Abstract
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.
Highlights
The liver is a major site for lipid processing and storage
Ca2+ uptake is mediated by the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane, which interacts with the InsP3R1 on the endoplasmic reticulum (ER) through linkage with molecular chaperone glucose-regulated protein 75 (GRP75) [53] (Figure 2)
Perspectives Ca2+, as an intracellular second messenger, modulates a myriad of cellular processes. These actions involve an intricate set of regulatory proteins that allow interplay between the Ca2+ stores (ER, mitochondria and lysosome) and transmit coordinated Ca2+ signals
Summary
The liver is a major site for lipid processing and storage. As such, liver dysfunction can lead to progressive lipid accumulation, a condition often predisposed to more severe diseases. First described in the 1980s, NAFLD comprises a histological spectrum ranging from excess lipid deposition (hepatic steatosis) to the more aggressive form with consistent liver injury and inflammation (non-alcoholic steatohepatitis, NASH) and advanced fibrosis [2]. The major supply of lipids delivered to the liver comes in the form of free fatty acids following lipolysis of triglycerides in the adipose tissue. This action is highly regulated by insulin [4]. We will provide an overview of the mechanisms by which Ca2+ signaling modulates hepatic lipid metabolism and their involvement in the processes related to NAFLD development. Alterations in Ca2+ Homeostasis and Organelle Dysfunction in Development of NAFLD
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