Objective: To detect the therapeutic efficacy of FGF21 analogues on the zebrafish model of non-alcoholic fatty liver disease. Methods: A zebrafish model of non-alcoholic fatty liver disease was established by providing the normal diet fed to wild-type zebrafish three times daily. PF-05231023 was administered exogenously at a final concentration of 0.5 μmol/L. Body length, body weight, triglycerides, and other indexes were measured after 20 days. Pathological changes were evaluated in liver tissue sections by HE staining. Quantitative PCR was used to identify expressional changes in genes related to lipid metabolism, endoplasmic reticulum stress, and inflammation. Results: QPCR and immunofluorescence staining results showed that FGF21 was highly expressed in the zebrafish model group. The addition of the FGF21 analogue PF-05231023 significantly reduced the body length and body weight (P < 0.01), and the triglyceride content (P < 0.05) in the zebrafish model group. The liver HE staining results showed that PF-05231023 had alleviated the large and tiny bullae fat, lesions, and others in the zebrafish model group. The quantitative PCR results demonstrated that PF-05231023 reduced the expression of lipogenic factors (P < 0.01), inflammatory-related factors (P < 0.001), and genes related to endoplasmic reticulum stress (P < 0.05), but raised lipid-oxidation-related factors (P < 0.05) in the zebrafish model group. The addition of PF-05231023 reduced oleic acid-induced lipid and triglyceride levels in HepG2 cells. Conclusion: FGF21 analogue addition can improve indexes in the zebrafish disease model of non-alcoholic fatty liver disease.
目的： 检测成纤维细胞生长因子21类似物对非酒精性脂肪性肝病斑马鱼模型的治疗效果。 方法： 采用每日给予3倍正常饮食的方式喂养野生型斑马鱼建立非酒精性脂肪性肝病斑马鱼模型，外源给予终浓度为0.5 μmol/L PF-05231023，20 d后检测其体长、体质量、体内甘油三酯等指标。肝脏组织切片HE染色评价病理学变化。定量PCR检测与脂质代谢、内质网应激及炎症等相关基因的表达变化。组间比较采用t检验进行统计学分析。 结果： QPCR和免疫荧光染色结果显示，成纤维细胞生长因子21在模型组斑马鱼高表达。加入成纤维细胞生长因子21类似物PF-05231023，显著降低模型组斑马鱼体长和体质量（P < 0.01）、模型组体内甘油三酯的含量（P < 0.05）。肝脏HE染色结果显示PF-05231023可以减轻模型组斑马鱼肝脏脂肪大泡和小泡等病变。定量PCR结果表明PF-05231023降低模型组脂质生成因子表达（P < 0.01），增加脂质氧化相关因子表达（P < 0.05）。PF-05231023降低模型组与炎症相关的因子表达（P < 0.001）。PF-05231023降低模型组与内质网应激相关基因表达（P < 0.05）。加入PF-05231023，可以减低油酸诱导HepG2细胞中的脂质和甘油三酯水平。 结论： 加入FGF21类似物，可以改善非酒精性脂肪性肝病斑马鱼模型的疾病指征。.
Keywords: Disease; Indications; Non-alcoholic fatty liver disease; Zebrafish.