title: Steatosis inhibits liver cell store-operated Ca²⁺ entry and reduces ER Ca²⁺ through a protein kinase C-dependent mechanism.
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.
authors.affiliation: *Department of Medical Biochemistry, School of Medicine, Flinders University, Adelaide, South Australia 5001, Australia.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Wilson
authors.affiliation: *Department of Medical Biochemistry, School of Medicine, Flinders University, Adelaide, South Australia 5001, Australia.
authors.forename: Eunüs S
authors.initials: ES
authors.lastname: Ali
authors.affiliation: †School of Medical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Nathan
authors.initials: N
authors.lastname: Scrimgeour
authors.affiliation: *Department of Medical Biochemistry, School of Medicine, Flinders University, Adelaide, South Australia 5001, Australia.
authors.forename: Alyce M
authors.initials: AM
authors.lastname: Martin
authors.affiliation: *Department of Medical Biochemistry, School of Medicine, Flinders University, Adelaide, South Australia 5001, Australia.
authors.forename: Jin
authors.initials: J
authors.lastname: Hua
authors.affiliation: ‡Medical Biochemistry, SA Pathology, Finders Medical Centre, Bedford Park, South Australia 5042, Australia.
authors.forename: George A
authors.initials: GA
authors.lastname: Tallis
authors.affiliation: †School of Medical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Grigori Y
authors.initials: GY
authors.lastname: Rychkov
authors.affiliation: *Department of Medical Biochemistry, School of Medicine, Flinders University, Adelaide, South Australia 5001, Australia.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Barritt
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000071740:ORAI1 Protein; D009765:Obesity / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D011924:Rats, Zucker; D000071737:Stromal Interaction Molecule 1
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D008562:Membrane Glycoproteins; D000071740:ORAI1 Protein; C532493:Orai1 protein, rat; D047428:Protein Kinase Inhibitors; C518857:Stim1 protein, rat; D000071737:Stromal Interaction Molecule 1; D011493:Protein Kinase C