Wilson Claire H, Ali Eunüs S, Scrimgeour Nathan, Martin Alyce M, Hua Jin, Tallis George A, Rychkov Grigori Y, Barritt Greg J
*Department of Medical Biochemistry, School of Medicine, Flinders University, Adelaide, South Australia 5001, Australia.
†School of Medical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.
Biochem J. 2015 Mar 1;466(2):379-90. doi: 10.1042/BJ20140881.
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.
肝细胞中的脂质积累可导致非酒精性脂肪性肝病（NAFLD），该病可进展为非酒精性脂肪性肝炎（NASH）和2型糖尿病（T2D）。激素引发的内质网（ER）钙库中Ca²⁺的释放以及随后通过SOCs（储存-操纵性Ca²⁺通道；SOCE）的Ca²⁺内流对这些钙库的补充在肝脏代谢调节中起关键作用。已知在脂肪变性的肝细胞中ER Ca²⁺稳态会发生改变。本研究调查了脂肪变性的肝细胞中储存-操纵性Ca²⁺内流是否改变以及相关机制。通过胺碘酮或棕榈酸酯在体外培养的肝细胞中诱导脂质积累，并在体内从肥胖Zucker大鼠分离的肝细胞中诱导脂质积累。脂质负载细胞中Ca²⁺的内流和释放速率显著降低。Ca²⁺内流的抑制与激素引发的细胞内Ca²⁺信号转导减少以及脂质积累增加有关。Ca²⁺内流受损与基质相互作用分子1（STIM1）或Orai1的表达改变无关。蛋白激酶C（PKC）的抑制可逆转脂质负载细胞中Ca²⁺内流的损伤。研究得出结论，脂肪变性通过PKC依赖性机制导致SOCE受到显著抑制。这通过正反馈增强脂质积累，并可能促进NASH和胰岛素抵抗的发展。
