Department of Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, Shanghai 201102, China.
State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
Can J Gastroenterol Hepatol. 2021 Jan 15;2021:8894685. doi: 10.1155/2021/8894685. eCollection 2021.
Our recent study demonstrated that growth differentiation factor 5 (GDF5) could promote white adipose tissue thermogenesis and alleviate high-fat diet- (HFD-) induced obesity in fatty acid-binding protein 4- (Fabp4-) GDF5 transgenic mice (TG). Here, we further investigated the effects of systemic overexpression of the GDF5 gene in adipocytes HFD-induced nonalcoholic fatty liver disease (NAFLD).
Fabp4-GDF5 TG mice were administered an HFD feeding. NAFLD-related indicators associated with lipid metabolism and inflammation were measured. A GDF5 lentiviral vector was constructed, and the LO2 NAFLD cell model was induced by FFA solution (oleic acid and palmitic acid). The alterations in liver function, liver lipid metabolism, and related inflammatory indicators were analyzed.
The liver weight was significantly reduced in the TG group, which was in accordance with the significantly downregulated expression of TNF, MCP1, Aim2, and SREBP-1c and significantly upregulated expression of CPT-1 and ACOX2 in TG mouse livers. Compared to that of cells in the FAA-free control group, LO2 cells with in situ overexpression of GDF5 developed lipid droplets after FFA treatment; the levels of triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were significantly increased in both the GDF5 lentivirus and control lentivirus groups compared with those of the FAA-free group. Additionally, the levels of FAS, SREBP-1, CPT-1, and inflammation-associated genes, such as ASC and NLRC4, were unaltered despite GDF5 treatment.
Systemic overexpression of GDF5 in adipose tissue in vivo significantly reduced HFD-induced NAFLD liver damage in mice. The overexpression of GDF5 in hepatocytes failed to improve lipid accumulation and inflammation-related reactions induced by mixed fatty acids, suggesting that the protective effect of GDF5 in NAFLD was mainly due to the reduction in adipose tissue and improvements in metabolism. Hence, our study suggests that the management of NAFLD should be targeted to reduce the overall amount of body fat and improve metabolic status before the progression to nonalcoholic steatohepatitis occurs.
我们最近的研究表明，生长分化因子 5（GDF5）可促进白色脂肪组织产热，减轻脂肪酸结合蛋白 4（Fabp4）-GDF5 转基因小鼠（TG）的高脂肪饮食（HFD）诱导的肥胖。在这里，我们进一步研究了脂肪细胞中 GDF5 基因的系统过表达对 HFD 诱导的非酒精性脂肪性肝病（NAFLD）的影响。
用 HFD 喂养 Fabp4-GDF5 TG 小鼠。测量与脂质代谢和炎症相关的 NAFLD 相关指标。构建 GDF5 慢病毒载体，用 FFA 溶液（油酸和棕榈酸）诱导 LO2NAFLD 细胞模型。分析肝肝功能、肝脂质代谢和相关炎症指标的变化。
TG 组的肝重明显减轻，TG 鼠肝中 TNF、MCP1、Aim2 和 SREBP-1c 的表达明显下调，CPT-1 和 ACOX2 的表达明显上调。与 FAA 无对照组相比，FFA 处理后原位过表达 GDF5 的 LO2 细胞出现脂滴；GDF5 慢病毒和对照慢病毒组的甘油三酯、丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平均明显高于 FAA 无组。此外，尽管 GDF5 治疗，但 FAS、SREBP-1、CPT-1 和炎症相关基因（如 ASC 和 NLRC4）的水平没有改变。
体内脂肪组织中 GDF5 的系统过表达可显著减轻 HFD 诱导的小鼠 NAFLD 肝损伤。混合脂肪酸诱导的肝细胞中 GDF5 的过表达未能改善脂质堆积和炎症相关反应，提示 GDF5 在 NAFLD 中的保护作用主要是由于脂肪组织减少和代谢改善。因此，我们的研究表明，在非酒精性脂肪性肝炎进展之前，应针对减少总体体脂量和改善代谢状态来管理 NAFLD。
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