AU - Kim, Young-Chae
AU - Seok, Sunmi
AU - Zhang, Yang
AU - Ma, Jian
AU - Kong, Bo
AU - Guo, Grace
AU - Kemper, Byron
AU - Kemper, Jongsook Kim
N1 - Funding Information:
The authors thank H. Eric Xu at Van Andel Research Institute for purified recombinant FGF19 and Sona Kang at University of California at Berkeley for the DNMT3A (C706S) plasmid. We also thank the Liver Tissue Cell Distribution System, University of Minnesota (NIH Contract # HHSN276201200017C) for liver specimens of NAFLD patients. Petri dish, mouse, and liver images in the figures are unmodified images provided by Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License [https://creativecommons.org/licenses/by/3.0/legalcode] This study was supported by an American Heart Association Scientist Development Award (16SDG27570006) to YK and by grants from the National Institutes of Health (DK062777 and DK095842) to JKK.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-19803-9
DO - 10.1038/s41467-020-19803-9
M3 - Article
C2 - 33235221
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5969
ER -