Elsevier

Nutrition

Volume 14, Issue 4, April 1998, Pages 376-390
Nutrition

Review Articles
The Role of Nitric Oxide in Hepatic Metabolism

https://doi.org/10.1016/S0899-9007(97)00492-9Get rights and content

Abstract

Nitric oxide (NO) may regulate hepatic metabolism directly by causing alterations in hepatocellular (hepatocyte and Kupffer cell) metabolism and function or indirectly as a result of its vasodilator properties. Its release from the endothelium can be elicited by numerous autacoids such as histamine, vasoactive intestinal peptide, adenosine, ATP, 5-HT, substance P, bradykinin, and calcitonin gene–related peptide. In addition, NO may be released from the hepatic vascular endothelium, platelets, nerve endings, mast cells, and Kupffer cells as a response to various stimuli such as endotoxemia, ischemia-reperfusion injury, and circulatory shock. It is synthesized by nitric oxide synthase (NOS), which has three distinguishable isoforms: NOS-1 (ncNOS), a constitutive isoform originally isolated from neuronal sources; NOS-2 (iNOS), an inducible isoform that may generate large quantities of NO and may be induced in a variety of cell types throughout the body by the action of inflammatory stimuli such as tumor necrosis factor and interleukin (IL)-1 and -6; and NOS-3 (ecNOS), a constitutive isoform originally located in endothelial cells. Another basis for differentiation between the constitutive and inducible enzymes is the requirement for calcium binding to calmodulin in the former. NO is vulnerable to a plethora of biologic reactions, the most important being those involving higher nitrogen oxides (NO2−), nitrosothiol, and nitrosyl iron–cysteine complexes, the products of which (for example, peroxynitrite), are believed to be highly cytotoxic. The ability of NO to react with iron complexes renders the cytochrome P450 series of microsomal enzymes natural targets for inhibition by NO. It is believed that this mechanism provides negative feedback control of NO synthesis. In addition, NO may regulate prostaglandin synthesis because the cyclooxygenases are other hem-containing enzymes. It may also be possible that NO-induced release of IL-1 inhibits cytochrome P450 production, which ultimately renders the liver less resistant to trauma. It is believed that Kupffer cells are the main source of NO during endotoxemic shock and that selective inhibition of this stimulation may have future beneficial therapeutic implications. NO release in small quantities may be beneficial because it has been shown to decrease tumor cell growth and levels of prostaglandin E2 and F2α (proinflammatory products) and to increase protein synthesis and DNA-repair enzymes in isolated hepatocytes. NO may possess both cytoprotective and cytotoxic properties depending on the amount and the isoform of NOS by which it is produced. The mechanisms by which these properties are regulated are important in the maintenance of whole body homeostasis and remain to be elucidated.

Introduction

The function of any organ critically depends on an efficient blood supply that provides adequate tissue perfusion. The discovery that the vascular endothelium can release a plethora of vasoactive substances has transformed our understanding of mechanisms that control peripheral vascular tone.[1]These vasoactive substances can exert powerful effects on the peripheral vasculature to elicit changes at a regional, localized level to induce redistribution of blood flow without necessarily affecting central vascular tone or pressure.[2]This is particularly pertinent in a metabolically active organ such as the liver because any factors that alter sinusoidal perfusion will affect hepatic metabolism. The naturally occurring vasodilator nitric oxide (NO) exerts profound effects on hepatic vascular tone.3, 4Surprisingly little is known regarding its direct actions on hepatic metabolism.

The mechanisms by which NO can elicit changes in hepatic metabolism can be broadly divided into two areas by 1) exerting a direct effect on hepatic uptake, storage, detoxification, and clearance mechanisms[5]and 2) exerting an indirect effect either by induction of changes in hepatic vascular tone, which would ultimately affect these mechanisms,3, 4or via modulation of the activity of other vasoactive substances such as prostaglandins.[6]

Currently, comparatively little is known regarding the direct mechanisms, and this offers a very exciting area of research. By contrast, limited research has concentrated on the role of endothelium-derived vasoactive substances in the control of hepatic vascular tone, although these have not necessarily been directly linked to hepatic metabolism. This review first presents an overview of hepatic anatomy, hepatic metabolic processes, the importance of hepatic blood flow on hepatic metabolism, the role of the hepatic artery (HA) in hepatic metabolism, and the discovery and biochemistry of NO. The remainder of the review has been divided into two main areas: 1) the direct effects that NO is believed to exert on hepatic metabolism and 2) the indirect effects that NO may exert on hepatic metabolism via its effects on hepatic blood flow.

The liver may be considered as a collection of numerous microscopic structural and functional units, the acini, whose effluents of blood and bile eventually drain into the main hepatic veins and common bile duct, respectively. Each functional unit, or acinus, comprises a cluster of cells that are arranged anatomically around the hepatic vasculature.[7]The hepatocellular architecture of the liver is highly complex partially because 1) the liver is composed of several cell types, 2) the ratio of different cell types may alter after hepatocellular injury owing to its high regenerative capacity, and 3) there are two afferent vasculatures, the HA and the portal vein (PV).

Liver cells can be divided into the hepatic parenchymal cells (hepatocytes) and the nonparenchymal hepatic cells, which are further subdivided into 1) endothelial cells; 2) smooth muscle cells, which probably comprise the intrahepatic vascular resistance sites; 3) Kupffer cells, the hepatic macrophages that are believed to be derived from monocytes and which make up to 90% of the total body tissue macrophage count[5]; and 4) Ito cells, which are responsible for fat storage but may also play a role in regulation of sinusoidal resistance.

The numerous and diverse functions of the liver range from the synthesis of proteins and peptides and storage of carbohydrates to detoxification of drugs and gut metabolites and the inactivation of hormones. The liver is also responsible for the formation of bile, urea, the metabolism of fat, and also has important immune functions. An efficient blood supply is critical to many vital metabolic functions of the liver. In addition, many metabolic and pharmacologic reactions carried out in the liver are oxygen dependent and rely on adequate oxygenation and efficient gaseous exchange. Curiously, the direct influence of hepatic blood flow on regulation of hepatic metabolism has still to be fully elucidated.

Regulation of hepatic metabolism depends on the maintenance of the total hepatic blood flow, approximately 75% of which is derived from the gut, via the PV, the remaining 25% being systemic blood supply from the HA. Diversion of PV blood from the liver to the systemic circulation, which was developed as a technique for surgical decompression of portal hypertension (portacaval shunting), has dramatic consequences on systemic and, of course, hepatic metabolism. When the first portacaval shunt was carried out in humans at the beginning of the 20th century,[8]it was noted that “absorption of albuminoides provoked a severe intoxication and that in limited amounts these substances produced sweats, muscular trembling, intense anxiety and cardiac arrhythmias.” Burton-Opiz[9]first suggested that a physiologic reciprocal flow interrelationship between the HA and PV circulations existed in the dog liver. He demonstrated that during periods of reduced PV flow, a reciprocal increase in HA flow could be observed, although total hepatic blood flow could not be fully regained. It was later suggested[10]that the prognosis of patients who had undergone PV decompression surgery for the relief of portal hypertension correlated with the magnitude of the resultant HA hyperemia. Although the hydrodynamic effects of portal hypertension may be relieved by surgical PV decompression, derangements in hepatic metabolism may develop as a result of a reduction in total hepatic blood flow.

It is possible that a critical value exists for total hepatic blood flow, below which hepatic function is reduced, because only reductions in portal venous flow will precipitate measurable derangements in hepatic function in the normal liver.[11]It would also be expected that this value would be greater than 25% of the total hepatic blood flow, if this hypothesis holds true, as this is the average percentage attributable to the HA component under normal conditions. A study[12]conducted to relate the magnitude of portal venous blood flow to body weight in healthy volunteers and patients with liver cirrhosis showed that subjects with a value of between 12 and 20 mL · min−1 · kg−1 had optimal liver function tests, and this was regarded as the normal range. Those with cirrhosis had a value of less than 12 mL · min−1 · kg−1 and poor hepatic function tests attributable to inadequate hepatic perfusion.

The role of the HA in hepatic metabolism has still not been fully elucidated.[13]It has been assumed that the role of the HA in hepatic metabolism was not of any particular importance except under pathologic conditions in which its compensatory role in the HA hyperemia after reductions in PV flow was suggested to be critical.[10]It has been suggested that HA ligation does not induce any noticeable alterations in hepatic metabolism in normal rats.[14]Powis[15]suggested that glucose synthesis from lactate was not different in the rat liver perfused via the PV or by both routes, and this was taken as evidence that the role of the HA in hepatic metabolism was minimal.[11]The evidence remains inconclusive.16, 17Moreover, the control of HA flow has been shown to be independent of hepatic metabolism.[18]

The role of the HA in drug removal and metabolite formation is poorly understood. Increasing the proportion of HA to PV flow in an unchanged total liver blood flow has been shown to reduce the hepatic extraction of lidocaine,[19]gentisamide, phenacetin, and acetaminophen, although vitamin D3 clearance remained unchanged.[13]It is possible that HA flow may influence drug and metabolic processes at two levels; by biliary excretion and by metabolism within hepatocytes. Simultaneous HA and PV perfusion of the liver may favor biliary excretion of HA- over PV-borne substances because only the HA perfuses the peribiliary plexus and biliary ductules.[7]The apparent reduction in hepatic extraction of certain drugs observed during increases in HA flow may be explained by 1) regional redistribution of sinusoidal perfusion, 2) an increased transit of a particular substrate through the liver due to the effects of increased HA perfusion pressure, 3) reductions in portal venous flow due to the hepatic arterial hyperemic (buffer) response, and 4) the opening of naturally occurring portal-systemic shunts20, 21induced by HA perfusion, which would directly prevent the sinusoidal uptake of a substrate.22, 23

Section snippets

Discovery and Biochemistry of Nitric Oxide

Furchgott and Zawadzki[24]demonstrated that removal of the vascular endothelium prevented the vascular relaxation elicited by acetylcholine. Ignarro et al.[25]first proposed that the identity of endothelium-derived relaxing factor was NO and suggested that glyceryl trinitrates might share a common pathway in eliciting vasodilatation. This hypothesis was based on the observation that nitrovasodilators and NO activate soluble guanylate cyclase to raise cyclic guanosine monophosphate levels (cGMP)

Direct Effects of Nitric Oxide on Hepatic Metabolism

Much of the literature available concerning the direct effects of NO on hepatic metabolism involves the characterization of various isoforms of NOS that have been identified. The degree of activation of NO cannot be directly measured in terms of receptor binding activity and is indirectly measured by the activity and expression of NO synthase. Much interest has centered on the role of Kupffer cell function on hepatocyte, and Kupffer cell metabolism, as they are both capable of synthesizing NO.

Indirect Effects of Nitric Oxide on Hepatic Metabolism

Hepatic metabolism critically depends on adequate delivery of blood to the liver, and total hepatic blood flow may extract up to 25% from the cardiac output. It is now known that NO may modulate PV and HA vascular tone and may, therefore, alter hepatic metabolism indirectly by inducing changes in hepatic blood flow. This is in contrast to its direct cytotoxic or cytoprotective actions on hepatocyte and Kupffer cell metabolism discussed earlier.

Conclusions

NO exerts many physiologic actions, the complexities of which have only begun to be addressed. It was originally difficult to believe that such a short-lived and simple molecule could exert profound effects and be of such physiologic significance. Perhaps, it is those characteristics that render the molecule so physiologically versatile. In this review, emphasis has been placed on some of the significant actions of NO that pertain to hepatic metabolism. It is implicit that any substance that

Acknowledgements

I thank Dr. R.T. Mathie and Ms. A. Hassanali for their helpful suggestions in the preparation of the manuscript, and Professor I.S. Benjamin for editing the text.

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