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 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.

[1]  F. Negro.  Natural history of NASH and HCC , 2020, Liver international : official journal of the International Association for the Study of the Liver.

[2]  G. Kristiansen,et al.  TGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptor , 2019, Scientific Reports.

[3]  F. Tacke,et al.  Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk with metabolism , 2019, JHEP reports : innovation in hepatology.

[4]  F. Tacke,et al.  An update on the recent advances in antifibrotic therapy , 2018, Expert review of gastroenterology & hepatology.

[5]  Mary E. B. McCulloch,et al.  ADGRE1 (EMR1, F4/80) Is a Rapidly-Evolving Gene Expressed in Mammalian Monocyte-Macrophages , 2018, Front. Immunol..

[6]  P. Proost,et al.  Chemokine-Induced Macrophage Polarization in Inflammatory Conditions , 2018, Front. Immunol..

[7]  F. Tacke,et al.  Recent advances in understanding liver fibrosis: bridging basic science and individualized treatment concepts , 2018, F1000Research.

[8]  T. Luedde,et al.  Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis , 2018, Hepatology.

[9]  M. Oosting,et al.  Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming , 2018, Cell.

[10]  G. Baffy.  Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease , 2018, Digestive Diseases and Sciences.

[11]  Michiel D’Hondt,et al.  Severe steatosis induces portal hypertension by systemic arterial hyporeactivity and hepatic vasoconstrictor hyperreactivity in rats , 2018, Laboratory Investigation.

[12]  J. Bosch,et al.  Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: The SportDiet study , 2017, Hepatology.

[13]  J. Trebicka,et al.  Mouse and Rat Models of Induction of Hepatic Fibrosis and Assessment of Portal Hypertension. , 2017, Methods in molecular biology.

[14]  Alexandra Dos Anjos Cassado,et al.  F4/80 as a Major Macrophage Marker: The Case of the Peritoneum and Spleen. , 2017, Results and problems in cell differentiation.

[15]  Y. Rotman,et al.  Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease , 2016, Gut.

[16]  N. Alkhouri,et al.  Portal Hypertension Complications Are Frequently the First Presentation of NAFLD in Patients Undergoing Liver Transplantation Evaluation , 2016, Digestive Diseases and Sciences.

[17]  C. Strassburg,et al.  Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis , 2015, Gut.

[18]  R. Franchis.  Expanding consensus in portal hypertension Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension , 2015 .

[19]  P. Boor,et al.  Seven weeks of Western diet in apolipoprotein-E-deficient mice induce metabolic syndrome and non-alcoholic steatohepatitis with liver fibrosis , 2015, Scientific Reports.

[20]  J. Trebicka,et al.  Mouse models of metabolic liver injury , 2015, Laboratory animals.

[21]  Zhen Wang,et al.  Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. , 2015, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[22]  R. de Franchis.  Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. , 2015, Journal of hepatology.

[23]  T. Sauerbruch,et al.  Future therapy of portal hypertension in liver cirrhosis – a guess , 2014, F1000prime reports.

[24]  J. Nattermann,et al.  Angiotensin‐II type 1 receptor‐mediated Janus kinase 2 activation induces liver fibrosis , 2014, Hepatology.

[25]  S. Sanderson,et al.  Prevalence and indicators of portal hypertension in patients with nonalcoholic fatty liver disease. , 2012, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[26]  J. Pollard,et al.  A Lineage of Myeloid Cells Independent of Myb and Hematopoietic Stem Cells , 2012, Science.

[27]  Richard A. Flavell,et al.  Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity , 2012, Nature.

[28]  Shira Zelber-Sagi,et al.  Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. , 2011, World journal of gastroenterology.

[29]  T. Luedde,et al.  Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury , 2011, Gut.

[30]  R. Groszmann,et al.  Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis , 2011, Hepatology.

[31]  T. Sauerbruch,et al.  Role of cannabinoid receptors in alcoholic hepatic injury: steatosis and fibrogenesis are increased in CB2 receptor‐deficient mice and decreased in CB1 receptor knockouts , 2011, Liver international : official journal of the International Association for the Study of the Liver.

[32]  F. Lammert,et al.  Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. , 2010, Journal of hepatology.

[33]  R. Schwabe,et al.  CCR2 promotes hepatic fibrosis in mice , 2009, Hepatology.

[34]  S. Amini,et al.  Monocyte chemoattractant protein-1 (MCP-1): an overview. , 2009, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[35]  R. Bataller,et al.  Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver. , 2009, American journal of physiology. Gastrointestinal and liver physiology.

[36]  P. Ursell,et al.  Clinical and pathologic risk factors for atherosclerosis in cirrhosis: a comparison between NASH-related cirrhosis and cirrhosis due to other aetiologies. , 2008, Journal of hepatology.

[37]  J. Sowers,et al.  Angiotensin II-induced non-alcoholic fatty liver disease is mediated by oxidative stress in transgenic TG(mRen2)27(Ren2) rats. , 2008, Journal of hepatology.

[38]  S. Saab,et al.  Complications of cirrhosis. , 2008, Disease-a-month : DM.

[39]  F. Lammert,et al.  Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats , 2007, Hepatology.

[40]  K. Schroder,et al.  G‐protein‐coupled receptor expression, function, and signaling in macrophages , 2007, Journal of leukocyte biology.

[41]  A. Alberti,et al.  Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications , 2004, Gut.

[42]  D. Brenner,et al.  Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells. , 2004, Gastroenterology.

[43]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[44]  J. Bosch,et al.  Complications of cirrhosis. I. Portal hypertension. , 2000, Journal of hepatology.

[45]  D. Ganten,et al.  Adrenal renin is released into the circulation of the hypertensive transgenic rat TGR (mRen-2)27. , 1992, Transactions of the Association of American Physicians.

[46]  C. Sigmund,et al.  Structure, Expression, and Regulation of the Murine Renin Genes , 1991, Hypertension.

[47]  D. Ganten,et al.  Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene , 1990, Nature.

[48]  S. Gordon,et al.  F4/80, a monoclonal antibody directed specifically against the mouse macrophage , 1981, European journal of immunology.