aDepartment of Human Genetics bDepartment of Medicine, David Geffen School of Medicine at UCLA cMolecular Biology Institute, University of California, Los Angeles, California, USA.
Curr Opin Lipidol. 2014 Apr;25(2):140-7. doi: 10.1097/MOL.0000000000000060.
Hepatic bile acid synthesis is controlled, in part, by a complex enterohepatic feedback regulatory mechanism. In this review, we focus on the role of the intestinal FGF15/19 hormone in modulating bile acid levels, and additional metabolic effects on glucose metabolism, nonalcoholic liver disease (NAFLD), and liver regeneration. We also highlight the newly identified intestinal protein, Diet1, which is a modulator of FGF15/19 levels.
Low FGF19 levels are associated with bile acid diarrhea and NAFLD. In contrast, high FGF19 levels are associated with diabetes remission following Roux-en-Y gastric bypass surgery, suggesting new therapeutic approaches against type 2 diabetes. The effect of FGF15/19 on liver plasticity is a double-edged sword: whereas elevated FGF15/19 levels improve survival of mice after partial hepatectomy, FGF19 mitogenic activity is associated with liver carcinoma. Finally, a recent study has identified Diet1, an intestinal factor that influences FGF15/19 levels in mouse intestine and human enterocytes. Diet1 represents the first factor shown to influence FGF15/19 levels at a post-transcriptional level.
The biological effects of FGF15/19 make it an attractive target for treating metabolic dysregulation underlying conditions such as fatty liver and type 2 diabetes. Further elucidation of the role of Diet1 in FGF15/19 secretion may provide a control point for the pharmacological modulation of FGF15/19 levels.
肝胆汁酸的合成部分受复杂的肠肝反馈调节机制控制。在这篇综述中，我们重点关注肠道 FGF15/19 激素在调节胆汁酸水平以及对葡萄糖代谢、非酒精性肝病（NAFLD）和肝再生的其他代谢作用。我们还强调了新发现的肠道蛋白 Diet1，它是 FGF15/19 水平的调节剂。
低 FGF19 水平与胆汁酸腹泻和 NAFLD 有关。相比之下，高 FGF19 水平与 Roux-en-Y 胃旁路手术后糖尿病缓解有关，这表明了针对 2 型糖尿病的新治疗方法。FGF15/19 对肝可塑性的影响是一把双刃剑：虽然升高的 FGF15/19 水平可改善部分肝切除术后小鼠的存活率，但 FGF19 的有丝分裂活性与肝癌有关。最后，最近的一项研究确定了 Diet1，这是一种影响 FGF15/19 水平的肠道因子，可影响小鼠肠道和人肠细胞中的 FGF15/19 水平。Diet1 是第一个被证明在转录后水平影响 FGF15/19 水平的因子。
FGF15/19 的生物学效应使其成为治疗脂肪肝和 2 型糖尿病等代谢失调的有吸引力的靶点。进一步阐明 Diet1 在 FGF15/19 分泌中的作用可能为 FGF15/19 水平的药理学调节提供一个控制点。
