Apple polyphenol extract alleviates lipid accumulation in free‐fatty‐acid‐exposed HepG2 cells via activating autophagy mediated by SIRT1/AMPK signaling

Abstract

Defective degradation of intracellular lipids induced by autophagy is causally linked to the development of non-alcoholic fatty liver disease (NAFLD). Natural agents that can restore autophagy could therefore have the potentials for clinical applications for this public health issue. Herein, we investigated the effects of apple polyphenol extract (APE) on fatty acid-induced lipids depositions in HepG2 cells. APE treatment alleviated palmitic acid and oleic acid-induced intracellular lipid accumulation, concomitant with the increased autophagy, restored lysosomal acidification, inhibited lipid synthesis and slight promotion of fatty acid oxidation. Mechanistically, APE up-regulated the expression of SIRT1, activated LKB1/AMPK pathway and inhibited mTOR signaling. Over-expressed or knock-down SIRT1 positively regulated AMPK and ATG7 expressions. SIRT1 and ATG7 knock-down impaired APE induction of improved lipid accumulation, increased intracellular TG content. Thus, APE induction of autophagy to ameliorate fatty acid-induced lipid deposition is SIRT1 dependent, APE conserved preventive potentials for clinical hepatosteatosis.

Dietary Polyphenols in Metabolic and Neurodegenerative Diseases: Molecular Targets in Autophagy and Biological Effects

“…Similar protective results related to lipid accumulation in a mice model of NAFLD in response to blueberry polyphenols were reported [118]. Very recently, the protective effect exerted by a polyphenol extract from apple in the activation of lipophagy and restoration of lysosomal pH was related to intervention through the SIRT1/AMPK signaling [119]. In fact, polyphenols such as quercetin can stimulate lysosomal biogenesis and, hence, the clearance capacity of the cells by facilitating the nuclear translocation of TFEB [64].…”

LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

“…In addition, macrophages produce different pro-inflammatory cytokines to maintain the inflammatory response when ER stress occurs. For example, activation of the PERK/ATF4/CHOP signaling pathway promotes the release of TNF-α and IL-1β, and activation of IRE1α/JNK signaling pathway stimulates the release of IL-1β, IL-6, and IL-8 ( Li D. et al, 2021 ; Song et al, 2021 ). However, activating the LKB1/AMPK signaling pathway robustly inhibits ER stress, reduces the production of pro-inflammatory cytokines, and alleviates cellular inflammatory responses ( Rao et al, 2019 ).…”

Dietary Anti-Aging Polyphenols and Potential Mechanisms

“…In addition to the direct action on eNOS expression/activity, polyphenols were reported to activate Sirt1 [182,183], which is an upstream regulator of eNOS [184,185], therefore Sirt1-mediated mitochondrial biogenesis might underlie the anti-aging actions of polyphenols against oxidative stress. Indeed, resveratrol treatment increased mitochondrial biogenesis in wild-type mice but not eNOS knockout mice [179].…”