Soluble Endoglin as a Potential Biomarker of Nonalcoholic Steatohepatitis (NASH) Development, Participating in Aggravation of NASH-Related Changes in Mouse Liver.

Stanislav Micuda,Katarina Tripska,Hana Lastuvkova,Eva Dolezelova,Jolana Schreiberova,Milos Hroch,Petr Nachtigal,Alena Ticha,Barbora Vitverova,Radomir Hyspler,Miguel Pericacho,Martina Vasinova,Ivone Cristina Igreja Sá,Iveta Najmanova,Samira Eissazadeh

doi:10.3390/ijms21239021

Abstract

Nonalcoholic steatohepatitis (NASH) is characterized by hepatic steatosis with inflammation and fibrosis. Membrane endoglin (Eng) expression is shown to participate in fibrosis, and plasma concentrations of soluble endoglin (sEng) are increased in patients with hypercholesterolemia and type 2 diabetes mellitus. We hypothesize that NASH increases both hepatic Eng expression and sEng in blood and that high levels of sEng modulate cholesterol and bile acid (BA) metabolism and affect NASH progression. Three-month-old transgenic male mice overexpressing human sEng and their wild type littermates are fed for six months with either a high-saturated fat, high-fructose high-cholesterol (FFC) diet or a chow diet. Evaluation of NASH, Liquid chromatography–mass spectrometry (LC/MS) analysis of BA, hepatic expression of Eng, inflammation, fibrosis markers, enzymes and transporters involved in hepatic cholesterol and BA metabolism are assessed using Real-Time Quantitative Reverse Transcription Polymerase Chain reaction (qRT-PCR) and Western blot. The FFC diet significantly increases mouse sEng levels and increases hepatic expression of Eng. High levels of human sEng results in increased hepatic deposition of cholesterol due to reduced conversion into BA, as well as redirects the metabolism of triglycerides (TAG) to its accumulation in the liver, via reduced TAG elimination by β-oxidation combined with reduced hepatic efflux. We propose that sEng might be a biomarker of NASH development, and the presence of high levels of sEng might support NASH aggravation by impairing the essential defensive mechanism protecting NASH liver against excessive TAG and cholesterol accumulation, suggesting the importance of high sEng levels in patients prone to develop NASH.

Highlights

Endoglin (Eng) is a transmembrane glycoprotein and co-receptor of transforming growth factor-β (Tgf-β) [1,2], which modulates Tgf-β signaling
Mice fed with an high-saturated fat, high-fructose, and high-cholesterol (FFC) diet, as previously described [25,35,36], showed significantly increased body weight, from the 2nd week of feeding for wild type (WT) and 3rd week for high human soluble endoglin mice (Figure 1A), which resulted in obesity (significantly increased body weight gain (~29%)) at the end of the 24th week (Figure 1B) when compared to mice fed with a chow diet
Eng expression and the presence of soluble endoglin (sEng) in the circulation was discussed in relation to many pathological conditions, including various metabolic disorders such as hypercholesterolemia, atherosclerosis, type 2 diabetes mellitus, and liver fibrosis [16,17]

Summary

Introduction

Endoglin (Eng) is a transmembrane glycoprotein and co-receptor of transforming growth factor-β (Tgf-β) [1,2], which modulates Tgf-β signaling. Significantly increased levels of sEng have been found in patients with hypercholesterolemia [12], type 2 diabetes mellitus [3], and in liver fibrosis induced by different causes (e.g., chronic hepatitis C, biliary atresia, cystic fibrosis-associated liver disease) [20,21]. These data suggest the importance of Eng and sEng in the process of liver fibrosis and liver alterations

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