Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A.
Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A.
复制标题
DOI：
10.1038/s41467-020-19803-9
复制
发表时间：
2020-11-24
影响因子：
16.6
通讯作者：
Kemper JK
中科院分区：
文献类型：
--
作者：
Kim YC;Seok S;Zhang Y;Ma J;Kong B;Guo G;Kemper B;Kemper JK
肝脏脂肪生成通常受到严格的调节，但在肥胖症中异常升高。成纤维细胞生长因子-15/19（小鼠FGF 15，人FGF 19）是胆汁酸诱导的晚期进食状态肠道激素，其通过不清楚的机制降低肝脏脂质水平。我们发现FGF 15/19和FGF 15/19激活的小异源二聚体伴侣（SHP/NR 0 B2）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顺式组，包括受FGF 19抑制的脂肪生成基因，具有重叠的CpG岛。小鼠中的FGF 19治疗或SHP过表达以DNA甲基转移酶-3a（DNMT 3A）依赖性方式抑制脂肪生成。FGF 19介导的通过磷酸化的SHP激活将DNMT 3A募集到脂肪生成基因，导致通过DNA甲基化的表观遗传抑制。在非酒精性脂肪性肝病（NAFLD）患者和肥胖小鼠中，SHP和DNMT 3A的占有率以及脂肪生成基因的DNA甲基化水平较低，基因表达升高。总之，FGF 15/19通过生理上激活SHP和DNMT 3A来抑制肝脏脂肪生成，这可能在NAFLD中失调。肝脏脂肪生成是一个受到严格调节的过程，在肥胖症中会增加。在这里，作者报告说，FGF 15/19，胆汁酸诱导的肠道激素，通过激活小异源二聚体伴侣（SHP）和促进DNA甲基转移酶DNMT 3A向脂肪生成基因的SHP依赖性募集，在晚期进食状态下抑制脂肪生成基因。
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. Hepatic lipogenesis is a tightly regulated process, which is elevated in obesity. Here the authors report that FGF15/19, bile acid-induced gut hormones, repress lipogenic genes in the late fed-state by activating small heterodimer partner (SHP) and promoting SHP-dependent recruitment of DNA methyltransferase DNMT3A to lipogenic genes.
登录
查看更多内容
影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
DOI：
10.1002/hep.29305
发表时间：
2017-12
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Akinrotimi O;Riessen R;VanDuyne P;Park JE;Lee YK;Wong LJ;Zavacki AM;Schoonjans K;Anakk S
通讯作者：
Anakk S
DOI：
10.1126/science.1198125
发表时间：
2011-03-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Feng D;Liu T;Sun Z;Bugge A;Mullican SE;Alenghat T;Liu XS;Lazar MA
通讯作者：
Lazar MA
影响因子：
20.8
作者：
Gadaleta, Raffaella Maria;Moschetta, Antonio
通讯作者：
Moschetta, Antonio
影响因子：
4.8
作者：
Bhatnagar, Sushant;Damron, Holly A.;Hillgartner, F. Bradley
通讯作者：
Hillgartner, F. Bradley