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Nonalcoholic fatty liver disease impairs expression of the type II inositol 1,4,5-trisphosphate receptor
Tanaporn Khamphaya1, Natsasi Chukijrungroat2, Vitoon Saengsirisuwan2
1Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand.
Abstract:
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide. It may result in several types of liver problems, including impaired liver regeneration (LR), but the mechanism for this is unknown. Because LR depends on calcium signaling, we examined the effects of NAFLD on expression of the type II inositol 1,4,5-trisphosphate receptor (ITPR2), the principle calcium release channel in hepatocytes. ITPR2 promoter activity was measured in Huh7 and HepG2 cells. ITPR2 and c-Jun protein levels were evaluated in Huh7 cells, in liver tissue from a rat model of NAFLD, and in liver biopsy specimens of patients with simple steatosis and nonalcoholic steatohepatitis (NASH). LR was assessed in wild-type and Itpr2 knockout (Itpr2-/- ) mice following 67% hepatectomy. Cell proliferation was examined in ITPR2-knockout HepG2 cells generated by the CRISPR/Cas9 system. c-Jun dose dependently decreased activity of the human ITPR2 promoter. c-Jun expression was increased and ITPR2 was decreased in fat-loaded Huh7 cells and in livers of rats fed a high-fat, high-fructose diet. Overexpression of c-Jun reduced protein and mRNA expression of ITPR2 in Huh7 cells, whereas knockdown of c-Jun prevented the decrease of ITPR2 in fat-loaded Huh7 cells. ITPR2 expression was decreased and c-Jun was increased in liver biopsies of patients with steatosis and NASH compared to controls. ITPR2-knockout cells exhibited less nuclear calcium signaling and cell proliferation than control cells. LR assessed by Ki-67 and proliferating cell nuclear antigen was markedly decreased in Itpr2-/- mice. Conclusion: Fatty liver induces a c-Jun-mediated decrease in ITPR2 in hepatocytes. This may account for the impaired LR that occurs in NAFLD. (Hepatology 2018;67:560-574).
Insights
Nonalcoholic fatty liver disease impairs liver regeneration by reducing the inositol 1,4,5-trisphosphate receptor type II (ITPR2) in liver cells. This decrease is mediated by increased c-Jun protein levels, impacting calcium signaling and cell proliferation.
Area of Science:
- Hepatology
- Molecular Biology
- Cell Biology
Background:
- Nonalcoholic fatty liver disease (NAFLD) is a prevalent global condition.
- Impaired liver regeneration (LR) is a known complication of NAFLD, but its underlying mechanisms remain unclear.
- Liver regeneration is critically dependent on intracellular calcium signaling pathways.
Purpose of the Study:
- To investigate the impact of NAFLD on the expression of the type II inositol 1,4,5-trisphosphate receptor (ITPR2), a key calcium release channel in hepatocytes.
- To elucidate the role of c-Jun in regulating ITPR2 expression and its contribution to impaired liver regeneration in NAFLD.
Main Methods:
- Assessed ITPR2 promoter activity in human hepatoma cell lines (Huh7 and HepG2).
- Quantified ITPR2 and c-Jun protein and mRNA levels in cell cultures, a rat model of NAFLD, and human liver biopsy samples.
- Evaluated liver regeneration and cell proliferation in wild-type and ITPR2-knockout mice and cells.
Main Results:
- c-Jun suppressed ITPR2 promoter activity in a dose-dependent manner.
- NAFLD conditions (in vitro and in vivo) led to increased c-Jun and decreased ITPR2 expression.
- ITPR2 deficiency in mice and cells resulted in reduced calcium signaling, cell proliferation, and impaired liver regeneration.
Conclusions:
- Fatty liver disease induces a decrease in hepatocyte ITPR2 expression, primarily mediated by elevated c-Jun levels.
- This c-Jun-driven reduction in ITPR2 is a potential mechanism underlying impaired liver regeneration observed in NAFLD.
- Targeting the c-Jun/ITPR2 pathway may offer therapeutic strategies for enhancing liver regeneration in NAFLD patients.