The Involvement of Calcium Channels in the Endoplasmic Reticulum Membrane in Nonalcoholic Fatty Liver Disease Pathogenesis

Overview

Journal Cureus

Specialty Biomedical Engineering

Date 2023 Nov 29

PMID 38024063

Authors

Sarah S Albalawi

Ahmed Aljabri

Mohannad Alshibani

Mohammed M Al-Gayyar

Affiliations

Soon will be listed here.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a prevalent and complex condition that affects millions of people globally. It occurs when fat, primarily triglycerides, accumulates in liver cells, leading to inflammation and damage. Calcium, an essential mineral, is involved in various physiological processes, including the regeneration process following liver injury. The endoplasmic reticulum (ER), a complex organelle involved in protein synthesis and lipid metabolism, regulates intracellular calcium levels. Dysregulation of this process can lead to calcium overload, oxidative stress, and cellular damage, all of which are hallmarks of NAFLD. Inositol 1,4,5-trisphosphate receptor (IP3R), a type of calcium ion channel, is found throughout the body, including the liver. IP3R is classified into three subtypes: IP3R1, IP3R2, and IP3R3, and it plays a critical role in regulating intracellular calcium levels. However, excessive calcium accumulation in the mitochondria due to an overload of calcium ions or increased IP3R activity can lead to NAFLD. Therefore, targeting calcium channels in the ER membrane may represent a promising therapeutic strategy for preventing and treating this increasingly prevalent metabolic disorder. It may help prevent mitochondrial calcium accumulation and reduce the risk of hepatic damage. This review article aimed to review the relationship between IP3R modulation and the pathogenicity of NAFLD, providing valuable insights to help researchers develop more effective treatments for the condition.

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References

Feriod C, Nguyen L, Jurczak M, Kruglov E, Nathanson M, Shulman G . Inositol 1,4,5-trisphosphate receptor type II (InsP3R-II) is reduced in obese mice, but metabolic homeostasis is preserved in mice lacking InsP3R-II. Am J Physiol Endocrinol Metab. 2014; 307(11):E1057-64. PMC: 4254986. DOI: 10.1152/ajpendo.00236.2014. View

Belosludtsev K, Dubinin M, Belosludtseva N, Mironova G . Mitochondrial Ca2+ Transport: Mechanisms, Molecular Structures, and Role in Cells. Biochemistry (Mosc). 2019; 84(6):593-607. DOI: 10.1134/S0006297919060026. View

Yu T, Zheng E, Li Y, Li Y, Xia J, Ding Q . Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes. Exp Cell Res. 2020; 399(2):112438. DOI: 10.1016/j.yexcr.2020.112438. View

Wagner 2nd L, Li W, Yule D . Phosphorylation of type-1 inositol 1,4,5-trisphosphate receptors by cyclic nucleotide-dependent protein kinases: a mutational analysis of the functionally important sites in the S2+ and S2- splice variants. J Biol Chem. 2003; 278(46):45811-7. DOI: 10.1074/jbc.M306270200. View

Oliva-Vilarnau N, Hankeova S, Vorrink S, Mkrtchian S, Andersson E, Lauschke V . Calcium Signaling in Liver Injury and Regeneration. Front Med (Lausanne). 2018; 5:192. PMC: 6039545. DOI: 10.3389/fmed.2018.00192. View

Ji T, Han Y, Yang W, Xu B, Sun M, Jiang S . Endoplasmic reticulum stress and NLRP3 inflammasome: Crosstalk in cardiovascular and metabolic disorders. J Cell Physiol. 2019; 234(9):14773-14782. DOI: 10.1002/jcp.28275. View

Iwai M, Michikawa T, Bosanac I, Ikura M, Mikoshiba K . Molecular basis of the isoform-specific ligand-binding affinity of inositol 1,4,5-trisphosphate receptors. J Biol Chem. 2007; 282(17):12755-64. DOI: 10.1074/jbc.M609833200. View

Bosanac I, Michikawa T, Mikoshiba K, Ikura M . Structural insights into the regulatory mechanism of IP3 receptor. Biochim Biophys Acta. 2004; 1742(1-3):89-102. DOI: 10.1016/j.bbamcr.2004.09.016. View

Beaulant A, Dia M, Pillot B, Chauvin M, Ji-Cao J, Durand C . Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis. J Hepatol. 2022; 77(3):710-722. DOI: 10.1016/j.jhep.2022.03.017. View

10.

Vanderheyden V, Devogelaere B, Missiaen L, De Smedt H, Bultynck G, Parys J . Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by reversible phosphorylation and dephosphorylation. Biochim Biophys Acta. 2009; 1793(6):959-70. PMC: 2693466. DOI: 10.1016/j.bbamcr.2008.12.003. View

11.

Yin X, Guo X, Liu Z, Wang J . Advances in the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci. 2023; 24(3). PMC: 9917647. DOI: 10.3390/ijms24032844. View

12.

Feriod C, Oliveira A, Guerra M, Nguyen L, Mitchell Richards K, Jurczak M . Hepatic Inositol 1,4,5 Trisphosphate Receptor Type 1 Mediates Fatty Liver. Hepatol Commun. 2017; 1(1):23-35. PMC: 5613674. DOI: 10.1002/hep4.1012. View

13.

Mandl J, Meszaros T, Banhegyi G, Csala M . Minireview: endoplasmic reticulum stress: control in protein, lipid, and signal homeostasis. Mol Endocrinol. 2013; 27(3):384-93. PMC: 5416932. DOI: 10.1210/me.2012-1317. View

14.

Szado T, Vanderheyden V, Parys J, De Smedt H, Rietdorf K, Kotelevets L . Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis. Proc Natl Acad Sci U S A. 2008; 105(7):2427-32. PMC: 2268153. DOI: 10.1073/pnas.0711324105. View

15.

Arruda A, Pers B, Parlakgul G, Guney E, Inouye K, Hotamisligil G . Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat Med. 2014; 20(12):1427-35. PMC: 4412031. DOI: 10.1038/nm.3735. View

16.

Younossi Z, Golabi P, Paik J, Henry A, Van Dongen C, Henry L . The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023; 77(4):1335-1347. PMC: 10026948. DOI: 10.1097/HEP.0000000000000004. View

17.

Vervloessem T, Yule D, Bultynck G, Parys J . The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca²⁺-release channel. Biochim Biophys Acta. 2014; 1853(9):1992-2005. PMC: 4465056. DOI: 10.1016/j.bbamcr.2014.12.006. View

18.

Petroni M, Brodosi L, Bugianesi E, Marchesini G . Management of non-alcoholic fatty liver disease. BMJ. 2021; 372:m4747. DOI: 10.1136/bmj.m4747. View

19.

Kruglov E, Gautam S, Guerra M, Nathanson M . Type 2 inositol 1,4,5-trisphosphate receptor modulates bile salt export pump activity in rat hepatocytes. Hepatology. 2011; 54(5):1790-9. PMC: 3205211. DOI: 10.1002/hep.24548. View

20.

Wu L, Lian W, Zhao L . Calcium signaling in cancer progression and therapy. FEBS J. 2021; 288(21):6187-6205. DOI: 10.1111/febs.16133. View