Role of SESTRIN2/AMPK/ULK1 pathway activation and lysosomes dysfunction in NaAsO < sub > 2 < /sub > -induced liver injury under oxidative stress

Ecotoxicol Environ Saf. 2023 Mar 10;254:114751. doi: 10.1016/j.ecoenv.2023.114751. Online ahead of print.ABSTRACTArsenic, a serious environmental poison to human health, is widely distributed in nature. As the main organ of arsenic metabolism, liver is easily damaged. In the present study, we found that arsenic exposure can cause liver injury in vivo and in vitro, to date the underlying mechanism of which is yet unclear. Autophagy is a process that depends on lysosomes to degrade damaged proteins and organelles. Here, we reported that oxidative stress can be induced and then activated the SESTRIN2/AMPK/ULK1 pathway, damaged lysosomes, and finally induced necrosis upon arsenic exposure in rats and primary hepatocytes, which was characterized by lipidation of LC3II, the accumulation of P62 and the activation of RIPK1 and RIPK3. Similarly, lysosomes function and autophagy can be damaged under arsenic exposure, which can be alleviated after NAC treatment and aggravated by Leupeptin treatment in primary hepatocytes. Moreover, we also found that the transcription and protein expressions of necrotic-related indicators RIPK1 and RIPK3 in primary hepatocytes were decreased after P62 siRNA. Taken together, the results revealed that arsenic can induce oxidative stress, activate SESTRIN2/AMPK/ULK1 pathway to damage lysosomes and autophagy, and eventually induce necrosis to damage liver.PMID:36907090 | DOI:10.1016/j.ecoenv.2023.114751
Source: Ecotoxicology and Environmental Safety - Category: Environmental Health Authors: Source Type: research