Impaired Rab7 and dynamin2 block fat turnover by autophagy in alcoholic fatty livers

Alcoholic liver disease (ALD) at early stages is characterized by hepatic steatosis, i.e., excessive accumulation of fat (e.g., triglyceride or triacylglycerol, esterified cholesterol) wrapped in lipid storage organelles called lipid droplets (LDs). While excessive hepatic steatosis can progress to more severe steatohepatitis or hepatocellular carcinoma in ALD, steatosis can be entirely reversible because hepatocytes have adopted several catabolic mechanisms to remove or break down the LDs. Therefore understanding the mechanisms of the catabolism of hepatic LDs may help to develop therapeutic interventions for ALD. In the liver, there are two major pathways that are thought to play critical roles in LD catabolism: lipolysis through cytosolic neutral lipases, such as adipose triglyceride lipase (ATGL), and the autophagic/lysosomal pathway. In adipocytes, the most characterized mechanisms for lipase-mediated LD catabolism is badrenergic agonist-mediated activation of cyclic adenosine monophosphate/protein kinase A, which phosphorylates and activates hormone-sensitive lipase (HSL) and LD-coating proteins perilipins. Phosphorylated perilipins then allow exposure of the stored lipids to HSL and ATGL, resulting in lipolysis. Compared to adipocytes, lipase-mediated LD catabolism in hepatocytes is less studied. Genetic ablation or overexpression of ATGL in the liver exacerbates or alleviates steatosis in mouse livers, respectively. These findings suggest that cytosolic lipases are also important regulators in LD turnover in hepatocytes. Interestingly, a more recent study reported that hepatocytes isolated from chronic ethanol-fed rats or acute ethanol-treated hepatoma cells that can metabolize ethanol showed significantly perturbed b-adrenergic stimuli-induced LD breakdown. Mechanistically, the authors found that ethanol inhibited protein kinase A-mediated phosphorylation of HSL and the recruitment of ATGL to the LD surface, resulting in the blockage of LD catabolism. In addition to the above lipase-mediated LD breakdown, another emerging pathway to breakdown LD in hepatocytes involves the lipases and acidic hydrolases in lysosomes, a process known as lipophagy. During lipophagy, LDs are selectively taken up by autophagosomes likely through directly recruiting autophagy machinery proteins, and then autophagosome-enwrapped LDs are further delivered to lysosomes where LDs are broken down to fatty acids. Although genetic deletion of autophagyrelated genes in mice leads to controversial results in hepatic steatosis and lipid metabolism likely due to the compensatory/secondary effects in these mice, studies Abbreviations: ALD, alcoholic liver disease; ALR, autophagic lysosome reformation; ATGL, adipose triglyceride lipase; Dyn2, dynamin2; EH, Eps15 Homology; HSL, hormone-sensitive lipase; LC3, microtubule-associated protein 1A/1B-light chain 3; LD, lipid droplet; TFEB, transcription factor EB.