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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, the development of fibrosis and portal hypertension in NAFLD patients requires treatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertens...

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Autores principales: Cremonese, Carla, Schierwagen, Robert, Uschner, Frank Erhard, Torres, Sandra, Tyc, Olaf, Ortiz, Cristina, Schulz, Martin, Queck, Alexander, Kristiansen, Glen, Bader, Michael, Sauerbruch, Tilman, Weiskirchen, Ralf, Walther, Thomas, Trebicka, Jonel, Klein, Sabine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246932/
https://www.ncbi.nlm.nih.gov/pubmed/32392802
http://dx.doi.org/10.3390/ijms21093308
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author Cremonese, Carla
Schierwagen, Robert
Uschner, Frank Erhard
Torres, Sandra
Tyc, Olaf
Ortiz, Cristina
Schulz, Martin
Queck, Alexander
Kristiansen, Glen
Bader, Michael
Sauerbruch, Tilman
Weiskirchen, Ralf
Walther, Thomas
Trebicka, Jonel
Klein, Sabine
author_facet Cremonese, Carla
Schierwagen, Robert
Uschner, Frank Erhard
Torres, Sandra
Tyc, Olaf
Ortiz, Cristina
Schulz, Martin
Queck, Alexander
Kristiansen, Glen
Bader, Michael
Sauerbruch, Tilman
Weiskirchen, Ralf
Walther, Thomas
Trebicka, Jonel
Klein, Sabine
author_sort Cremonese, Carla
collection PubMed
description Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment. 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. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this 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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spelling pubmed-72469322020-06-02 Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats Cremonese, Carla Schierwagen, Robert Uschner, Frank Erhard Torres, Sandra Tyc, Olaf Ortiz, Cristina Schulz, Martin Queck, Alexander Kristiansen, Glen Bader, Michael Sauerbruch, Tilman Weiskirchen, Ralf Walther, Thomas Trebicka, Jonel Klein, Sabine Int J Mol Sci Article Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment. 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. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this 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. MDPI 2020-05-07 /pmc/articles/PMC7246932/ /pubmed/32392802 http://dx.doi.org/10.3390/ijms21093308 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cremonese, Carla
Schierwagen, Robert
Uschner, Frank Erhard
Torres, Sandra
Tyc, Olaf
Ortiz, Cristina
Schulz, Martin
Queck, Alexander
Kristiansen, Glen
Bader, Michael
Sauerbruch, Tilman
Weiskirchen, Ralf
Walther, Thomas
Trebicka, Jonel
Klein, Sabine
Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats
title Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats
title_full Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats
title_fullStr Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats
title_full_unstemmed Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats
title_short Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats
title_sort short-term western diet aggravates non-alcoholic fatty liver disease (nafld) with portal hypertension in tgr(mren2)27 rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246932/
https://www.ncbi.nlm.nih.gov/pubmed/32392802
http://dx.doi.org/10.3390/ijms21093308
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