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.