Alcohol‐Induced Liver Injury: Down‐regulation and Redistribution of Rab3D Results in Atypical Protein Trafficking

Abstract

Previous work from our laboratories has identified multiple defects in endocytosis, protein trafficking, and secretion, along with altered Golgi function after alcohol administration. Manifestation of alcohol-associated liver disease (ALD) is associated with an aberrant function of several hepatic proteins, including asialoglycoprotein receptor (ASGP-R), their atypical distribution at the plasma membrane (PM), and secretion of their abnormally glycosylated forms into the bloodstream, but trafficking mechanism is unknown. Here we report that a small GTPase, Rab3D, known to be involved in exocytosis, secretion, and vesicle trafficking, shows ethanol (EtOH)-impaired function, which plays an important role in Golgi disorganization. We used multiple approaches and cellular/animal models of ALD, along with Rab3D knockout (KO) mice and human tissue from patients with ALD. We found that Rab3D resides primarily in trans-and cis-faces of Golgi; however, EtOH treatment results in Rab3D redistribution from trans-Golgi to cis-medial-Golgi. Cells lacking Rab3D demonstrate enlargement of Golgi, especially its distal compartments. We identified that Rab3D is required for coat protein I (COPI) vesiculation in Golgi, and conversely, COPI is critical for intra-Golgi distribution of Rab3D. Rab3D/COPI association was altered not only in the liver of patients with ALD but also in the donors consuming alcohol without steatosis. In Rab3D KO mice, hepatocytes experience endoplasmic reticulum (ER) stress, and EtOH administration activates apoptosis. Notably, in these cells, ASGP-R, despite incomplete glycosylation, can still reach cell surface through ER-PM junctions. This mimics the effects seen with EtOH-induced liver injury. Conclusion: We revealed that down-regulation of Rab3D contributes significantly to EtOH-induced Golgi disorganization, and abnormally glycosylated ASGP-R is excreted through ER-PM connections, bypassing canonical (ER→Golgi→PM) anterograde transportation. This suggests that ER-PM sites may be a therapeutic target for ALD. (Hepatology Communications 2021;0:1-15).

Hawthorn or semen cassiae-alleviated high-fat diet-induced hepatic steatosis in rats via the reduction of endoplasmic reticulum stress

“…It has been reported that PERK and ATF6 are the main branches of UPR pathways, which are regulated under the activation of GRP78. 16,17 HFD boosted hepatocyte ER stress, as evidenced by increased GRP78, PERK, and ATF6 (Fig. 2I).…”

Alcohol and Prostate Cancer: Time to Draw Conclusions

“…This, in turn, leads to intracellular accumulation of newly synthesized proteins and subsequent ER stress [179][180][181][182][183][184][185]. In addition, EtOH and its metabolites alter the activity of different Rab proteins, the conductors of post-Golgi transportation, and endocytosis [186][187][188][189][190][191][192][193][194]. Our laboratory revealed that alcohol-induced Golgi disorganization is associated with impairment of both coat protein I (COPI) and coat protein II (COPII) vesiculation and monomerization of the Golgi scaffold proteins, golgins [180,195].…”

Multiomics Approach Captures Hepatic Metabolic Network Altered by Chronic Ethanol Administration

“…An early manifestation of ALD is the development of hepatic steatosis or a fatty liver that can be reversed by alcohol abstinence [5,6]. However, a continuous consumption of alcohol can progress to alcoholic hepatitis, cirrhosis, and eventually death [4,7]. Thus, there is a critical need to understand the molecular mechanism of ALD in order to diagnose the disease at its earliest stages (i.e., steatosis) to prevent progression to the later stages and a fatal outcome.…”