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

Author:

Wilson Claire H.1,Ali Eunüs S.1,Scrimgeour Nathan2,Martin Alyce M.1,Hua Jin1,Tallis George A.3,Rychkov Grigori Y.2,Barritt Greg J.1

Affiliation:

1. Department of Medical Biochemistry, School of Medicine, Flinders University, Adelaide, South Australia 5001, Australia

2. School of Medical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia

3. Medical Biochemistry, SA Pathology, Finders Medical Centre, Bedford Park, South Australia 5042, Australia

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.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

Reference56 articles.

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