Host-derived Antiviral Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Republic of Korea.
Molecular Hepatology Section, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3 (H42, Floor 4), 68167, Mannheim, Germany; Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, 83523 Qena, Egypt.
Redox Biol. 2024 May;71:103107. doi: 10.1016/j.redox.2024.103107. Epub 2024 Mar 5.
Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.
成纤维细胞生长因子 23（FGF23）是内分泌 FGF 家族的一员，与 FGF15/19 和 FGF21 一起。最近的报告表明，在病理条件下，肝脏会产生 FGF23，尽管肝 FGF23 的作用仍不清楚。在这里，我们研究了肝 FGF23 在酒精性肝病（ALD）中的作用，并阐明了其潜在的分子机制。比较了酒精性肝炎患者和健康对照者肝脏中的 FGF23 表达。在大麻素受体 1（CB1R）、雌激素相关受体 γ（ERRγ）或 FGF23 的肝细胞特异性敲除（LKO）小鼠中检查了 FGF23 的作用。动物单独或与 ERRγ 反向激动剂一起用含酒精的液体饮食喂养。FGF23 主要在人肝的肝细胞中表达，在 ALD 患者中上调。在小鼠中，慢性酒精喂养会导致肝脏损伤，并在肝脏中诱导 FGF23，但在其他器官中没有。FGF23 是由 ERRγ 转录调节的，以响应酒精介导的 CB1R 激活。酒精诱导的肝 FGF23 和血浆 FGF23 水平的上调在 ERRγ-LKO 小鼠中丢失，而反向激动剂介导的 ERRγ 反式激活抑制可显著改善酒精性肝损伤。此外，对酒精的肝 CYP2E1 诱导是 FGF23 依赖性的。与此一致，FGF23-LKO 小鼠通过减少肝细胞凋亡和氧化应激，显示出肝 CYP2E1 表达降低和 ALD 改善。我们认识到 CBIR-ERRγ-FGF23 轴通过肝 CYP2E1 诱导促进 ALD 病理。因此，我们提出 FGF23 是治疗 ALD 的潜在治疗靶点。
