Giantin Is Required for Post-Alcohol Recovery of Golgi in Liver Cells

Carol Casey,Sonia Manca,Paul Thomes,Armen Petrosyan

doi:10.3390/biom8040150

Abstract

In hepatocytes and alcohol-metabolizing cultured cells, Golgi undergoes ethanol (EtOH)-induced disorganization. Perinuclear and organized Golgi is important in liver homeostasis, but how the Golgi remains intact is unknown. Work from our laboratories showed that EtOH-altered cellular function could be reversed after alcohol removal; we wanted to determine whether this recovery would apply to Golgi. We used alcohol-metabolizing HepG2 (VA-13) cells (cultured with or without EtOH for 72 h) and rat hepatocytes (control and EtOH-fed (Lieber–DeCarli diet)). For recovery, EtOH was removed and replenished with control medium (48 h for VA-13 cells) or control diet (10 days for rats). Results: EtOH-induced Golgi disassembly was associated with de-dimerization of the largest Golgi matrix protein giantin, along with impaired transport of selected hepatic proteins. After recovery from EtOH, Golgi regained their compact structure, and alterations in giantin and protein transport were restored. In VA-13 cells, when we knocked down giantin, Rab6a GTPase or non-muscle myosin IIB, minimal changes were observed in control conditions, but post-EtOH recovery was impaired. Conclusions: These data provide a link between Golgi organization and plasma membrane protein expression and identify several proteins whose expression is important to maintain Golgi structure during the recovery phase after EtOH administration.

Highlights

The Golgi apparatus is the central sorting and transportation hub involved in the posttranslational modification and sorting of cargo molecules, and delivering them to appropriate cellular locations or to the exocytic and endocytic pathways [1]
Using both a rat model and the recombinant HepG2 (VA-13) cells that efficiently express hepatic alcohol dehydrogenase (ADH) [41], we found that recovery of Golgi after EtOH withdrawal is associated with re-dimerization of giantin
We wanted to establish a relevance for these effects in the human condition, we analyzed Golgi morphology in liver tissue samples obtained from patients with normal liver so we analyzed Golgi morphology in liver tissue samples obtained from patients with normal liver function and patients with alcoholic liver cirrhosis

Summary

Introduction

The Golgi apparatus is the central sorting and transportation hub involved in the posttranslational modification and sorting of cargo molecules, and delivering them to appropriate cellular locations or to the exocytic and endocytic pathways [1]. Golgi is a highly organized, perinuclear, ribbon-like structure, composed of stacks of flattened and elongated cisternae. Multiple studies have demonstrated that in hepatocytes, ethanol (EtOH) administration and subsequent metabolism can alter the structure of the Golgi [8,9,10]. Such fragments of Golgi are capable of eliciting antibody production, and anti-Golgi antibodies are markedly elevated in the sera of end-stage liver disease induced by heavy alcohol consumption, underscoring the clinical relevance

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