Steatosis inhibits liver cell store-operated Ca 2+ entry and reduces ER Ca 2+ through a protein kinase C-dependent mechanism

Claire Wilson, Md Eunus Ali, Nathan Scrimgeour, Alyce Martin, Jin Hua, George Tallis, Grigori Rychkov, Gregory Barritt

    Research output: Contribution to journalArticlepeer-review

    38 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 Ca 2+ from the endoplasmic reticulum (ER) stores and subsequent replenishment of these stores by Ca 2+ 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 Ca 2+ 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 Ca 2+ entry and release were substantially reduced in lipid-loaded cells. Inhibition of Ca 2+ entry was associated with reduced hormone-initiated intracellular Ca 2+ signalling and enhanced lipid accumulation. Impaired Ca 2+ 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 Ca 2+ 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

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