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Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes.
- Source :
-
Experimental cell research [Exp Cell Res] 2021 Feb 15; Vol. 399 (2), pp. 112438. Date of Electronic Publication: 2021 Jan 05. - Publication Year :
- 2021
-
Abstract
- Palmitic acid (PA)-induced hepatocyte apoptosis is critical for the progression of nonalcoholic fatty liver disease (NAFLD). Inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is an intracellular Ca <superscript>2+</superscript> -release channel and is involved in PA-induced hepatocyte apoptosis. While the expression of IP3R1 is elevated in patients with NAFLD and in hepatocytes treated with PA, it remains unclear how PA promotes the expression of IP3R1. In present study, our results showed that PA induced mitochondrial dysfunction and apoptosis, which is accompanied with the increase of the IP3R1 expression in hepatic cells. The inhibition of IP3R1 expression using siRNA ameliorated the PA-induced mitochondrial dysfunction. Furthermore, PA enhanced the stability of the IP3R1 protein instead of an increase in its mRNA levels. PA also promoted the phosphorylation of IP3R1 at the Tyr353 site and increased the phosphorylation of src in hepatic cells. Moreover, an inhibitor of src kinase (SU6656) significantly reduced the Tyr353 phosphorylation of IP3R1 and decreased its stability. In addition, SU6656 improved mitochondrial function and reduced apoptosis in hepatocytes. Conclusion: PA promotes the Tyr353 phosphorylation of IP3R1 by activating the src pathway and increasing the protein stability of IP3R1, which consequently results in mitochondrial Ca <superscript>2+</superscript> overload and mitochondrial dysfunction in hepatic cells. Our results also suggested that inhibition of the src/IP3R1 pathway, such as by SU6656, may be a novel potential therapeutic approach for the treatment of NAFLD.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Cells, Cultured
Hep G2 Cells
Hepatocytes physiology
Humans
Indoles pharmacology
Mitochondria drug effects
Mitochondria metabolism
Non-alcoholic Fatty Liver Disease metabolism
Non-alcoholic Fatty Liver Disease pathology
Phosphorylation drug effects
Protein Stability
Signal Transduction drug effects
Sulfonamides pharmacology
src-Family Kinases antagonists & inhibitors
src-Family Kinases physiology
Apoptosis drug effects
Hepatocytes drug effects
Inositol 1,4,5-Trisphosphate Receptors metabolism
Palmitic Acid pharmacology
src-Family Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2422
- Volume :
- 399
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Experimental cell research
- Publication Type :
- Academic Journal
- Accession number :
- 33358861
- Full Text :
- https://doi.org/10.1016/j.yexcr.2020.112438