Hepatic Microcirculation in Fatty Liver Disease

Farrell, Geoffrey C.; Teoh, Narcissus; McCuskey, Robert S.

doi:10.1002/ar.20715

Cited by 235 publications

(201 citation statements)

References 71 publications

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“…PTX leads to increased tissue perfusion and improved regional microcirculation and tissue oxygenation. PTX improves liver npg perfusion in humans [30,31] . PTX may therefore lessen the acute hepatic injury induced by a high-fat diet and may be partially associated with increased hepatic arterial blood flow and alleviation of early hepatic circulatory disturbances in rats with NASH.…”

Section: Discussionmentioning

confidence: 98%

Pentoxifylline alleviates high-fat diet-induced non-alcoholic steatohepatitis and early atherosclerosis in rats by inhibiting AGE and RAGE expression

Zhao

Zheng

et al. 2010

Acta Pharmacol Sin

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Aim:To investigate the expression of advanced glycation end products (AGEs) and their receptor RAGE in the livers and blood vessels of rats with non-alcoholic steatohepatitis (NASH) and the effect of pentoxifylline (PTX) on liver and artery function in rats with NASH. Methods: Sprague-Dawley rats were fed a high-fat diet for 12 weeks and given PTX by gavage for 4 weeks. The effects of PTX on hepatic liver and vessel function as well as the expression of AGE and RAGE in rats with NASH were assessed. The intima-media thickness (IMT) of the aorta and carotid artery was evaluated using ultrasonography. Results: Serum aspartic aminotransferase (AST) and blood levels of glucose (GLU) were reduced in the PTX group relative to the NASH group. The IMT of the aorta and carotid artery was increased in the NASH group compared with the control group. The IMT was reduced in NASH rats after treatment with PTX. Rats with NASH demonstrated higher AGE and RAGE protein levels in the liver and arteries compared with those of control rats. PTX treatment in NASH rats resulted in a decrease in AGE and RAGE protein levels in the liver and arteries compared with those in the NASH group. Conclusion: Early atherosclerosis was observed in rats with NASH induced by a 16-week high-fat diet. High expression of AGE and RAGE in the livers and arteries of rats with NASH may contribute to the pathogenesis of NASH and early atherosclerosis. PTX showed protective effects on hepatic and arterial function, partially through inhibition of AGE and RAGE expression.

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Section: Discussionmentioning

confidence: 98%

Pentoxifylline alleviates high-fat diet-induced non-alcoholic steatohepatitis and early atherosclerosis in rats by inhibiting AGE and RAGE expression

Zhao

Zheng

et al. 2010

Acta Pharmacol Sin

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“…NAFLD is associated with hepatic sinusoid microcirculation (Farrell et al 2008). Liver sinusoidal endothelial cells (LSECs) play important roles in regulating hepatic sinus function.…”

Section: Introductionmentioning

confidence: 99%

oxLDL induces injury and defenestration of human liver sinusoidal endothelial cells via LOX1

Zhang¹,

Liu²,

Liu³

et al. 2014

Journal of Molecular Endocrinology

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Non-alcoholic fatty liver disease is associated with hepatic microangiopathy and liver inflammation caused by type 2 diabetes mellitus. Oxidised LDL (oxLDL) is involved in proinflammatory and cytotoxic events in various microcirculatory systems. The lectin-like oxLDL receptor 1 (LOX1) plays a crucial role in oxLDL-induced pathological transformation. However, the underlying mechanism of oxLDL's effects on liver microcirculation disturbances remains unclear. In this study, we investigated the effects of oxLDL on LOX1 (OLR1) expression and function, as well as on the fenestration features of human liver sinusoidal endothelial cells (HLSECs) in vitro. Primary HLSECs were obtained and cultured. The cells were treated with various concentrations of oxLDL (25, 50, 100 and 200 mg/ml), and the cytotoxicity and expression of LOX1 were examined. Furthermore, LOX1 knockdown was performed using siRNA technology, and the changes in intracellular reactive oxygen species (ROS), NFkB, p65, (p65), endothelin 1 (ET1 (EDN1)), eNOS (NOS3) and caveolin 1 (CAV1) levels were measured. Cells were treated with 100 mg/ml oxLDL, and the fenestra morphology was visualised using scanning electron microscopy. oxLDL significantly increased LOX1 expression at both the mRNA and protein levels in HLSECs in a dose-and time-dependent manner. oxLDL stimulation increased ROS generation and NFkB activation, upregulated ET1 and caveolin 1 expression, downregulated eNOS expression and reduced the fenestra diameter and porosity. All of these oxLDLmediated effects were inhibited after LOX1 knockdown. These results reveal a mechanism by which oxLDL stimulates the production of LOX1 through the ROS/NFkB signalling pathway and by which LOX1 mediates oxLDL-induced endothelial injury and the defenestration of HLSECs. Key Words" oxidised LDL " lectin-like oxLDL receptor 1 " endothelial injury " defenestration " human liver sinusoidal endothelial cells

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“…Reduction in sinusoidal flow and sinusoidal narrowing have been described. 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.…”

mentioning

confidence: 99%

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

Francque

Laleman²,

Verbeke³

et al. 2012

Laboratory Investigation

110

124

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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.

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Hepatic Microcirculation in Fatty Liver Disease

Cited by 235 publications

References 71 publications

Pentoxifylline alleviates high-fat diet-induced non-alcoholic steatohepatitis and early atherosclerosis in rats by inhibiting AGE and RAGE expression

Pentoxifylline alleviates high-fat diet-induced non-alcoholic steatohepatitis and early atherosclerosis in rats by inhibiting AGE and RAGE expression

oxLDL induces injury and defenestration of human liver sinusoidal endothelial cells via LOX1

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

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