NO sensitizes rat hepatocytes to proliferation by modifying S-adenosylmethionine levels

Garcı́a-Trevijano, Elena R.; Martínez‐Chantar, María Luz; Latasa, María U.; Mato, José M.; Avila, Matı́as A.

doi:10.1053/gast.2002.33020

Cited by 74 publications

(82 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…24,32 Additionally, exogenous SAMe prevents the development of HCC in rats treated with hepatocarcinogen, 33,34 inhibits the growth of hepatoma cells, 30 and blocks the mitogenic effect of hepatocyte growth factor (HGF) in hepatocytes. 35 Conversely, chronic SAMe depletion in Mat1a (Ϫ/Ϫ) mice is associated with increased proliferating cell nuclear antigen expression and the spontaneous development of HCC. 26,36 Despite having higher baseline hepatic staining for proliferating cell nuclear antigen, Mat1a (Ϫ/Ϫ) mice with low hepatic SAMe levels have impaired liver regeneration after PH because of an inability to upregulate cyclin D1.…”

Section: Same Regulation Of Hepatocyte Growthmentioning

confidence: 99%

“…35 Cyclin D1 mRNA levels are regulated by HuR, a RNA-binding protein that increases the half-life of a variety of cell cycle genes. In hepatocytes, HGF regulates cytoplasmic HuR content via phosphorylation and activation of the AMP-activated protein kinase (AMPK), and SAMe inhibits this process through a mechanism that involves the activation of protein phosphatases, probably protein phosphatase 2A.…”

Section: Same Regulation Of Hepatocyte Growthmentioning

confidence: 99%

See 1 more Smart Citation

Role of S-adenosyl-L-methionine in liver health and injury

2007

Self Cite

View full text Add to dashboard Cite

S-Adenosylmethionine (SAMe) has rapidly moved from being a methyl donor to a key metabolite that regulates hepatocyte growth, death, and differentiation. Biosynthesis of SAMe occurs in all mammalian cells as the first step in methionine catabolism in a reaction catalyzed by methionine adenosyltransferase (MAT). Decreased hepatic SAMe biosynthesis is a consequence of all forms of chronic liver injury. In an animal model of chronic liver SAMe deficiency, the liver is predisposed to further injury and develops spontaneous steatohepatitis and hepatocellular carcinoma. However, impaired SAMe metabolism, which occurs in patients with mutations of glycine N-methyltransferase (GNMT), can also lead to liver injury. This suggest that hepatic SAMe level needs to be maintained within a certain range, and deficiency or excess can both lead to abnormality. SAMe treatment in experimental animal models of liver injury shows hepatoprotective properties. Meta-analyses also show it is effective in patients with cholestatic liver diseases. Recent data show that exogenous SAMe can regulate hepatocyte growth and death, independent of its role as a methyl donor. This raises the question of its mechanism of action when used pharmacologically. Indeed, many of its actions can be recapitulated by methylthioadenosine (MTA), a by-product of SAMe that is not a methyl donor. A better understanding of why liver injury occurs when SAMe homeostasis is perturbed and mechanisms of action of pharmacologic doses of SAMe are essential in defining which patients will benefit from its use. (HEPATOLOGY 2007;45: 1306-1312.)

show abstract

Section: Same Regulation Of Hepatocyte Growthmentioning

confidence: 99%

Section: Same Regulation Of Hepatocyte Growthmentioning

confidence: 99%

Role of S-adenosyl-L-methionine in liver health and injury

2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mato's group demonstrated that knockout mice lacking this gene were predisposed to liver injury, exhibited increased expression of genes involved in cellular proliferation 158 , had impaired liver regeneration, had lower levels of SAMe, and spontaneously developed hepatocellular carcinomas 159,160 . S-nitrosylation of MAT I/III significantly decreased the levels of SAMe, and sensitized rat hepatocytes to enhanced proliferation 150,161,162 , which is mediated by hepatocyte growth factor scatter factor (HGF), and probably involves IGF-1 priming 163 . HGF is turned on by lower levels of SAMe 150 .…”

Section: S-nitrosylation Of Liver Methionine Adenosyltransferasementioning

confidence: 99%

Nitric Oxide and Cancer Development

et al. 2007

View full text Add to dashboard Cite

Abstract:The role of nitric oxide (NO) in cancer development has become a very active research area. This review presents an overview of many studies that implicate an important role of NO in the development of cancer. These include results in experimental models as well as many observations made on NO and inducible nitric oxide synthase (iNOS) in human cancers. Our survey of the literature has allowed us to conclude that in general large levels of NO will kill cancer cells but paradoxically at intermediate to lower levels NO prevents cancer cell apoptosis and enhances tumor growth. This basic tenet has been demonstrated in many experimental models. The mechanistic basis of how intermediate levels of NO mediate tumor development is an active area of research and is the subject of this review. NO mediated S-nitrosylation of key enzymes and regulatory proteins plays a critical role. Key proteins S-nitrosylated which enhance tumor development include several caspases involved in apoptosis, PTEN the tumor suppressor protein, Bcl-2 the mitochondrial protein which protects from apoptosis, OGG1 the DNA repair protein and methionine adenosyl transferase the liver protein which synthesizes adenosylmethionine. The S-nitrosylation of these proteins enhances DNA mutations, prevents cancer cell apoptosis and enhances oncogenic cell growth. (J Toxicol Pathol 2007; 20: 77-92)

show abstract

“…In the regenerating liver, NO plays a role in the triggering of the regenerating cascade [19,20,[25][26][27]. In addition, in vitro studies have shown that NO sensitizes hepatocytes to hepatic growth factor-induced proliferation by modifying the production of s-adenosylmethionine [6]. The liver at 3 weeks after birth shows significantly high NO production when the organ is in the late maturation stage of development.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Production and its Contribution to Hepatocyte Proliferation in Normal Juvenile Rats

Inukai

Uchida

Miyazaki

et al. 2010

The Journal of Veterinary Medical Science

View full text Add to dashboard Cite

ABSTRACT. Nitric oxide (NO) has been reported as a key mediator in enhancing hepatocyte proliferation during liver regeneration. Juvenile hepatocytes have a strong ability to proliferate while still in their undifferentiated state but the mechanism of NO production and its contribution to hepatocyte proliferation are not yet fully understood. The present study was designed to investigate NO production in the normal liver and its contribution to hepatocyte proliferation in juvenile rats. Endogenous NO production was evaluated quantitatively using a spin trap followed by electron paramagnetic resonance spectroscopy with the Fe-N, N-diethyldithiocarbamate complex as an NOtrapping reagent in the rat liver. NO production in the liver significantly peaked at 3 weeks after birth, but NO synthase (NOS) 3 expression did not change between 2 to 5 weeks after birth, while NOS 1 and NOS 2 mRNA were not detected. Hepatocyte proliferation, measured by the incorporation of 5-bromo-2'-deoxyuridine into the DNA, was found to decline significantly when endogenous NO production was inhibited by the administration of the NOS inhibitor N G -nitro-L-arginine methyl ester. These findings indicate that endogenous NO production peaked at 3 weeks after birth and hepatocyte proliferation declined significantly when NO production was inhibited. Thus, this study provides a novel insight into the contribution of NO to hepatic growth and liver maturation in juveniles.KEY WORDS: electron paramagnetic resonance (EPR) spectroscopy, hepatocyte, nitric oxide.

show abstract

NO sensitizes rat hepatocytes to proliferation by modifying S-adenosylmethionine levels

Cited by 74 publications

References 37 publications

Role of S-adenosyl-L-methionine in liver health and injury

Role of S-adenosyl-L-methionine in liver health and injury

Nitric Oxide and Cancer Development

Nitric Oxide Production and its Contribution to Hepatocyte Proliferation in Normal Juvenile Rats

Contact Info

Product

Resources

About