Steatosis as main determinant of portal hypertension through a restriction of hepatic sinusoidal area in a dietary rat nash model

Abstract

Background & Aims: Portal hypertension (PH) can be present in pre-cirrhotic stages, even in absence of fibrosis in non-alcoholic steatohepatitis (NASH) patients. Liver endothelial dysfunction (ED) has been shown as responsible for this effect in short-term dietary animal models. We evaluated the persistence of PH and underlying mechanisms in a long-term rat model of NASH. Methods: Sprague-Dawley rats were fed 8 or 36 weeks with control diet or high-fat high-glucose/fructose diet. Metabolic parameters, histology, ED and haemodynamics were characterized. Structural characteristics of liver sections were analysed using image analysis. Results: Both interventions reproduced NASH histological hallmarks (with steatosis being particularly increased at 36 weeks), but neither induced fibrosis. The 36-week intervention induced a significant increase in portal pressure (PP) compared to controls (12.1 vs 8.7 mmHg, P < .001) and the 8-week model (10.7 mmHg, P = .006), but all features of ED were normalized at 36 weeks. Image analysis revealed that the increased steatosis at 36-week was associated to an increase in hepatocyte area and a significant decrease in the sinusoidal area, which was inversely correlated with PP. The analysis provided a critical sinusoidal area above which animals were protected from developing PH and below which sinusoidal flux was compromised and PP started to increase. Conclusion: Liver steatosis per se (in absence of fibrosis) can induce PH through a decrease in the sinusoidal area secondary to the increase in hepatocyte area in a longterm diet-induced rat model of NASH. Image analysis of the sinusoidal area might predict the presence of PH. | 2733 BARBERÁ Et Al.

Idiopathic Non-Cirrhotic Portal Hypertension and Porto-Sinusoidal Vascular Disease: Review of Current Data

“…There is growing evidence that PH can occur in alcoholic fatty liver disease and NAFLD even in the absence of significant fibrosis/cirrhosis and that it correlates with the degree of steatosis [95][96][97][98][99][100][101]. Although the exact etiopathogenesis remains unclear, multiple hypotheses have been proposed.…”

Portal Hypertension in Nonalcoholic Fatty Liver Disease: Challenges and Paradigms

“…Impaired hepatic blood flow due to narrowing of the sinusoidal space has been demonstrated in rats fed choline-deficient diet, 26 New Zealand white rabbits fed high cholesterol diet, 27 the Zucker obese-rat model, 28 rats fed a methionine-choline deficient diet, 29,30 and in the rat model of human NAFLD using the cafeteria diet, 31 In all these reports, increased HVR developed in association with massive steatosis but without significant histological evidence of fibrosis, and without a significant increase in the expression of profibrotic genes, 32 Similarly, when steatohepatitis was induced in rats by high-fat glucose-fructose diet, increased PVP was demonstrated before significant fibrosis developed, 33,34 More recently, digital image analysis of hepatocellular fat and sinusoidal areas in the high-fat glucose-fructose diet model of NAFLD found an inverse correlation between vascular space and PVP. 35 Steatosis has also been associated with endothelial dysfunction and ineffective vasoregulation, implying that steatosis contributes to both the structural and dynamic components of increased HVR. [30][31][32] Clinical studies provide additional evidence for the development of portal hypertension in precirrhotic NAFLD (Table 1).…”

Liver steatosis induces portal hypertension regardless of fibrosis in patients with NAFLD: A proof of concept case report

“…endothelial dysfunction, imbalance in vasoactive substances) 2 , 3 and structural sinusoidal disturbances secondary to fatty liver changes could promote PH, even in the absence of fibrosis. 4 , 5 Our group reported that steatosis was the main determinant of PH in a 36-week dietary NASH rat model. 5 The main mechanism was the architectural distortion of the sinusoid area caused by accumulation of lipid droplets and morphological changes in hepatocytes, which led to sinusoidal compression and increased intrahepatic vascular resistance ( Fig.…”

“… 4 , 5 Our group reported that steatosis was the main determinant of PH in a 36-week dietary NASH rat model. 5 The main mechanism was the architectural distortion of the sinusoid area caused by accumulation of lipid droplets and morphological changes in hepatocytes, which led to sinusoidal compression and increased intrahepatic vascular resistance ( Fig. 1 C)…”

“…Nonetheless, several studies have suggested that PH can be present in the early stages of NASH, when fibrosis is far less advanced or even absent. [2] , [3] , [4] , [5] , [6] , [7] , [8] …”