Calcium Signaling As a Therapeutic Target for Liver Steatosis

Insulin resistance in hepatocytes, endoplasmic reticulum stress, and lipid storage capacities are all important in the development of hepatic steatosis. Store-operated Ca2+ entry in liver cells has important regulatory properties in liver lipid synthesis. Calcium deficiency caused by reduced store-operated Ca2+ entry (SOCE) function may be a new crucial player in the development of liver steatosis. Reduced SOCE function increases the rate of accumulation of intracellular lipids, raising the possibility that reduced SOCE function may contribute to nonalcoholic steatohepatitis and insulin resistance. Therapies able to reactivate SOCE and/or reduce protein kinase C action and/or stimulate SERCA activity may be useful in treatment of hepatic steatosis, insulin resistance, and type 2 diabetes. Hepatic steatosis, the first step in nonalcoholic fatty liver disease (NAFLD), can arise from various pathophysiological conditions. While lipid metabolism in the liver is normally balanced such that there is no excessive lipid accumulation, when this homeostasis is disrupted lipid droplets (LDs) accumulate in hepatocytes resulting in cellular toxicity. The mechanisms underlying this accumulation and the subsequent hepatocellular damage are multifactorial and poorly understood, with the result that there are no currently approved treatments for NAFLD. Impaired calcium signaling has recently been identified as a cause of increased endoplasmic reticulum (ER) stress contributing to hepatic lipid accumulation. This review highlights new findings on the role of impaired Ca2+ signaling in the development of steatosis and discusses potential new approaches to NAFLD treatment based on these new insights. Hepatic steatosis, the first step in nonalcoholic fatty liver disease (NAFLD), can arise from various pathophysiological conditions. While lipid metabolism in the liver is normally balanced such that there is no excessive lipid accumulation, when this homeostasis is disrupted lipid droplets (LDs) accumulate in hepatocytes resulting in cellular toxicity. The mechanisms underlying this accumulation and the subsequent hepatocellular damage are multifactorial and poorly understood, with the result that there are no currently approved treatments for NAFLD. Impaired calcium signaling has recently been identified as a cause of increased endoplasmic reticulum (ER) stress contributing to hepatic lipid accumulation. This review highlights new findings on the role of impaired Ca2+ signaling in the development of steatosis and discusses potential new approaches to NAFLD treatment based on these new insights. allosteric activation is the activation/regulation of an enzyme by the binding of an effector molecule at a site other than the enzyme’s active site. short, synthetic, single-stranded oligodeoxynucleotides that can alter RNA and reduce, restore, or modify protein expression through several mechanisms. the programmed death of cells that occurs as a normal and controlled part of an organism’s development or growth. the synthesis of glucose from non-sugar precursors, such as lactate, pyruvate, and the carbon skeleton of glucogenic amino acids. describes the situation where having only a single functioning copy of a gene is not enough for normal function, so that loss-of-function mutations cause a dominant phenotype. the chief functional cells of the liver; perform a number of metabolic, endocrine, and secretory functions. Roughly 80% of the mass of the liver is contributed by hepatocytes. elevated amount of sugar (glucose) in the blood beyond normal, often associated with diabetes mellitus. a dimeric peptide hormone (51 amino acids) comprising an A chain and a B chain linked by disulfide bonds. It is produced by β cells of pancreatic islets. decreased cellular response to insulin. regulation of the intracellular concentration of calcium ions in cells. a process of fatty acid and triglyceride synthesis from glucose or other substrates. a disorder of energy utilization and storage defined by the presence of at least three of the five following medical conditions: high blood pressure, high blood glucose, abdominal obesity, high serum triglycerides, and low high-density lipoprotein (HDL) levels. related to microsomes. A microsome is a fragment of ER and attached ribosomes obtained by the centrifugation of homogenized cells. an umbrella term for a range of liver conditions in which fat accumulates in the liver. In general, hepatic steatosis is considered as the first step in NAFLD. NASH is a type of NAFLD. inflammation and liver cell damage along with fat in the liver. a chronic multifactorial disease in which excess accumulation of fat results in adverse health consequences. Clinically, obesity in adults is defined as body mass index >30 kg/m2. highly reactive chemical compounds that contain oxygen. They are generated by diverse metabolic processes. At low concentrations ROS act as signaling molecules, but at higher concentrations they cause macromolecular damage. process describing the abnormal accumulation of lipids within a cell. In general, hepatic steatosis is considered the first step in NAFLD. a plasma membrane Ca2+ channel activated by a decrease in Ca2+ in the ER; acts to restore the level of calcium in the ER. The entry of Ca2+ into the cell is termed store-operated Ca2+ entry (SOCE). SOC channels are defined by the fact that they are activated by the decrease in Ca2+ in the ER. a chronic condition in which the body fails to properly use and store glucose. the ER responds to the burden of unfolded proteins in its lumen (ER stress) by activating several intracellular signaling pathways, collectively termed the unfolded protein response.