Xu Yunhui, Lu Yongke
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1700 3rd Avenue, Huntington, WV, 25755, USA.
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1700 3rd Avenue, Huntington, WV, 25755, USA; Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, 1700 3rd Avenue, Huntington, WV, 25755, USA.
Biochem Biophys Res Commun. 2022 Sep 3;619:84-89. doi: 10.1016/j.bbrc.2022.05.099. Epub 2022 Jun 11.
Fibroblast growth factor 21 (FGF21) is regulated by peroxisome proliferator activated receptor α (PPARα) in the liver. FGF21 regulates lipid metabolism via fibroblast growth factor receptor 1 (FGFR1). FGF21 protect against alcoholic fatty liver (AFL), however, FGF21 does not exert protective effect through liver FGFR1. We have previously shown that PPARα agonist WY-14,643 induces FGF21 and adipose atrophy but fails to protect against chronic ethanol-induced AFL in mice lacking adipose FGFR1. In this study we tested the direct role of the FGF21 in regulation of adipose tissue mass and ethanol induced-hepatic triglyceride (TG) accumulation in normal control (fgfr1) mice and in adipose FGFR1 knockout mice (fgfr1). First, we tested whether WY-14,643 effects on adipose atrophy and AFL can be recapitulated in binge alcohol model. As in chronic model, adipose tissue mass and serum free fatty acid (FFA) were decreased by WY-14,643 in the fgfr1 mice but not in the fgfr1 mice. However, in contrast to the chronic model, binge ethanol-induced AFL was blunted by WY-14,643 to a greater extent in the fgfr1 mice than in the fgfr1 mice. Similarly, circulating FGF21 was elevated by binge ethanol to a greater extent in the fgfr1 mice than in the fgfr1 mice on top of WY-14,643 treatment. Accordingly, we tested the involvement of the FGF21 in adipose atrophy and AFL. Consistent with FGFR1-dependent effects of WY-14,643 on adipose atrophy and AFL, recombinant mouse FGF21 (rFGF21) injection induced adipose atrophy, blunted AFL and serum TG elevation to a greater extent in the fgfr1 mice than in the fgfr1 mice. These results indicated the consistency of adipose FGFR1 dependent effect of WY-14,643 and FGF21 in PPARα-mediated regulation of adipose tissue mass and fat mobilization from adipose tissues to the liver, suggesting that adipose tissues crosstalk with liver through an interaction between liver PPARα-FGF21 and adipose FGFR1 to maintain adipose tissue mass.
成纤维细胞生长因子21（FGF21）在肝脏中受过氧化物酶体增殖物激活受体α（PPARα）调控。FGF21通过成纤维细胞生长因子受体1（FGFR1）调节脂质代谢。FGF21可预防酒精性脂肪肝（AFL），然而，FGF21并非通过肝脏FGFR1发挥保护作用。我们之前已经表明，PPARα激动剂WY-14,643可诱导FGF21生成和脂肪萎缩，但在缺乏脂肪组织FGFR1的小鼠中，无法预防慢性乙醇诱导的AFL。在本研究中，我们测试了FGF21在正常对照（fgfr1）小鼠和脂肪组织FGFR1基因敲除小鼠（fgfr1）中对脂肪组织质量调节以及乙醇诱导的肝脏甘油三酯（TG）蓄积的直接作用。首先，我们测试了在暴饮酒精模型中是否能重现WY-14,643对脂肪萎缩和AFL的影响。与慢性模型一样，在fgfr1小鼠中，WY-14,643可降低脂肪组织质量和血清游离脂肪酸（FFA），但在fgfr1小鼠中则无此作用。然而，与慢性模型不同的是，在fgfr1小鼠中，暴饮乙醇诱导的AFL被WY-14,643抑制的程度比fgfr1小鼠更大。同样，在WY-14,643处理的基础上，暴饮乙醇使fgfr1小鼠循环中的FGF21升高的程度比fgfr1小鼠更大。因此，我们测试了FGF21在脂肪萎缩和AFL中的作用。与WY-14,643对脂肪萎缩和AFL的FGFR1依赖性作用一致，注射重组小鼠FGF21（rFGF21）在fgfr1小鼠中比在fgfr1小鼠中更能诱导脂肪萎缩、减轻AFL和血清TG升高。这些结果表明，WY-14,643和FGF21在PPARα介导的脂肪组织质量调节以及脂肪组织向肝脏的脂肪动员中存在脂肪组织FGFR1依赖性作用的一致性，提示脂肪组织通过肝脏PPARα-FGF21与脂肪组织FGFR1之间的相互作用与肝脏进行串扰，以维持脂肪组织质量。
