Metabolic disorders and cancer: Hepatocyte store-operated Ca²⁺ channels in nonalcoholic fatty liver disease

In steatotic hepatocytes, intracellular Ca²⁺ homeostasis is substantially altered compared to normal. Decreased Ca²⁺ in the endoplasmic reticulum (ER) can lead to ER stress, an important mediator of the progression of liver steatosis to nonalcoholic steatohepatitis, type 2 diabetes, and hepatocellular carcinoma. Store-operated Ca²⁺ channels (SOCs) in hepatocytes are composed principally of Orai1 and STIM1 proteins. Their main role is the maintenance of adequate Ca²⁺ in the lumen of the ER. In steatotic hepatocytes, store-operated Ca²⁺ entry (SOCE) is substantially inhibited. This inhibition is associated with a decrease in Ca²⁺ in the ER. Lipid-induced inhibition of SOCE is mediated by protein kinase C (PKC) and may involve the phosphorylation and subsequent inhibition of Orai1. Experimental inhibition of SOCE enhances lipid accumulation in normal hepatocytes incubated in the presence of exogenous fatty acids. The antidiabetic drug exendin-4 reverses the lipid-induced inhibition of SOCE and decreases liver lipid with rapid onset. It is proposed that lipid-induced inhibition of SOCE in the plasma membrane and of SERCA2b in the ER membrane leads to a persistent decrease in ER Ca²⁺, ER stress, and the ER stress response, which in turn enhances (amplifies) lipid accumulation. A low level of persistent SOCE due to chronic ER Ca²⁺ depletion in steatotic hepatocytes may contribute to an elevated cytoplasmic-free Ca²⁺ concentration leading to the activation of calcium-calmodulin kinase II (CaMKII), decreased lipid removal by autophagy, and insulin resistance. It is concluded that lipid-induced inhibition of SOCE plays an important role in the progression of liver steatosis to insulin insensitivity and hepatocellular carcinoma.