Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated...

Area of Science:

• Hepatology
• Molecular Biology
• Cellular Biology

Background:

• Palmitic acid (PA) induces hepatocyte apoptosis, a key factor in nonalcoholic fatty liver disease (NAFLD) progression.
• Inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is implicated in PA-induced apoptosis, with elevated expression in NAFLD patients and PA-treated hepatocytes.
• The precise mechanism by which PA increases IP3R1 expression remains to be elucidated.

Purpose of the Study:

• To investigate the mechanism by which palmitic acid (PA) enhances Inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) expression in hepatic cells.
• To explore the role of the src pathway in PA-induced IP3R1 stabilization and subsequent mitochondrial dysfunction.
• To evaluate the therapeutic potential of targeting the src/IP3R1 pathway for NAFLD treatment.

Main Methods:

• Utilized hepatic cell models treated with palmitic acid (PA).
• Assessed mitochondrial function, apoptosis markers, and IP3R1 expression levels (mRNA and protein).
• Employed siRNA for IP3R1 inhibition and SU6656, a src kinase inhibitor, to investigate pathway involvement.

Main Results:

• PA induced mitochondrial dysfunction and apoptosis, correlating with increased IP3R1 expression.
• PA enhanced IP3R1 protein stability rather than mRNA levels, involving phosphorylation at Tyr353.
• Inhibition of src kinase (SU6656) reduced IP3R1 phosphorylation and stabilized IP3R1, improving mitochondrial function and reducing apoptosis.

Conclusions:

• Palmitic acid promotes IP3R1 phosphorylation via src pathway activation, increasing protein stability and leading to mitochondrial Ca2+ overload and dysfunction.
• Targeting the src/IP3R1 pathway, for instance with SU6656, presents a potential therapeutic strategy for nonalcoholic fatty liver disease.