Non-alcoholic steatohepatitis induces non-fibrosis-related portal hypertension associated with splanchnic vasodilation and signs of a hyperdynamic circulation<i>in vitro</i>and<i>in vivo</i>in a rat model

Francque, Sven; Wamutu, S.; Chatterjee, Shyama; Marck, Eric Van; Herman, Arnold G.; Ramon, Albert; Jung, Alexander; Vermeulen, Wim; Winter, Benedicte Y. De; Pelckmans, Paul; Michielsen, P.

doi:10.1111/j.1478-3231.2009.02136.x

Cited by 48 publications

(64 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…10 In the present series we confirm the presence of PHT in patients with NAFLD, in the absence of significant fibrosis, confirming our experimental findings. As some patients were taking antihypertensive drugs, the results might even underestimate the problem.…”

Section: Discussionsupporting

confidence: 91%

“…This rise in portal pressure is associated with systemic vascular hyporeactivity, increased splanchnic blood flow and signs of a hyperdynamic circulation. 10 These features resemble the hemodynamic changes that are well documented in cirrhotic PHT. 11,12 We subsequently examined the hepatic venous pressure gradient (HVPG) in a prospectively included series of patients with overweight and hence a risk of NAFLD.…”

Section: Introductionsupporting

confidence: 52%

See 1 more Smart Citation

Visceral adiposity and insulin resistance are independent predictors of the presence of non-cirrhotic NAFLD-related portal hypertension

et al. 2010

View full text Add to dashboard Cite

Introduction: We previously demonstrated in an animal model that steatosis, in the absence of fibrosis, induces a significant rise in portal pressure, indicating substantial changes in liver hemodynamics. As assessment of portal pressure is an invasive procedure, non-invasive parameters are needed to identify patients at risk. Aims: To study the portal pressure in nonalcoholic fatty liver disease patients and to identify factors that are possibly related to steatosis-induced changes in liver hemodynamics. Materials and methods: Patients presenting with a problem of overweight or obesity, and in whom non-invasive investigations showed signs of liver involvement, were proposed for transjugular hepatic vein catheterization and liver biopsy. The biopsy was scored according to the Nonalcoholic Steatohepatitis Clinical Research Network Scoring System. Results: A total of 50 consecutive patients were studied. Their mean age was 47.9 ± 1.8 years; 31 (62%) were female. Hepatic venous pressure gradient was normal in 36 (72%) and elevated in 14 (28%) patients. The degree of steatosis was the only histological parameter that differed significantly between the two groups (P ¼ 0.016), and was a predictor of the presence of portal hypertension (PHT) in regression analysis (P ¼ 0.010). Comparing normal versus portal hypertensive patients, waist circumference (117 ± 2 versus 128 ± 4 cm, P ¼ 0.005), waist-hip ratio (0.96 ± 0.06 versus 1.04 ± 0.03, P ¼ 0.003), visceral fat (229 ± 15 versus 292 ± 35 cm 2 , P ¼ 0.022), fasting insulin (15.4 ± 1.7 versus 21.8 ± 2.4 mU ml À1 , P ¼ 0.032), fasting c-peptide (1.22 ± 0.06 versus 1.49 ± 0.09 nmol l À1 , P ¼ 0.035) and homeostasis model assessment-insulin resistance (HOMA IR) (3.28 ± 0.29 versus 4.81 ± 0.57, P ¼ 0.019) were significantly higher. Age, gender, liver enzymes, ferritin and high-sensitive C-reactive protein were not significantly different. In regression analysis, waist circumference (P ¼ 0.008) and HOMA IR (P ¼ 0.043) were independent predictors of PHT. Conclusions: Estimates of both visceral adiposity and IR are predictors for the presence of PHT, related to the degree of steatosis, and may help in identifying patients who are at risk of developing steatosis-related complications.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Introductionsupporting

confidence: 52%

Visceral adiposity and insulin resistance are independent predictors of the presence of non-cirrhotic NAFLD-related portal hypertension

et al. 2010

View full text Add to dashboard Cite

show abstract

“…We also showed that this increase in portal pressure was related to the severity of the steatosis and occurred in the complete absence of fibrosis. Furthermore, we showed that the increase in portal pressure coincides with the development of severe steatosis and precedes necro-inflammatory changes, 10 leading to the hypothesis that steatosis-related increase in intrahepatic resistance might, via local ischaemia, contribute to the progression of NAFLD to NASH. These findings appeared to be clinically relevant, as we could demonstrate portal hypertension in a group of obese NAFLD patients with severe steatosis but minor degrees of fibrosis.…”

mentioning

confidence: 77%

“…12 We previously demonstrated in a detailed analysis of our model that the MCD diet in our male Wistar rats rapidly induces steatosis, which is already almost 100% at week 3, whereas signs of inflammation and oxidative stress develop only beyond 4 weeks of MCD diet. 10 The protocols were approved by the Antwerp University Ethical Committee on Animal Experiments, and the animals received human care and were treated according to the Helsinki declaration, the national guidelines for animal protection and the 'Guide for the Care and Use of Laboratory Animals' (National Institutes of Health, 1985).…”

Section: Materials and Methods Animal Modelmentioning

confidence: 99%

“…8,9 We recently reported that portal pressure is significantly elevated in severe NAFLD in a rat model. 10 This indicates an important increase of the intrahepatic resistance with haemodynamic repercussions in severe steatosis. We also showed that this increase in portal pressure was related to the severity of the steatosis and occurred in the complete absence of fibrosis.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture

Francque

Laleman²,

Verbeke³

et al. 2012

Laboratory Investigation

Self Cite

110

124

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease can progress to steatohepatitis and fibrosis, and is also associated with impaired liver regeneration. The pathophysiology remains elusive. We recently showed that severe steatosis is associated with an increase in portal pressure, suggesting liver flow impairment. The objective of this study is to directly assess total intrahepatic resistance and its potential functional and structural determinants in an in situ perfusion model. Male Wistar rats fed a control (n ¼ 30) or a methionine-choline-deficient (MCD) diet (n ¼ 30) for 4 weeks were compared. Liver tissue and serum analysis, in vivo haemodynamic measurements, in situ perfusion experiments and vascular corrosion casts were performed. The MCD group showed severe steatosis without inflammation or fibrosis on histology. Serum levels and liver tissue gene expression of interleukin (IL)-6, tumour necrosis factor-a, IL-1b and interferon-g, liver tissue myeloperoxidase activity and liver immunohistochemistry with anti-CD68 and anti-a smooth muscle actin were comparable between groups, excluding significant inflammation. Flow-pressure curves were significantly different between groups for all flows (slope values: 0.1636±0.0605 mm Hg/ml/min in controls vs 0.7270±0.0408 mm Hg/ml/min in MCD-fed rats, Po0.001), indicating an increased intrahepatic resistance, which was haemodynamically significant (portocaval pressure gradient 2.2 ± 1.1 vs 8.2 ± 1.3 mm Hg in controls vs MCD, Po0.001). Dose-response curves to acetylcholine were significantly reduced in MCD-fed rats (Po0.001) as was the responsiveness to methoxamine (Po0.001). Vascular corrosion casts showed a replacement of the regular sinusoidal anatomy by a disorganized pattern with multiple interconnections and vascular extensions. Liver phosphorylated endothelial NO synthase (eNOS)/eNOS and serum nitrite/nitrate were not increased in severe steatosis, whereas liver thromboxane synthase expression, liver endothelin-1 (ET-1) expression and serum andothelin-1 concentration were significantly increased. Severe steatosis induces a haemodynamically significant increase in intrahepatic resistance, which precedes inflammation and fibrogenesis. Both functional (endothelial dysfunction and increased thromboxane and ET-1 synthesis) and structural factors are involved. This phenomenon might significantly contribute to steatosis-related disease.

show abstract

Hepatic endothelin-1 and endocannabinoids-dependent effects of hyperleptinemia in nonalcoholic steatohepatitis-cirrhotic rats

Yang

Tsai²,

Huang³

et al. 2012

Hepatology

View full text Add to dashboard Cite

Leptin, the ob gene product, is a protein released from adipocytes and has been detected in fibrotic and cirrhotic livers. Leptin in brain has an inhibitory effect on food intake. Nonalcoholic steatohepatitis (NASH) is characterized by hyperleptinemia. This study explores the possible mechanisms of hyperleptinemia in relation to increased intrahepatic resistance (IHR) and portal hypertension in NASH cirrhotic rats. NASH cirrhotic rats with hyperleptinemia were induced in Zucker (fa/fa) and lean rats by feeding the animals a high fat/methionine-choline-deficient (HF/MCD) diet with and without exogenous administration of recombinant leptin. Portal venous pressure (PVP), IHR, plasma and hepatic levels of various substances, histopathology of the liver, the hepatic hydroxyproline content, and the expression of various hepatic protein and messenger RNA (mRNA) were measured. Hepatic microcirculatory dysfunction and the vasoconstrictive response to endothelin-1 were also observed using a liver perfusion system and intravital microscopy. Finally, the effect of leptin on hepatic stellate cells (HSCs) was evaluated. Both in HF/MCD-Zucker and HF/MCD1leptin lean rats, significant hepatic fibrogenesis and cirrhosis, marked portal hypertension, microcirculatory dysfunction, an enhanced vasoconstrictive response to endothelin-1, and an increased IHR were found to be associated with higher levels of hepatic endothelin-1 and endocannabinoids, expression levels of the cannabinoid type 1 receptor, endothelin-1 type A receptor (ET A R), activator protein-1, transforming growth factor beta (TGF-b) 1 , osteopontin, tumor necrosis factor alpha (TNF-a), leptin, and the leptin receptor (OBRb). Interestingly, acute incubation of leptin directly increases the expression of ET A R, OBRb and activator protein-1 in HSCs. Conclusion: An HF/MCD diet and hyperleptinemia increase hepatic endocannabinoids production, promote hepatic fibrogenesis, enhance the hepatic vasoconstrictive response to endothelin-1, and aggravate hepatic microcirculatory dysfunction; these events subsequently increase IHR and portal hypertension in NASH cirrhotic rats. (HE-PATOLOGY 2012;55:1540-1550 M ost obese humans and rodents (fa/fa rats) with nonalcoholic steatohepatitis (NASH) of the liver usually have high circulating levels of leptin.1-3 However, this endogenous hyperleptinemia does not seem to reduce appetite or increase energy expenditure and is termed leptin resistance. 3,4A methionine choline-deficient (MCD) diet results in liver injury similar to human NASH. 4,5 Feeding an animalAbbreviations:: HF/MCD, high fat/methionine-choline-deficient; HSC, hepatic stellate cells; IHR, intrahepatic resistance; NASH, nonalcoholic steatohepatitis; OBRb: leptin receptor.From the

show abstract

Non-alcoholic steatohepatitis induces non-fibrosis-related portal hypertension associated with splanchnic vasodilation and signs of a hyperdynamic circulationin vitroandin vivoin a rat model

Cited by 48 publications

References 38 publications

Visceral adiposity and insulin resistance are independent predictors of the presence of non-cirrhotic NAFLD-related portal hypertension

Visceral adiposity and insulin resistance are independent predictors of the presence of non-cirrhotic NAFLD-related portal hypertension

Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture

Hepatic endothelin-1 and endocannabinoids-dependent effects of hyperleptinemia in nonalcoholic steatohepatitis-cirrhotic rats

Contact Info

Product

Resources

About