Abstract
This review describes the influence of ethanol consumption on hepatic lipophagy, a selective form of autophagy during which fat-storing organelles known as lipid droplets (LDs) are degraded in lysosomes. During classical autophagy, also known as macroautophagy, all forms of macromolecules and organelles are sequestered in autophagosomes, which, with their cargo, fuse with lysosomes, forming autolysosomes in which the cargo is degraded. It is well established that excessive drinking accelerates intrahepatic lipid biosynthesis, enhances uptake of fatty acids by the liver from the plasma and impairs hepatic secretion of lipoproteins. All the latter contribute to alcohol-induced fatty liver (steatosis). Here, our principal focus is on lipid catabolism, specifically the impact of excessive ethanol consumption on lipophagy, which significantly influences the pathogenesis alcohol-induced steatosis. We review findings, which demonstrate that chronic ethanol consumption retards lipophagy, thereby exacerbating steatosis. This is important for two reasons: (1) Unlike adipose tissue, the liver is considered a fat-burning, not a fat-storing organ. Thus, under normal conditions, lipophagy in hepatocytes actively prevents lipid droplet accumulation, thereby maintaining lipostasis; (2) Chronic alcohol consumption subverts this fat-burning function by slowing lipophagy while accelerating lipogenesis, both contributing to fatty liver. Steatosis was formerly regarded as a benign consequence of heavy drinking. It is now recognized as the “first hit” in the spectrum of alcohol-induced pathologies that, with continued drinking, progresses to more advanced liver disease, liver failure, and/or liver cancer. Complete lipid droplet breakdown requires that LDs be digested to release their high-energy cargo, consisting principally of cholesteryl esters and triacylglycerols (triglycerides). These subsequently undergo lipolysis, yielding free fatty acids that are oxidized in mitochondria to generate energy. Our review will describe recent findings on the role of lipophagy in LD catabolism, how continuous heavy alcohol consumption affects this process, and the putative mechanism(s) by which this occurs.
Highlights
It is evident that autophagy is critical for maintaining normal liver function and it has a crucial role in ablating fatty liver disease that arises from excessive drinking
Autophagy activity in the alcohol-induced fatty liver is affected by the duration of ethanol consumption/exposure, the amount of ethanol administered, and the way in which it is administered, there is solid evidence that chronic ethanol consumption retards the lipophagic/autophagic clearance of LDs that accumulate during the pathogenesis of alcohol-induced fatty liver
The reasons for retarded removal of LDs are threefold: (1) Ethanol oxidation disrupts the autophagic/lipophagic machinery that degrade LDs; (2) alcohol-metabolism changes the phospholipid composition of the LD membrane, which, in turn, alters its content of resident proteins, conferring greater membrane resistance to lipophagy and lipolysis; and (3) ethanol metabolism thwarts the mitochondrial oxidation of fatty acids extracted from LDs by inhibiting PPAR-α and disrupting mitochondrial function
Summary
Heavy drinking is a major cause of liver disease worldwide (O’Shea et al, 2010). Current trends indicate that, in the United States, between 2007 and 2014, alcohol-induced liver disease (AILD) became the second most frequent cause of cirrhosis and hepatocellular carcinoma (HCC)-related mortality after non-alcoholic fatty liver disease (NAFLD) (Kim et al, 2019). Fatty liver (steatosis) is the earliest response to excessive drinking in 90% or more of alcohol abusers (O’Shea et al, 2010; You and Arteel, 2019). Steatosis is characterized by excessive deposition of fat, seen microscopically as intracellular lipid droplets (LDs). These are hydrophobic islands of stored fat, each surrounded by a phospholipid monolayer, which, itself, harbors specific proteins that maintain LD integrity. LDs interact with mitochondria, lysosomes, peroxisomes, and membranes of the Golgi apparatus (Barbosa et al, 2015) Each of the latter organelles has a functional interaction with LDs, the extent of which appears to depend on the cell’s lipid content (Krahmer et al, 2018). The classical autophagy/lipophagy pathway, mentioned in the Abstract has some non-canonical variations to be described
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