Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Pediatric Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain.
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain.
Diabetes. 2016 Oct;65(10):3185-99. doi: 10.2337/db16-0155. Epub 2016 Aug 2.
Fibroblast growth factor 21 (FGF21), a peptide hormone with pleiotropic effects on carbohydrate and lipid metabolism, is considered a target for the treatment of diabetes. We investigated the role of peroxisome proliferator-activated receptor (PPAR) β/δ deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARβ/δ-null mice and in mouse primary hepatocytes when this receptor was knocked down by small interfering RNA (siRNA). Increased Fgf21 was associated with enhanced protein levels in the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2α and activating transcription factor (ATF) 4, which is essential for Fgf21-induced expression. siRNA analysis demonstrated that HRI regulates Fgf21 expression in primary hepatocytes. Enhanced Fgf21 expression attenuated tunicamycin-induced endoplasmic reticulum stress, as demonstrated by using a neutralizing antibody against FGF21. Of note, increased Fgf21 expression in mice fed a high-fat diet or hepatocytes exposed to palmitate was accompanied by reduced PPARβ/δ and activation of the HRI-eIF2α-ATF4 pathway. Moreover, pharmacological activation of HRI increased Fgf21 expression and reduced lipid-induced hepatic steatosis and glucose intolerance, but these effects were not observed in Fgf21-null mice. Overall, these findings suggest that HRI is a potential target for regulating hepatic FGF21 levels.
成纤维细胞生长因子 21（FGF21）是一种具有多种碳水化合物和脂质代谢作用的肽类激素，被认为是治疗糖尿病的靶点。我们研究了过氧化物酶体增殖物激活受体（PPAR）β/δ 缺乏在肝 FGF21 调节中的作用。在 PPARβ/δ 敲除小鼠的肝脏和用小干扰 RNA（siRNA）敲低该受体的小鼠原代肝细胞中观察到 Fgf21 表达增加。Fgf21 的增加与血红素调节的真核起始因子 2α（eIF2α）激酶（HRI）的蛋白水平增强相关。这种增加导致磷酸化 eIF2α 和激活转录因子（ATF）4 的水平增强，这对于 Fgf21 诱导的表达是必需的。siRNA 分析表明，HRI 调节原代肝细胞中的 Fgf21 表达。增强的 Fgf21 表达减弱了衣霉素诱导的内质网应激，这是通过使用针对 FGF21 的中和抗体来证明的。值得注意的是，高脂饮食喂养的小鼠或暴露于棕榈酸的肝细胞中 Fgf21 表达增加伴随着 PPARβ/δ 的减少和 HRI-eIF2α-ATF4 途径的激活。此外，HRI 的药理学激活增加了 Fgf21 的表达，并减少了脂质诱导的肝脂肪变性和葡萄糖不耐受，但在 Fgf21 敲除小鼠中未观察到这些效应。总的来说，这些发现表明 HRI 是调节肝 FGF21 水平的潜在靶点。
