Steatosis inhibits liver cell store-operated Ca2+ entry and reduces ER Ca2+ through a protein kinase C-dependent mechanism

Claire H. Wilson, Eunüs S. Ali, Nathan Scrimgeour, Alyce M. Martin, Jin Hua, George A. Tallis, Grigori Y. Rychkov, Greg J. Barritt

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Lipid accumulation in hepatocytes can lead to non-alcoholic fatty liver disease (NAFLD), which can progress to non-alcoholic steatohepatitis (NASH) and Type 2 diabetes (T2D). Hormone-initiated release of Ca2+ from the endoplasmic reticulum (ER) stores and subsequent replenishment of these stores by Ca2+ entry through SOCs (store-operated Ca2+ channels; SOCE) plays a critical role in the regulation of liver metabolism. ER Ca2+ homoeostasis is known to be altered in steatotic hepatocytes. Whether store-operated Ca2+ entry is altered in steatotic hepatocytes and the mechanisms involved were investigated. Lipid accumulation in vitro was induced in cultured liver cells by amiodarone or palmitate and in vivo in hepatocytes isolated from obese Zucker rats. Rates of Ca2+ entry and release were substantially reduced in lipid-loaded cells. Inhibition of Ca2+ entry was associated with reduced hormone-initiated intracellular Ca2+ signalling and enhanced lipid accumulation. Impaired Ca2+ entry was not associated with altered expression of stromal interaction molecule 1 (STIM1) or Orai1. Inhibition of protein kinase C (PKC) reversed the impairment of Ca2+ entry in lipid-loaded cells. It is concluded that steatosis leads to a substantial inhibition of SOCE through a PKC-dependent mechanism. This enhances lipid accumulation by positive feedback and may contribute to the development of NASH and insulin resistance.

Original languageEnglish
Pages (from-to)379-390
Number of pages12
JournalBiochemical Journal
Volume466
DOIs
Publication statusPublished - 1 Mar 2015

Keywords

  • Hepatocytes
  • Orai1
  • Steatosis
  • Store-operated calcium entry [SOCE]
  • Stromal interaction molecule 1 (STIM1)
  • Zucker rat

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Wilson, C. H., Ali, E. S., Scrimgeour, N., Martin, A. M., Hua, J., Tallis, G. A., ... Barritt, G. J. (2015). Steatosis inhibits liver cell store-operated Ca2+ entry and reduces ER Ca2+ through a protein kinase C-dependent mechanism. Biochemical Journal, 466, 379-390. https://doi.org/10.1042/BJ20140881