Abstract
Objective 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). Methods 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. Results The liver weight was significantly reduced in the TG group, which was in accordance with the significantly downregulated expression of TNFα, MCP1, Aim2, and SREBP-1c and significantly upregulated expression of CPT-1α 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-1α, and inflammation-associated genes, such as ASC and NLRC4, were unaltered despite GDF5 treatment. Conclusion 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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a metabolic disease, the incidence of which has rapidly increased in recent years [1]
We found that the weight and body mass index (BMI) of adolescents are related to single nucleotide polymorphisms in growth differentiation factor 5 (GDF5) [11]
After 72 h of lentiviral infection, the results showed that the expression of GDF5-flag was significantly increased in the GDF5 and GDF5 + FFA groups compared with the other groups (Figure 6(a)). e protein levels of NAFLD-related genes, such as FAS, CPT-1α, PPARα, and SREBP-1, were measured, and the results demonstrated that the levels of these markers in the three FFAtreated groups did not differ significantly from those in the FFA-free group, and no significant differences were observed between the three FFA-treated groups (Figures 6(b)–6(d))
Summary
Nonalcoholic fatty liver disease (NAFLD) is a metabolic disease, the incidence of which has rapidly increased in recent years [1]. NAFLD is caused by fat accumulation in hepatocytes, and when NAFLD is insufficiently controlled, it may progress to nonalcoholic steatohepatitis (NASH) [2]. NASH is a kind of progressive fatty liver disease that may worsen with time and eventually lead to serious complications such as cirrhosis, hepatocellular carcinoma (HCC), and liver failure [3]. NAFLD is the most common cause of chronic liver disease in Western developed countries, with an incidence of approximately 30% [4]; the incidence of NAFLD in China is expected to double over the 10 years. Current studies have confirmed that NAFLD is mainly associated with insulin resistance, obesity, type 2 diabetes, intestinal flora, and other metabolic disorders [10]
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