The role of nitric oxide in the modulation of hepatic microcirculation and tissue oxygenation in an experimental model of hepatic steatosis☆
Introduction
Hepatic steatosis which is the result of the abnormal accumulation of triacylglycerol within the cytoplasm of hepatocytes, attributed to the effects of alcohol excess, obesity, diabetes or drugs is a common histological finding in human liver biopsies (Ijaz et al., 2003). Fatty liver affects about 25% of the donors for liver transplantation since severe steatosis is associated with a high risk of primary non-function following liver transplantation. This poor initial function of fatty livers has been shown to be associated with an impairment of the hepatic microcirculation (HM) (Aiba et al., 2001, McCuskey et al., 2004). A significant reduction in HM in liver donors with steatosis was found as compared to normal liver donors (Seifalian et al., 1997, Seifalian et al., 1998, Astarcioglu et al., 2004). Experimental studies in animal models with fatty liver showed that fatty infiltration, classified as mild (<30%), moderate (30–60%) or severe (>60%), reduced total hepatic blood flow and hepatic parenchymal microcirculation and there was an inverse correlation between the degree of fat infiltration and both total hepatic blood flow and flow in the microcirculation (Seifalian et al., 1999). The compromised HM has been suggested to be the result of sinusoidal compression due to the steatosis and hepatocyte enlargement (Akamatsu et al., 1993, Ijaz et al., 2003). However, the precise mechanisms behind the decreased microcirculation in fatty liver have yet to be clarified.
Nevertheless, it is generally accepted that blood flow in the HM is normally maintained by a balance of vasodilators, such as nitric oxide (NO) and vasoconstrictors, like endothelin 1. The role of NO in the regulation of systemic and hepatic hemodynamics involved in liver disease has been extensively studied (Clemens and Zhang, 1999, Rockey, 2001, Wiest and Groszmann, 1999, Yang et al., 2003, Koti et al., 2005). Infusion of an NOS inhibitor enhanced ethanol-induced vasoconstriction in the portal vein whereas the simultaneous infusion of an NO precursor reversed it. These results have suggested that endogenous NO acts as a vasodilator to reduce ethanol-induced vasoconstriction, thus improving the HM (Oshita et al., 1994). An l-arginine infusion was found to selectively augment the portal blood flow in cirrhotic liver (Kakumitsu et al., 1998). NO administration and arginine supplementation in sepsis also demonstrated beneficial effects on hemodynamics and microcirculation (Luiking et al., 2004). However, it is not known if endogenous NO is involved in the hepatic hemodynamic changes resulted from steatosis. There is a general consensus that fatty liver compromises HM regardless of the reason why fatty liver develops in the first place. This may be one of the fundamental reasons why fatty livers tend to be more susceptible to the injurious effects of ischemia and reperfusion. However, there is no published data to date showing the role of NO in the regulation of HM in fatty liver. Therefore, this study investigated the effects of NO stimulation and inhibition on HM and tissue oxygenation in an experimental model of moderate hepatic steatosis induced by rich cholesterol diet.
Section snippets
Animal model and surgical preparation
The study was conducted under a license granted by the Home Office in accordance with the Animals (Scientific Procedures) Act 1986. Male Sprague–Dawley rats weighing between 250 and 300 g were used in this study. Hepatic steatosis was induced by feeding animals with commercial high (2%) cholesterol diet for 12 weeks. The control animals were fed ad libitum. The development of the hepatic steatosis was examined macroscopically and confirmed by histology and tissue lipid analysis.
Prior to the
Animal model of hepatic steatosis
All animals tolerated the high cholesterol diet with no mortality. At laparotomy, liver showed moderate fatty change and, histologically, macrovesicular steatosis was seen under light microscopy. Total lipids in liver tissue of the fatty animals were significantly increased as compared with controls (Fig. 1A). However, there were no significant differences in plasma levels of cholesterol and triglyceride between control and fatty animals (Fig. 1B). There was no significant hepatocellular injury
Discussion
Disrupted HM observed in fatty liver (Hakamada et al., 1997, Teramoto et al., 1993) has been suggested to be the result of sinusoidal compression due to hepatocyte enlargement (Akamatsu et al., 1993) and decreased erythrocyte deformability (Shiraishi et al., 1993). In the present study, HM in the fatty liver induced by high cholesterol diet was significantly reduced that was consistent with significant reductions in PVF while hepatic arterial flow remained unchanged. These results have
Acknowledgments
This study was supported by RMO grant and internal departmental grant.
References (46)
- et al.
Novel nitric oxide donor (FK409) ameliorates liver damage during extended liver resection with warm ischemia in dogs
J. Am. Coll. Surg.
(2001) - et al.
Role of nitric oxide in the regulation of the hepatic microcirculation in vivo
J. Hepatol.
(1997) - et al.
Sinusoidal flow block after warm ischemia in rats with diet-induced fatty liver
J. Surg. Res.
(1997) - et al.
Role of endogenous nitric oxide in ischemia–reperfusion injury in rat liver
J. Surg. Res.
(1995) - et al.
Mechanisms of ischemic injury are different in the steatotic and normal rat liver
Hepatology
(2000) - et al.
Ischemic preconditioning increases the tolerance of fatty liver to hepatic ischemia–reperfusion injury in the rat
Am. J. Pathol.
(2002) - et al.
Protective role of nitric oxide in ischemia and reperfusion injury of the liver
J. Am. Coll. Surg.
(1999) - et al.
Hepatic sinusoidal fibrosis induced by cholesterol and stilbestrol in the rabbit: 1. Morphology and inhibition of fibrogenesis by dipyridamole
Hepatology
(1996) - et al.
Interpretation of the laser Doppler flow signal from the liver of the rat
Microvasc. Res.
(1993) - et al.
The action of nitric oxide on hepatic haemodynamics during secondary biliary cirrhosis in the rat
Eur. J. Pharmacol.
(2003)
Effect of chronic alcohol intake on rat liver microcirculation assessed by the multiple indicator dilution technique
Alcohol Alcohol., Suppl.
Measurement of hepatic perfusion in rats by laser Doppler flowmetry
Am. J. Physiol.
Laser-Doppler flowmetry for estimating liver blood flow
Am. J. Physiol.
The effects of vascular bed expansion in steatotic rat liver graft viability
Transpl. Int.
Role of nitric oxide in porcine liver circulation under normal and endotoxemic conditions
J. Appl. Physiol.
Regulation of sinusoidal perfusion: in vivo methodology and control by endothelins
Semin. Liver Dis.
Changes in tissue oxygenation of the porcine liver measured by near-infrared spectroscopy
Liver Transplant. Surg.
Assessment of hepatic ischaemia reperfusion injury by measuring intracellular tissue oxygenation using near infrared spectroscopy
Liver
Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase
Am. J. Physiol.: Regul., Integr. Comp. Physiol.
Selective inhibition of inducible nitric oxide synthase maintains haemodynamic stability without untoward consequences for hepatic function or morphology
Eur. J. Surg.
Relationship between hypercholesterolaemia, endothelial dysfunction and hypertension
J. Hypertens.
Impairment of hepatic microcirculation in fatty liver
Microcirculation
Effects of l-arginine on the systemic, mesenteric, and hepatic circulation in patients with cirrhosis
Hepatology
Cited by (54)
Gasotransmitters in non-alcoholic fatty liver disease: just the tip of the iceberg
2023, European Journal of PharmacologyPerfusion and ischemia-reperfusion injury in liver transplantation
2022, Bulletin de l'Academie Nationale de MedecineNitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH
2022, Journal of Controlled ReleaseCitation Excerpt :Furthermore, histological analyses also confirmed that the SH-Man-HSA alone did not result in a decrease in lipid accumulation in hepatocytes or vacuolar degeneration or fibrosis in small lobules in the MCD diet group (Supporting Fig. S3E). Ijaz, S. et al. reported that NO ameliorates hepatic microcirculatory dysfunction and increases hepatic blood flow in a rat model of hepatic steatosis [40]. To reproduce the phenomena in our mice model, we used a nitroglycerin patch (Nitroderm TTS®; Sunpharma Co., Tokyo, Japan), which is an NO donor supplied via a transdermal therapeutic system (NO-TTS).
Anastomotic bilio-biliary stricture after adult liver transplantation: A retrospective study over 20 years in a single center
2020, Clinics and Research in Hepatology and GastroenterologyRole of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease
2019, Journal of Hepatology
- ☆
Presented in part at the 38th Annual Meeting of the European Association for Study of the Liver, Geneva, Switzerland, 3–6 July, 2003.