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.

肝脏脂肪生成通常受到严格调节，但肥胖异常升高。成纤维细胞生长因子15/19（小鼠FGF15，人FGF19）是胆汁酸诱导的晚期摄食状态肠道激素，其通过不清楚的机制降低肝脂质水平。我们显示，FGF15 / 19和FGF15 / 19激活的小异二聚体伴侣（SHP / NR0B2）在脂肪生成的转录抑制中起作用。比较基因组分析显示，大多数SHP病，包括受FGF19抑制的生脂基因，都有重叠的CpG岛。小鼠中的FGF19处理或SHP过表达以DNA甲基转移酶3a（DNMT3A）依赖性方式抑制脂肪生成。FGF19介导的SHP通过磷酸化激活将DNMT3A募集到脂肪生成基因，从而通过DNA甲基化导致表观遗传抑制。在非酒精性脂肪肝病（NAFLD）患者和肥胖小鼠中，SHP和DNMT3A的占有率以及致脂基因的DNA甲基化均较低，且基因表达升高。总之，FGF15 / 19通过生理上激活SHP和DNMT3A来抑制肝脏脂肪生成，这在NAFLD中可能失调。