The Role of Nitric Oxide in Hepatic Metabolism

• Published in: Nutrition 1998-04, Vol.14 (4), p.376-390
• Main Author: Alexander, Barry
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; cirrhosis; endotoxemia; Fundamental and applied biological sciences. Psychology; hepatic hemodynamics; Humans; Kupffer cells; Kupffer Cells - metabolism; Liver - anatomy & histology; Liver - blood supply; Liver - metabolism; Liver. Bile. Biliary tracts; nitric oxide; Nitric Oxide - physiology; Nitric Oxide Synthase - metabolism; portal hypertension; purines; Vertebrates: digestive system
• ISSN: 0899-9007; 1873-1244
• DOI: 10.1016/S0899-9007(97)00492-9

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 (NO 2 −), 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 P 450 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 P 450 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 E 2 and F 2α (proinflammatory products) and to increase protein synthesis and DNA-repair enzymes in isolated hepato