Abstract
Background: Salvianolic acid A (Sal A), a natural polyphenol compound extracted from Radix Salvia miltiorrhiza (known as Danshen in China), possesses a variety of potential pharmacological activities. The aim of this study is to determine mechanisms of hepatoprotective effects of Sal A against lipotoxicity both in cultured hepatocytes and in a mouse model of fatty liver disease. Methods: High-fat and high-carbohydrate diet (HFCD)-fed C57BL/6J mice were employed to establish hepatic lipotoxicity in a mouse model. Two doses of Sal A were administered every other day via intraperitoneal injection (20 and 40 mg/kg BW, respectively). After a 10-week intervention, liver injury was detected by immunohistochemical and biochemical analyses. For in vitro studies, we used HepG2, a human hepatoma cell line, and exposed them to palmitic acid to induce lipotoxicity. The protective effects of Sal A on palmitic acid-induced lipotoxicity were examined in Sal A-pretreated HepG2 cells. Results: Sal A treatments attenuated body weight gain, liver injury, and hepatic steatosis in mice exposed to HFCD. Sal A pretreatments ameliorated palmitic acid-induced cell death but did not reverse effects of HFCD- or palmitate-induced activations of JNK, ERK1/2, and PKA. Induction of p38 phosphorylation was significantly reversed by Sal A in HFCD-fed mice but not in palmitate-treated HepG2 cells. However, Sal A rescued hepatic AMP-activated protein kinase (AMPK) suppression and sirtuin 1 (SIRT1) downregulation by both HFCD feeding in mice and exposure to palmitate in HepG2 cells. Sal A dose-dependently up-regulated p-AMPK and SIRT1 protein levels. Importantly, siRNA silencing of either AMPK or SIRT1 gene expression abolished the protective effects of Sal A on lipotoxicity. Moreover, while AMPK silencing blocked Sal A-induced SIRT1, silencing of SIRT1 had no effect on Sal A-triggered AMPK activation, suggesting SIRT1 upregulation by Sal A is mediated by AMPK activation. Conclusion: Our data uncover a novel mechanism for hepatoprotective effects of Sal A against lipotoxicity both in livers from HFCD-fed mice and palmitic acid-treated hepatocytes.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and becoming a new health challenge with the prevalence of 20% in the general population, up to 70% in patients with type 2 diabetes, and 65–85% in patients with obesity (Lobstein et al, 2004; Chalasani et al, 2012)
Salvianolic acid A (Sal A) rescued hepatic AMPactivated protein kinase (AMPK) suppression and sirtuin 1 (SIRT1) downregulation by both HFCD feeding in mice and exposure to palmitate in HepG2 cells
While AMPK silencing blocked Sal A-induced SIRT1, silencing of SIRT1 had no effect on Sal A-triggered AMPK activation, suggesting SIRT1 upregulation by Sal A is mediated by AMPK activation
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and becoming a new health challenge with the prevalence of 20% in the general population, up to 70% in patients with type 2 diabetes, and 65–85% in patients with obesity (Lobstein et al, 2004; Chalasani et al, 2012). NAFLD represents a continuum of hepatic injuries, which progress from simple hepatic steatosis to nonalcoholic steatohepatitis, with some patients even progressing to fibrosis, cirrhosis, and liver failure (Angulo, 2002). There is no Food and Drug Administration (FDA)approved drug for NAFLD. Modifying lifestyle, such as weight loss by a combination of decreased caloric intake and increased physical activity, is an effective treatment of NAFLD and is the most common recommendation by clinicians. The aim of this study is to determine mechanisms of hepatoprotective effects of Sal A against lipotoxicity both in cultured hepatocytes and in a mouse model of fatty liver disease
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