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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