Effects of Ethanol Feeding in Early-Stage NAFLD Mice Induced by Western Diet

Maximilian Joseph Brol,Jonel Trebicka,Stella Georgiou,Robert Schierwagen,Ditlev Nytoft Rasmussen,Cristina Ortiz,Ema Anastasiadou,Maja Thiele,Aleksander Krag,Vasiliki I Pantazopoulou,Sandra Torres,Sabine Klein,Larissa Eberle,Vasiliki Filippa,Sönke Detlefsen,Frank Erhard Uschner

doi:10.3390/livers1010003

Abstract

Background: The prevalence of metabolic liver diseases is increasing and approved pharmacological treatments are still missing. Many animal models of nonalcoholic fatty liver disease (NAFLD) show a full spectrum of fibrosis, inflammation and steatosis, which does not reflect the human situation since only up to one third of the patients develop fibrosis and nonalcoholic steatohepatitis (NASH). Methods: Seven week old C57Bl/J mice were treated with ethanol, Western diet (WD) or both. The animals’ liver phenotypes were determined through histology, immunohistochemistry, Western blotting, hepatic triglyceride content and gene expression levels. In a human cohort of 80 patients stratified by current alcohol misuse and body mass index, liver histology and gene expression analysis were performed. Results: WD diet and ethanol-treated animals showed severe steatosis, with high hepatic triglyceride content and upregulation of fatty acid synthesis. Mild fibrosis was revealed using Sirius-red stains and gene expression levels of collagen. Inflammation was detected using histology, immunohistochemistry and upregulation of proinflammatory genes. The human cohort of obese drinkers showed similar upregulation in genes related to steatosis, fibrosis and inflammation. Conclusions: We provide a novel murine model for early-stage fatty liver disease suitable for drug testing and investigation of pathophysiology.

Highlights

Despite public health efforts, the prevalence of chronic liver diseases (CLD) is still increasing, causing an important health care burden, especially in Europe and the United States [1,2]
Emerging evidence supports the fact that the strict separation of alcoholic and nonalcoholic liver disease is no longer justifiable, suggesting a novel entity of metabolic dysfunction-associated liver disease (MAFLD) [6]
Western diet (WD) feeding alone led to an increase of body weight, but ethanol as a cofactor decreased body weight compared to WD back to baseline (Table 2)

Summary

Introduction

The prevalence of chronic liver diseases (CLD) is still increasing, causing an important health care burden, especially in Europe and the United States [1,2]. Emerging evidence supports the fact that the strict separation of alcoholic and nonalcoholic liver disease is no longer justifiable, suggesting a novel entity of metabolic dysfunction-associated liver disease (MAFLD) [6]. Given these facts, there is an urgent need for preclinical models covering both a nutritive and alcoholic etiology with mild to moderate liver fibrosis for elucidating pathogenic mechanisms, screening for new therapeutic options and developing diagnostic tools in this new entity. Many animal models of nonalcoholic fatty liver disease (NAFLD) show a full spectrum of fibrosis, inflammation and steatosis, which does not reflect the human situation since only up to one third of the patients develop fibrosis and nonalcoholic steatohepatitis (NASH). The human cohort of obese drinkers showed similar upregulation in genes related to steatosis, fibrosis and inflammation

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