Short-term western diet aggravates non-alcoholic fatty liver disease (NAFLD) with portal hypertension in TGR(mREN2)27 rats

  • Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially,thedevelopmentoffibrosisandportalhypertensioninNAFLDpatientsrequirestreatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. Asexpected,WDinducedobesityandliverfibrosisasconfirmedbySiriusRedandOilRed O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increasedduringfeedingofWD,indicatinginfiltrationofmacrophagesintotheliver,eventhoughthis increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.

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Author:Carla-Luisa Elsa Cremonese, Robert SchierwagenORCiDGND, Frank Erhard UschnerORCiDGND, Sandra Torres NúñezORCiD, Olaf Tyc, Cristina OrtizORCiD, Martin SchulzORCiD, Alexander David Roger QueckORCiDGND, Glen Kristiansen, Michael Bader, Tilman SauerbruchORCiDGND, Ralf WeiskirchenORCiDGND, Thomas WaltherGND, Jonel TrebickaORCiDGND, Sabine KleinORCiD
Parent Title (English):International journal of molecular sciences
Place of publication:Basel
Document Type:Article
Date of Publication (online):2020/05/07
Date of first Publication:2020/05/07
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/08/11
Tag:ADGRE1; EMR1; F4/80; NAFLD; TGR(mREN2)27; Western diet; immunity; liver fibrosis; macrophage; portal hypertension
Issue:9, art. 3308
Page Number:14
First Page:1
Last Page:14
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0