Punicalagin Inhibits Palmitate Acid-induced Lipoapoptosis through Inhibition of ER Stress, and Activation of SIRT1/Autophagy in HepG2 Cells

Abstract

Lipid metabolism balance plays a vital role in maintaining normal levels of sterols, triglycerides, and free fatty acids (FFA). Inhibiting FFA-induced lipotoxicity is considered a highly potential treatment for nonalcoholic fatty liver disease (NAFLD) and other lipid metabolism diseases. Punicalagin (PU), a pomegranate-derived polyphenol, has been found to effectively regulate lipid metabolism and prevent fatty liver, cardiovascular and other chronic diseases caused by lipid metabolism disorders. In the present study, we found that PU protects HepG2 cells from palmitic acid (PA)-induced lipapoptosis. Silent information regulator 1 (SIRT1) plays a key role in protecting against lipapoptosis in HepG2 cells. Knockdown of SIRT1 significantly diminished the protective effect of PU. Besides, PU could be able to reactivate weakened autophagy and inhibit PA-induced ER stress. Our findings supported that PU can effectively attenuate FFA-induced lipotoxicity via activating SIRT1/autophagy and inhibiting ER stress.

Punicalagin’s Protective Effects on Parkinson’s Progression in Socially Isolated and Socialized Rats: Insights into Multifaceted Pathway

“…These effects could be attributed to PUN's capability to reverse the repressive effects of SI, MnCl 2 , or SI + MnCl 2 on the AMPK/SIRT-1 pathway. AMPK activation leads to SIRT-1 activation by increasing NAD/NADH ratio, promoting autophagy and upregulated the expression of the autophagy-related gene beclin-1, leading to enhanced clearance of aggregated misfolded α-syn and subsequently suppressing neuronal apoptosis while promoting neuronal survival and improving locomotor function in PD [118][119][120] Importantly, the clearance of accumulated misfolded α-syn through enhanced autophagy may alleviate ER stress and return ER homeostasis, resulting in the suppression of neuronal apoptosis in dopaminergic neurons [121]. Additionally, SIRT-1 can sequester the pro-apoptotic protein Bax within the cytoplasm, preserving dopaminergic neurons and inhibiting neuronal apoptosis [122].…”

“…It is worth noting that AMPK and SIRT-1 mutually stimulate each other's activity, and there is a positive amplification loop between AMPK and AKT [123,124]. Earlier studies have documented the valuable properties of PUN in numerous disease states, partly by acting as an AMPK activator to enhance autophagy through the AMPK/SIRT-1 pathway [118,119].…”

Regulation of autophagy by plant‐based polyphenols: A critical review of current advances in glucolipid metabolic diseases and food industry applications

“…When cells are subjected to nutritional stress, sirtuin1 (SIRT1) influences alternative energy pathways, resulting in changes in lipid metabolism in a variety of pathophysiological settings. In vitro studies reveal that in punicalagin-or ferulic acid-treated hepatocytes exposed to PA; silencing SIRT1 greatly reduced autophagy and increased lipoapoptosis, supporting the concept that Sirt1 plays a vital role in punicalagin-or ferulic acid-regulated autophagy in lipotoxicity (Xu et al, 2021a;Zhang et al, 2020a). In vivo studies have evaluated whether pentamethylquercetin (PMQ) exerts antiobesity activities through SIRT1-regulated autophagic signaling.…”