The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

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.

Keywords: autophagy; lipid droplet; lipid homeostasis; lipophagy; non-alcoholic fatty liver disease.

Figure 1

Overview of the main pathways contributing to TG accumulation in NAFLD. 1) fatty acid uptake, 2) de novo lipogenesis, 3) TG secretion, and 4) fatty acid oxidation. ATP, adenosine triphosphate; TG, triglyceride; VLDL, very-low-density lipoprotein.

Figure 2

The process of lipophagy. Lipophagy – Key regulator mTOR inhibits TFEB in autophagy induction. MSL induces TFEB that upregulates autophagy. LC3-I assembles at the autophagosome envelope elongating the bi-layer. P62 secures ‘chunks’ of the LD as lipid-cargo in the lumen of the autophagosome. After LC3-I is spliced by ATG4 to LC3-II, the autophagosome closes carrying its cargo. Upon fusion with the acidic lysosome (LAMP and V-ATPase driven), LAL can hydrolyze TG and CE into FFA and free cholesterol, respectively. FFA are directed towards either beta-oxidation or to the ER for further metabolism. Cytosolic Lipolysis – At basal conditions, LDs are covered in PLIN2 molecules that regulate the accessibility for lipolytic enzymes. When stimulated PLIN2 releases and grants access at the membrane for ATGL and HSL (bound to PLIN5), which activate under phosphorylation. When stimulated, SIRT1 activates CMA to release PLIN2 and replace PLIN5 at the LD membrane, thereby mediating the lipolytic activity through autophagy. ATP, adenosine triphosphate; ATG4, autophagy-regulating protease 4; ATGL, adipose triglyceride lipase; CE, cholesteryl esters; CMA, chaperone mediated autophagy; ER, endoplasmic reticulum; FFA, free fatty acid; HSL, hormone sensitive lipase; LAL, lysosome acid lipase; LAMP, lysosomal-associated membrane protein; LD, lipid droplet; mTOR, mammalian target of rapamycin; PLIN, perilipin; TFEB, transcription factor EB; TG, triglyceride; V-ATPase, Vacuolar-type-H⁺-ATPase.