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

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.

Role and Mechanism of Gut Microbiota in Human Disease

“…Furthermore, fibroblast growth factor-15/19 is a bile acid-induced gut hormone in the late fed phase that acts to decrease hepatic lipogenesis. Fibroblast growth factor-15/19 suppresses hepatic lipogenesis through an epigenetic mechanism by activating its downstream nuclear receptor small heterodimer partner, which in turn recruits the DNA methyltransferase DNA methyltransferase-3a to lipogenic gene loci such as fatty acid synthase ( Kim Y. C. et al, 2020 ). This study may shed new light on protection against metabolic diseases.…”

The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

“…SHP knockout mice show decreased expression of genes involved in lipogenesis (PPAR γ and ACC) and increased expression of genes involved in lipid oxidation and export (PPAR α and VLDL) [ 256 ]. A new study reported that SHP overexpression in mice inhibits lipogenesis in a DNA methyltransferase-3a- (DNMT3A-) dependent manner [ 257 ]. Moreover, SHP expression is regulated by other NRs in livers.…”

Role of FGF15 in Hepatic Surgery in the Presence of Tumorigenesis: Dr. Jekyll or Mr. Hyde?

“…This is the case of aldafermin (NGM282), a drug that shows positive results in the treatment of liver diseases as non-alcoholic steatohepatitis (NASH) [130] or primary sclerosing cholangitis [131]. Other studies support the idea that FGF15 could be used as a potential therapeutic option in other liver diseases [132,133]. Studies reported by our group indicated that a single dose of FGF15 in BD and cardiac death (CD) donors promote less damage and regenerative failure in liver grafts without observing hepatic tumor signals [20,21].…”