Deranged hepatocyte intracellular Ca²⁺ homeostasis and the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in men, and the sixth in women. Non-alcoholic fatty liver disease (NAFLD) is now one of the major risk factors for HCC. NAFLD, which involves the accumulation of excess lipid in cytoplasmic lipid droplets in hepatocytes, can progress to non-alcoholic steatosis, fibrosis, and HCC. Changes in intracellular Ca²⁺ constitute important signaling pathways for the regulation of lipid and carbohydrate metabolism in normal hepatocytes. Recent studies of steatotic hepatocytes have identified lipid-induced changes in intracellular Ca²⁺, and have provided evidence that altered Ca²⁺ signaling exacerbates lipid accumulation and may promote HCC. The aims of this review are to summarise current knowledge of the lipid-induced changes in hepatocyte Ca²⁺ homeostasis, to comment on the mechanisms involved, and discuss the pathways leading from altered Ca²⁺ homeostasis to enhanced lipid accumulation and the potential promotion of HCC. In steatotic hepatocytes, lipid inhibits store-operated Ca²⁺ entry and SERCA2b, and activates Ca²⁺ efflux from the endoplasmic reticulum (ER) and its transfer to mitochondria. These changes are associated with changes in Ca²⁺ concentrations in the ER (decreased), cytoplasmic space (increased) and mitochondria (likely increased). They lead to: inhibition of lipolysis, lipid autophagy, lipid oxidation, and lipid secretion; activation of lipogenesis; increased lipid; ER stress, generation of reactive oxygen species (ROS), activation of Ca²⁺/calmodulin-dependent kinases and activation of transcription factor Nrf2. These all can potentially mediate the transition of NAFLD to HCC. It is concluded that lipid-induced changes in hepatocyte Ca²⁺ homeostasis are important in the initiation and progression of HCC. Further research is desirable to better understand the cause and effect relationships, the time courses and mechanisms involved, and the potential of Ca²⁺ transporters, channels, and binding proteins as targets for pharmacological intervention.