Abstract
Objective: Insulin resistance (IR) is a risk factor for non-alcoholic fatty liver disease (NAFLD), which is characterized by lipid accumulation in hepatocytes. AMP-activated protein kinase (AMPK)-induced sterol regulatory element binding protein-1c (SREBP-1c) phosphorylation is crucial for proper regulation of lipid metabolism in the liver. Astragaloside IV (AST-IV) was found to decrease lipid accumulation in hepatocytes by activating AMPK, which is required to regulate lipid metabolism in liver tissue by inducing SREBP-1c phosphorylation.Method: To evaluate the direct effect of AST on lipid accumulation in hepatocytes with IR and elucidate the underlying mechanisms, we induced IR in HepG2 cells, and used compound C and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) (an AMPK inhibitor and agonist, respectively) as control substances. We evaluated glucose, triglyceride (TG), and non-esterified fatty acid (NEFA) production, as well as SREBP-1c transcription, SREBP-1c protein expression, and downstream gene expression with or without the presence of AST. We also investigated whether phosphorylation of SREBP-1c at Ser372 was required for AST function.Results: We found that AST attenuated IR and lipid accumulation in HepG2 cells. As an AMPK activator, AST promoted gene expression and activation of AMPK by increasing phosphorylation of AMPKa. AST also inhibited translocation of SREBP-1c into the nucleus of insulin-resistant HepG2 cells by inducing phosphorylation of SREBP-1c at Ser372.Conclusion: This study demonstrated that AST attenuates IR and lipid accumulation in HepG2 cells by regulating AMPK-dependent phosphorylation of SREBP-1c at Ser372, suggesting AST as a promising drug for treating hepatic steatosis.
Highlights
Non-alcoholic fatty liver disease, which includes non-alcoholic fatty liver (NAFL), and non-alcoholic steatohepatitis (NASH), is characterized by lipid accumulation in the hepatocytes of individuals who do not consume excessive amounts of alcohol
HepG2 cells treated with a combination of astragalosides A (AST) and AICAR displayed a normal level of glucose consumption when compared with control cells, indicating that the combination of AST and AICAR had restored insulin sensitivity in the HepG2 cells (Figure 1B, p < 0.05)
These results indicated that AST might reverse IR in HepG2 cells via activation of AMP-activated protein kinase (AMPK) (Figure 1B, p < 0.05)
Summary
Non-alcoholic fatty liver disease, which includes NAFL, and NASH, is characterized by lipid accumulation in the hepatocytes of individuals who do not consume excessive amounts of alcohol. Studies reported that 27% of urban Chinese adults had NAFLD (Fan, 2013; Lankarani et al, 2013), and that prevalence increased to 58–74% in an obese population (Luyckx et al, 1998). The underlying pathological mechanism of NAFLD remains unclear, a causal relationship between lipid accumulation in hepatocytes and IR has been reported during the development of NAFLD, obesity, type 2 diabetes, and dyslipidemia (Petersen et al, 2006; Loomba et al, 2012). Lipotoxicity induced by high levels of free fatty acids (FFA) and cholesterol metabolites in the liver results in increased levels of oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction, all of which impair glucose metabolism and glycogen synthase activity (Kumashiro et al, 2011; Buzzetti et al, 2016). Because no effective and safe treatment is available for NAFLD, except for lifestyle intervention-mediated weight loss, it is extremely important to develop new and effective therapeutic methods
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