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.
Highlights
Hepatolenticular degeneration (HLD) is an autosomal recessive copper metabolism disorder caused by mutations in the ATP7B gene (Lutsenko et al, 2007; Schilsky, 2014)
The results showed that the level of fibrosis was significantly increased after copper treatment (p < 0.01), suggesting that copper accumulation can activate acidsensitive ion channel 1a and activate hepatic stellate cells (Figure 1B)
The abnormal gene is located on chromosome 13 q14 ∼ q21; this gene is known as the ATP7B gene, and it encodes a P-type copper transporter ATPase (ATP7B protein) (Chang and Hahn, 2017)
Summary
Hepatolenticular degeneration (HLD) is an autosomal recessive copper metabolism disorder caused by mutations in the ATP7B gene (Lutsenko et al, 2007; Schilsky, 2014). The excretion of copper ions enters the biliary tract, and free copper accumulates in the liver, causing inflammation and acidification of the tissue, which activates hepatic stellate cells. ECM is unbalanced degradation and deposition in the liver, making liver fibrosis the main pathological change in the liver of HLD patients (Sun and Kisseleva, 2015; Gerosa et al, 2019). The accumulation of copper in hepatolenticular degeneration is accompanied by inflammation and acidification, but the mechanism underlying the development of fibrosis is currently less well studied (Wu et al, 2019). We have tried to prove that ASIC1a is activated by acidification caused by copper accumulation and plays a role in promoting fibrosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
