Abstract
Impaired autophagy has been implicated in the pathogenesis of nonalcoholic fatty liver disease. Catalpol (CAT), a bioactive compound from Rehmannia (Di Huang) glutinosa, is known to ameliorate insulin resistance and the histological NAFLD spectrum in obese mice. Here, we investigated the effects of CAT on hepatic steatosis and autophagy in ob/ob and high-fat diet-induced obese mice, as well as in hepatocytes. In ob/ob mice, CAT reduced liver weight, liver triglyceride and cholesterol content, and hepatic lipogenic enzyme levels and increased fatty acid oxidase levels. In addition, CAT administration increased LC3-II levels and decreased SQSTM1/P62 levels in ob/ob mice. Similar effects on hepatic steatosis and autophagy were observed in high-fat diet-induced mice after administration of CAT. Additionally, we found that CAT stimulated AMPK and increased nuclear translocation of transcription factor EB (TFEB) in obese mice and hepatocytes. Inhibition of AMPK completely blocked the effects of CAT on TFEB nuclear localization, hepatic autophagy, and liver steatosis. These findings revealed that diminished AMPK/TFEB-dependent autophagy is involved in the pathogenesis of liver steatosis in obesity, and that CAT might be a novel therapeutic candidate for treatment of this condition.
Highlights
The incidence of nonalcoholic fatty liver disease (NAFLD), which often accompanies obesity, is on the rise worldwide
After CAT administration, protein levels of LC3-II, a well-established marker of autophagy induction, increased, while levels of sequestosome 1 (SQSTM1)/p62 protein, which accumulates when autophagy is suppressed, decreased (Figure 1F). These results indicate that CAT might prevent liver steatosis by inducing autophagy
Because free fatty acid (FFA)-induced lipotoxicity and resulting cell death are important features of the pathogenesis of NAFLD [18], we investigated the effect of CAT on caspase-3 (CASP3) activity in high-fat diet (HFD) mice
Summary
The incidence of nonalcoholic fatty liver disease (NAFLD), which often accompanies obesity, is on the rise worldwide. NAFLD is strongly associated with obesity, insulin resistance, and subclinical systemic inflammatory state; lifestyle modification, weight loss, insulin-sensitizing agents, and bariatric surgery are commonly recommended treatments [1]. There are no safe and effective pharmacologic therapies available for the treatment of NAFLD. Catalpol (CAT), an iridoid glucoside isolated from the root of Rehmannia glutinosa that has anti-oxidant [5] and anti-inflammatory [6] effects, can counteract antiinsulin resistance in an animal model of diabetes [7]. CAT reduced obesity- and diet-induced insulin resistance and inflammation, which are both major contributors to NAFLD pathogenesis [6, 8]. Yan et al [9] reported that CAT ameliorated hepatic steatosis as well as insulin resistance in HFD/streptozocin (HFD/STZ)-induced diabetic mice.
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