Hepatic galectin-3 is associated with lipid droplet area in non-alcoholic steatohepatitis in a new swine model

Luis V Herrera-Marcos,Gonzalo Gonzalo-Romeo,Sonia Gascón,Roberto Martínez-Beamonte,Tania Herrero-Continente,Víctor Alastrué-Vera,José M Lou-Bonafonte,Jesús Osada,Dolores Gutiérrez-Blázquez,Cristina Barranquero,Agustín García-Gil,Juan J Puente-Lanzarote,Antonio Güemes,Manuel Macías-Herranz,Carmen Arnal,Joaquín C Surra,María J Rodríguez-Yoldi

doi:10.1038/s41598-022-04971-z

Abstract

Non-alcoholic fatty liver disease (NAFLD) is currently a growing epidemic disease that can lead to cirrhosis and hepatic cancer when it evolves into non-alcoholic steatohepatitis (NASH), a gap not well understood. To characterize this disease, pigs, considered to be one of the most similar to human experimental animal models, were used. To date, all swine-based settings have been carried out using rare predisposed breeds or long-term experiments. Herein, we fully describe a new experimental swine model for initial and reversible NASH using cross-bred animals fed on a high saturated fat, fructose, cholesterol, cholate, choline and methionine-deficient diet. To gain insight into the hepatic transcriptome that undergoes steatosis and steatohepatitis, we used RNA sequencing. This process significantly up-regulated 976 and down-regulated 209 genes mainly involved in cellular processes. Gene expression changes of 22 selected transcripts were verified by RT-qPCR. Lipid droplet area was positively associated with CD68, GPNMB, LGALS3, SLC51B and SPP1, and negatively with SQLE expressions. When these genes were tested in a second experiment of NASH reversion, LGALS3, SLC51B and SPP1 significantly decreased their expression. However, only LGALS3 was associated with lipid droplet areas. Our results suggest a role for LGALS3 in the transition of NAFLD to NASH.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is currently a growing epidemic disease that can lead to cirrhosis and hepatic cancer when it evolves into non-alcoholic steatohepatitis (NASH), a gap not well understood
NAFLD is largely categorized into simple steatosis, corresponding to the presence of steatosis without additional liver damage, and nonalcoholic steatohepatitis (NASH) which is thought to be a progressive condition which can lead to advanced fibrosis, cirrhosis, hepatocellular carcinoma and liver failure[7,8,9,10]
Using fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score38, 17% of pigs consuming the steatotic diet for two months were categorized as NAFLD, 75% of pigs as NASH with score 1 for ballooning and 8% as NASH with ballooning score 2, reinforcing the interpretation that our model of NAFLD may progress to NASH

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is currently a growing epidemic disease that can lead to cirrhosis and hepatic cancer when it evolves into non-alcoholic steatohepatitis (NASH), a gap not well understood To characterize this disease, pigs, considered to be one of the most similar to human experimental animal models, were used. NAFLD is largely categorized into simple steatosis, corresponding to the presence of steatosis without additional liver damage, and nonalcoholic steatohepatitis (NASH) which is thought to be a progressive condition which can lead to advanced fibrosis, cirrhosis, hepatocellular carcinoma and liver failure[7,8,9,10] This classification corresponds to the “two-hit hypothesis”, an initial framework for understanding the pathogenesis of NASH11. Selected examples of its use in swine include characterization of microRNA in adipose tissue, inflammation-related genes in NASH-induced in Bama minipigs[19,20], meat quality[21] or immune response in peripheral or intestinal c ells[22,23]

Methods

Results

Conclusion