Key role of extracellular vesicles in the induction of necroptosis and apoptosis by a mixture of polycyclic aromatic hydrocarbons in the context of a steatohepatitis-like state

Abstract

A positive association between human exposure to environmental pollutants and progression from benign hepatic steatosis to advanced chronic liver diseases has been documented. Among chemicals found in air pollution, polycyclic aromatic hydrocarbons (PAHs) are of particular concern, due to their omnipresence in the environment. Ingestion of contaminated food is the primary route of exposure. Previous studies on the ability of PAHs to induce the pathological progression of liver steatosis have been limited to the analysis of individual PAHs. The aim of this study was therefore to examine the effects of a mixture of PAHs whose composition closely recapitulates that of contaminated food. The PAH mixture elicited both a steatohepatitis-like state in steatotic WIF-B9 hepatocytes (100 nM for 72 hours) and the progression of steatohepatitis in rats fed a lipid-enriched diet (0.8 mg/kg for 90 days). The PAH mixture induced transient necroptosis at 5 hours followed by a gradual increase in cellular apoptosis. PAH metabolism-dependent necroptosis appeared to be responsible for the development of the secondary apoptosis. Hepatocyte exposure induced a necroptosis-dependent release of extracellular vesicles (EVs), that appeared to be protective against necroptosis; however, those necroptotic EVs triggered apoptosis in recipient hepatocytes. Blocking of ASGR EV receptors with asialofetuin inhibited the interaction of EVs with hepatocytes and hence apoptosis. In conclusion, EV release seems to be crucial to avoid necroptosis, but inhibition of EV uptake can protect against apoptosis.