Dysregulated Autophagy in Hepatocytes Promotes Bisphenol A–Induced Hepatic Lipid Accumulation in Male Mice

Abstract

Accumulating evidence suggests that bisphenol A (BPA) exposure is associated with nonalcoholic fatty liver disease. Disruption of autophagy causes lipid accumulation in hepatocytes. Whether and how BPA regulates autophagy remains to be explored. We investigated the effect of BPA on autophagy in hepatocytes and examined the influence of BPA-regulated autophagy on hepatic lipid accumulation. Male CD1 mice were treated with BPA for 8 weeks, followed by histological and biochemical evaluation of liver lipids and autophagy. Also, the effects of BPA on autophagy and hepatic lipid accumulation were examined in primary hepatocytes and HepG2 cells. Lipid content in HepG2 cells and/or primary hepatocytes was increased obviously after BPA exposure. In addition, BPA exposure caused accumulation of autophagosomes in HepG2 cells and enhanced colocalization of Bodipy 493/503 with microtubule associated protein light-chain 3. These changes were accompanied with increased expression levels of p-mammalian target of rapamycin, p-p70S6 kinase, p-ULK1 and decreased expression levels of Atg5. BPA exposure also downregulated the expression of cathepsin L and decreased cytoplasmic retention of acridine orange in HepG2 cells. The impaired autophagic degradation was further evidenced by increased levels of p62 in BPA-treated HepG2 cells. At the whole animal level, BPA treatment induced lipid accumulation in livers of male CD1 mice, which was accompanied with changes in hepatic autophagy-related proteins. Moreover, induction of autophagy by Torin1 protected against BPA-induced lipid accumulation whereas suppression of autophagy by chloroquine exacerbated BPA-induced lipid accumulation in HepG2 cells. BPA dysregulates autophagy in hepatocytes, which is linked to BPA-induced hepatic lipid accumulation.

Non-alcoholic Fatty Liver Disease Induced by Perinatal Exposure to Bisphenol a Is Associated With Activated mTOR and TLR4/NF-κB Signaling Pathways in Offspring Rats

“…More appearance of autophagosomes does not necessarily represent enhanced autophagy, which may be due to lessened degradation, ultimately leading to ineffective autophagy. A recent study also reported that BPA exposure resulted in autophagosome accumulation in HepG2 cells and increased expression of LC3B II/I and p62 proteins, the same results were also found in the liver of male CD1 mice directly exposed to BPA in drinking water (40). Our study supports that NAFLD induced by perinatal exposure to BPA is associated with dysregulated autophagy in the liver of male and female offspring.…”

“…Autophagy is a cellular process also known as programmed cell death type 2, which can lead to a form of non-apoptotic cell death (39). The destruction of autophagy is associated with a number of metabolic disorders, including type 2 diabetes, obesity, liver damage, and NAFLD (40). A study identified a significant function of autophagy in lipid metabolism, called lipophagy (41).…”

Mechanisms for Improving Hepatic Glucolipid Metabolism by Cinnamic Acid and Cinnamic Aldehyde: An Insight Provided by Multi-Omics

“…AC significantly upregulated SEC61A1, the mutation of which was reported to cause ER stress in hepatocytes, and the mutant mice displayed a diabetic phenotype ( 80 ). AL significantly increased Cathepsin S, which was demonstrated to decrease in impaired hepatic lipid metabolic situations as a lysosomal enzyme ( 81 ). Along with the aforementioned ATP6V1C1, which assures the acidity environment inside lysosomes, it is deducible that the treatments improved the autophagy in hepatocytes and contributed to lipid metabolism.…”

SIRT1/mTOR pathway‐mediated autophagy dysregulation promotes Pb‐induced hepatic lipid accumulation in HepG2 cells

“…It is well demonstrated that autophagy is a vital process in lipid metabolism. Yang et al 17 demonstrated that bisphenol A (BPA) exposure is associated with NAFLD, induction of autophagy by Torin1 (autophagy activator) protected against BPA‐induced lipid accumulation, whereas suppression of autophagy by CQ exacerbated BPA‐induced lipid accumulation; Zhao et al 45 pointed that multi‐walled carbon nanotube (MWCNTs)‐induced lipid accumulation in HepG2 cells through the modulation of lipophagy pathway; Miyamae et al 46 suggested that tetrandrine could result in lipid accumulation in hepatic stellate cell and the blocked autophagy might be responsible for this phenomenon; Besides, our previous reports also proved that palmitic acid (PA) and 1,3‐dichloro‐2‐propanol (1,3‐DCP)‐induced lipid accumulation was related to blocked autophagy, and activation of autophagy could relieve this effect 16,30 . Currently, limited studies address the effect of Pb on lipid accumulation, and the mechanism remains unclear.…”

“…Numerous studies have demonstrated a critical function for autophagy in lipid metabolism, which is termed lipophagy. In fact, in the process of lipophagy, lipidation of microtubule associated protein light‐chain 3 (LC3) that locate in the autophagic vacuole membrane could selectively interact with lipid drops (LDs) and sequestrate LDs into double‐membrane autophagosomes, and then autophagosomes fuse with lysosomes to form autolysosomes and there is subsequent degradation of the LDs by lysosomal enzymes within the autolysosomes and finally produce free fatty acids and released into the cytoplasm 16–18 . Of importance, liver is an essential metabolic organ and highly depends on autophagy to regulate lipid metabolism and dysregulated autophagy may lead to lipid accumulation.…”