Inhibition of ASIC1a-Mediated ERS Improves the Activation of HSCs and Copper Transport Under Copper Load

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.

Diclofenac Sodium Nanomedicine Results in Pain-relief and Differential Expression of the RNA Transcriptome in the Spinal Cord of Spared Nerve Injury Rats

“…At various time points, 1 milliliter of venous blood was collected and transferred to EP tubes. The samples were placed in a 4°C refrigerator overnight and then centrifuged at 3,000 revolutions per minute for 15 minutes at 4°C [47], the upper serum layer was retained while the rest was discarded. Follow the instructions on the ELISA kits [31,48].…”

Pathology and physiology of acid‑sensitive ion channels in the digestive system (Review)

“…Therefore, the early occurrence of hepatolenticular degeneration is the same as that of liver fibrosis. Kong et al ( 115 ) induced HSC-T6 activation with CuSO 4 , and found that ASIC1a was highly expressed in activated HSC-T6 cells. They speculated that ASIC1a played a role in promoting the process of hepatolenticular degeneration fibrosis.…”

Circ0038632 modulates MiR-186/DNMT3A axis to promote proliferation and metastasis in osteosarcoma

“…Recently, increasing studies revealed that circRNAs were deeply involved in malignancy ( 2 ). CircRNA_103801 induces osteosarcoma proliferation, migration, and invasion processes by mediating miR-338-3p ( 3 ). CircTADA2A accelerates the malignant progression of osteosarcoma via modulating miR-203a-3p ( 4 ).…”