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Article

Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats

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Department of Internal Medicine I, Goethe University Frankfurt, 60323 Frankfurt, Germany
2
Institute for Pathology, University of Bonn, 53127 Bonn, Germany
3
Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany
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Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany
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Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, 52074 Aachen, Germany
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Department of Pharmacology and Therapeutics, University College Cork, T12 YN60 Cork, Ireland
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Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, 17489 Greifswald, Germany
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Institute for Bioengineering of Catalonia, 08028 Barcelona, Spain
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European Foundation for the Study of Chronic Liver Failure, 08021 Barcelona, Spain
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Faculty of Health Sciences, University of Southern Denmark, 5000 Odense, Denmark
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(9), 3308; https://doi.org/10.3390/ijms21093308
Received: 3 April 2020 / Revised: 5 May 2020 / Accepted: 6 May 2020 / Published: 7 May 2020
(This article belongs to the Special Issue Pathophysiology of Liver Fibrosis and Its Therapies)
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. View Full-Text
Keywords: ADGRE1; EMR1; F4/80; immunity; liver fibrosis; macrophage; NAFLD; portal hypertension; TGR(mREN2)27; Western diet ADGRE1; EMR1; F4/80; immunity; liver fibrosis; macrophage; NAFLD; portal hypertension; TGR(mREN2)27; Western diet
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MDPI and ACS Style

Cremonese, C.; Schierwagen, R.; Uschner, F.E.; Torres, S.; Tyc, O.; Ortiz, C.; Schulz, M.; Queck, A.; Kristiansen, G.; Bader, M.; Sauerbruch, T.; Weiskirchen, R.; Walther, T.; Trebicka, J.; Klein, S. Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats. Int. J. Mol. Sci. 2020, 21, 3308. https://doi.org/10.3390/ijms21093308

AMA Style

Cremonese C, Schierwagen R, Uschner FE, Torres S, Tyc O, Ortiz C, Schulz M, Queck A, Kristiansen G, Bader M, Sauerbruch T, Weiskirchen R, Walther T, Trebicka J, Klein S. Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats. International Journal of Molecular Sciences. 2020; 21(9):3308. https://doi.org/10.3390/ijms21093308

Chicago/Turabian Style

Cremonese, Carla, Robert Schierwagen, Frank E. Uschner, Sandra Torres, Olaf Tyc, Cristina Ortiz, Martin Schulz, Alexander Queck, Glen Kristiansen, Michael Bader, Tilman Sauerbruch, Ralf Weiskirchen, Thomas Walther, Jonel Trebicka, and Sabine Klein. 2020. "Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats" International Journal of Molecular Sciences 21, no. 9: 3308. https://doi.org/10.3390/ijms21093308

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