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

Abstract

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.

CEUS and Fibroscan in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

“…Our results suggest the hypothesis that in patients with NAFLD, there is a reduced vascular compliance in the liver due to augmented hepatic vascular resistance to portal blood flow and an increased hepatic vascular tone that starts before the onset of fibrosis. This change was previously demonstrated by Francque et al [18] in an experimental animal model; in their study, Wistar rats fed with a methionine-and choline-deficient diet for four weeks developed severe steatosis associated with a significant increase in intrahepatic resistance before the onset of fibrosis and inflammation. These changes involved functional (liver endothelial dysfunction and vasoconstrictor overproduction) and structural (sinusoidal altered microvascular architecture) factors.…”

Portal Hypertension as Immune Mediate Disease

“…KCs- derived TNF-a is mitogenic and chemoattractant for HSC (24). However, the nature of these data is still controversial (25). Tokushige et al reported a significant increase of serum TNF-a levels and altereted Th1/Th2 balance (26).…”

The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease

“…The dysfunction of LSECs is known to augment intrahepatic resistance to impair microcirculation in the liver [18,26]. In fact, increased intrahepatic resistance has been demonstrated in an isolated-perfused rat liver obtained from a cafeteria diet-fed model of NAFLD [27], a methionine-choline-deficient model of NASH [28], and from a model of LPS-induced endotoxemia [29]. While the assessment of intrahepatic micro-circulation is technically limited in mice [30], impaired blood flow in the liver may accelerate hepatocyte cell death in hypoxic micro-environments.…”