Emerging roles of calcium signaling in the development of non‐alcoholic fatty liver disease

The liver plays a central role in energy metabolism. Dysregulated hepatic lipid metabolism is a major cause of non‐alcoholic fatty liver disease (NAFLD), a chronic liver disorder closely linked to obesity and insulin resistance. NAFLD is rapidly emerging as a global health problem with currently no approved therapy. While early stages of NAFLD are often considered benign, the disease can progress to an advanced stage that involves chronic inflammation, with increased risk for developing end‐stage disease including fibrosis and liver cancer. Hence, there is an urgent need to identify potential pharmacological targets. Ca²⁺ is an essential signaling molecule involved in a myriad of cellular processes. Intracellular Ca²⁺ is intricately compartmentalized, and the Ca²⁺ flow is tightly controlled by a network of Ca²⁺ transport and buffering proteins. Impaired Ca²⁺ signaling is strongly associated with endoplasmic reticulum stress, mitochondrial dysfunction and autophagic defects, all of which are etiological factors of NAFLD. In this review, we describe the recent advances that underscore the critical role of dysregulated Ca²⁺ homeostasis in lipid metabolic abnormalities and discuss the feasibility of targeting Ca²⁺ signaling as a potential therapeutic approach.