Abstract
Fenofibrate is widely used in clinical therapy to effectively ameliorate the development of non-alcoholic fatty liver disease (NAFLD); however, its specific molecular mechanism of action remains largely unknown. MicroRNAs (miRNAs) are key mediators in regulating endoplasmic reticulum (ER) stress during NAFLD, and the deregulation of miRNAs has been demonstrated in NAFLD pathophysiology. The present study aimed to identify whether fenofibrate could influence miRNA expression in NAFLD and investigate the specific mechanism of action of fenofibrate in lipid metabolism disorder-associated diseases. We found that fenofibrate alleviated ER stress and increased the levels of SERCA2b, which serves as a regulator of ER stress. Additionally, the levels of let-7 miRNA were regulated by fenofibrate; let-7 was found to target the 3′ untranslated region of SERCA2b. The present data suggest that the protective effects of fenofibrate against insulin resistance and its suppressive activity against excessive hepatic lipid accumulation may be related to the alteration of the let-7/SERCA2b axis and alleviation of ER stress.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is typically characterized by excessive accumulation of abnormal amounts of lipids in hepatocytes (Antonucci et al, 2017; Quesada-Vázquez et al, 2020)
The results indicated that fenofibrate treatment reduced homeostasis model assessment-insulin resistance (HOMA-IR) values (Figure 3A; Supplementary Table S2) and increased homeostasis model assessmentinsulin sensitivity index (HOMA-ISI) (Figure 3B; Supplementary Table S2)
The expression of let-7 family members was upregulated in diet-induced obese (DIO) mice, which were effectively reduced by fenofibrate
Summary
Non-alcoholic fatty liver disease (NAFLD) is typically characterized by excessive accumulation of abnormal amounts of lipids in hepatocytes (Antonucci et al, 2017; Quesada-Vázquez et al, 2020). Accumulating evidence has revealed that hepatic endoplasmic reticulum (ER) stress critically promotes the development of NAFLD (Puri et al, 2008). ER stress occurs when ER function is disturbed by misfolded protein accumulation or depleted ER calcium levels. The overexpression of SERCA2b improves ER stress and ameliorates NAFLD phenotypes in mice with obesity (Park et al, 2010; Fu et al, 2011; Chemaly et al, 2018). These results confirm that SERCA2b regulates ER stress during NAFLD
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