It is currently thought that excess fatty acid-induced lipotoxicity in hepatocytes is a critical initiator in the development of nonalcoholic fatty liver disease (NAFLD). Lipotoxicity can induce hepatocyte death; thus, reducing lipotoxicity is one of the most effective therapeutic methods to combat NAFLD. Abundant evidence has shown that hesperidin (HSP), a type of flavanone mainly found in citrus fruits, is able to ameliorate NAFLD, but the molecular mechanisms are unclear. We previously reported that pyroptosis contributed to NAFLD development and that inhibiting pyroptosis contributed to blunting the progression of NAFLD in rat models. Therefore, we questioned whether HSP could contribute to ameliorating NAFLD by modulating pyroptosis. In this study, a high-fat diet (HFD) induced dyslipidemia and hepatic lipotoxicity in rats, and HSP supplementation ameliorated dyslipidemia and insulin resistance. In addition, the HFD also caused pyroptosis in the liver and pancreas, while HSP supplementation ameliorated pyroptosis. In vitro, we found that HSP ameliorated palmitic acid-induced lipotoxicity and pyroptosis in HepG2 and INS-1E cells. In conclusion, we showed for the first time that HSP has a protective effect against liver and pancreas damage in terms of pyroptosis and provides a novel mechanism for the protective effects of HSP on NAFLD.
Purpose It is demonstrated that unsaturated fatty acids can counteract saturated fatty acids-induced lipotoxicity, but the molecular mechanisms are unclear. In this study, we investigated the protective effects of monounsaturated oleic acid (OA) against saturated palmitic acid (PA)-induced cytotoxicity in rat β cells as well as islets, and mechanistically focused on its regulation on endoplasmic reticulum (ER) stress. Methods Rat insulinoma cell line INS-1E cells and primary islets were treated with PA with or without OA for 24 h to determine the cell viability, apoptosis, and ER stress. SD rats were fed with high-fat diet (HFD) for 16 w, then, HFD was half replaced by olive oil to observe the protective effects of monounsaturated fatty acids rich diet. Results We demonstrated that PA impaired cell viability and insulin secretion of INS-1E cells and rat islets, but OA robustly rescued cells from cell death. OA substantially alleviated either PA or chemical ER stressors (thapsigargin or tunicamycin)-induced ER stress. Importantly, OA attenuated the activity of PERK-eIF2α-ATF4-CHOP pathway and regulated the ER Ca 2+ homeostasis. In vivo, only olive oil supplementation did not cause significant changes, while high-fat diet (HFD) for 32 w obviously induced islets ER stress and impaired insulin sensitivity in SD rats. Half replacement of HFD with olive oil (a mixed diet) has ameliorated this effect. Conclusion OA alleviated PA-induced lipotoxicity in INS-1E cells and improved insulin sensitivity in HFD rats. The amelioration of PA triggered ER stress may be responsible for its beneficial effects in β cells.
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