Abstract
Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver disorder worldwide. NAFLD comprises a spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually end-stage liver disease. The cause of NAFLD is multifactorial with genetic susceptibility and an unhealthy lifestyle playing a crucial role in its development. Disrupted hepatic lipid homeostasis resulting in hepatic triglyceride accumulation is an hallmark of NAFLD. This disruption is commonly described based on four pathways concerning 1) increased fatty acid influx, 2) increased de novo lipogenesis, 3) reduced triglyceride secretion, and 4) reduced fatty acid oxidation. More recently, lipophagy has also emerged as pathway affecting NAFLD development and progression. Lipophagy is a form of autophagy (i.e. controlled autolysosomal degradation and recycling of cellular components), that controls the breakdown of lipid droplets in the liver. Here we address the role of hepatic lipid homeostasis in NAFLD and specifically review the current literature on lipophagy, describing its underlying mechanism, its role in pathophysiology and its potential as a therapeutic target.
Highlights
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver diseases that is characterized by an increased hepatic triglyceride (TG) content in the absence of excessive alcohol use
In this review we have described the four classical pathways that contribute to hepatic TG accumulation in NAFLD (Figure 1) and addressed a recently discovered novel pathway that concerns the lysosomal turnover of LDs, known as lipophagy (Figure 2)
We have summarized data from numerous in vitro, in vivo and observational human studies that demonstrate that lipophagy is an important pathway contributing to disrupted hepatic lipid homeostasis in NAFLD
Summary
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver diseases that is characterized by an increased hepatic triglyceride (TG) content (i.e. steatosis) in the absence of excessive alcohol use. Progressive stages of NAFLD, e.g. steatohepatitis and hepatic fibrosis, occur when excessive lipid accumulation overwhelms the capacity of the liver to store, secrete and oxidize fatty acids [5]. In this lipotoxic environment, necroinflammation and fibrogenesis can occur. PLIN5 was shown to regulated the phosphorolytic state of lipolytic enzymes (ATGL, HSL, and MGL), and thereby altering their lipolytic activity [75] These examples of dysfunction of LDassociated proteins elegantly illustrate the regulatory and inducible axis between LDs, cytosolic lipolysis, and lipophagy. The presence of a second lipolytic enzyme, e.g. ATGL, necessarily contributes to the degradation of the LD [82, 83]
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