AUTHOR=Kong Lingjin , Huang Huiping , Luan Shaohua , Liu Hui , Ye Manping , Wu Fanrong TITLE=Inhibition of ASIC1a-Mediated ERS Improves the Activation of HSCs and Copper Transport Under Copper Load JOURNAL=Frontiers in Pharmacology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.653272 DOI=10.3389/fphar.2021.653272 ISSN=1663-9812 ABSTRACT=

Hepatolenticular degeneration (HLD) is an autosomal recessive genetic disease caused by the toxic accumulation of copper in the liver. Excessive copper will disrupt the redox balance in cells and tissues, causing ischemia, hypoxia, and inflammation. Acid-sensitive ion channel 1a is a cationic channel activated by extracellular acid and allowing Ca2+ and Na+ to flow into cells. Its expression appears in inflammation, arthritis, fibrotic tissue, and damaged environment, but its role in hepatolenticular degeneration has not been studied. This study established a Wistar rat model of high copper accumulation and used CuSO4 to induce the activation of HSC-T6 in an in vitro experiment. In vivo, Wistar rats were examined to determine the serum copper concentration, serum ALT and AST activities, and liver copper accumulation, and liver tissue HE staining and immunohistochemical analyses were conducted. The expression of ASIC1a, α-SMA, Collagen-Ι, GRP78, XBP1, ATP7B, and CCS were detected. Besides, immunofluorescence technology can detect the expression of the phosphorylated protein in vitro. It is suggested that ASIC1a is involved in the quality control of the endoplasmic reticulum, which degrades mutant ATP7B and increases the accumulation of copper. After blocking or silencing the expression of ASIC1a, ELISA can detect the level of inflammatory factors, the expression of endoplasmic reticulum stress-related factors, and ATP7B was improved in a higher copper environment reduction of copper deposition was observed in liver Timm’s staining. Collectively, we conclude that ASIC1a is involved in the HSC activation induced by copper accumulation and promotes the occurrence of hepatolenticular fibrosis.