Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation

Lu, Shelly C.; Álvarez, Luis; Huang, Zong–Zhi; Chen, Lixin; An, Wei; Corrales, Fernando J.; Avila, Matı́as A.; Kanel, Gary C.; Mato, José M.

doi:10.1073/pnas.091016398

Cited by 408 publications

(438 citation statements)

References 46 publications

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“…30 Furthermore, reduced expression of Gjb2 (Cx26) is known to contribute to the promotion and progression of hepatocarcinogenesis in rats. 31 Of interest, our microarray analysis unveiled the altered expression of genes involved in Wnt/b-catenin signaling; down-regulation of the Wnt antagonist Sox17 (P ¼ 0.009), up-regulation of a Wnt downstream effector Cyclin D1 (P ¼ 0.001), and modestly increased expression of the Wnt receptor Fzd7 (P ¼ 0.098).…”

Section: Discussionmentioning

confidence: 99%

Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

et al. 2010

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We previously reported that forced expression of Bmi1 (B lymphoma Moloney murine leukemia virus insertion region 1 homolog) in murine hepatic stem/progenitor cells purified from fetal liver enhances their self-renewal and drives cancer initiation. In the present study, we examined the contribution of the Ink4a/Arf tumor suppressor gene locus, one of the major targets of Bmi1, to stem cell expansion and cancer initiation. Bmi1 2/2 Deltalike protein (Dlk) 1 hepatic stem/progenitor cells showed de-repression of the Ink4a/Arf locus and displayed impaired growth activity. In contrast, Ink4a/Arf 2/2 Dlk 1 cells gave rise to considerably larger colonies containing a greater number of bipotent cells than wild-type Dlk 1 cells. Although Ink4a/Arf 2/2 Dlk 1 cells did not initiate tumors in recipient nonobese diabetic/severe combined immunodeficiency mice, enforced expression of Bmi1 in Ink4a/Arf 2/2 Dlk 1 cells further augmented their self-renewal capacity and resulted in tumor formation in vivo. Microarray analyses successfully identified five downregulated genes as candidate downstream targets for Bmi1 in hepatic stem/progenitor cells. Of these genes, enforced expression of sex determining region Y-box 17 (Sox17) in Dlk 1 cells strongly suppressed colony propagation and tumor growth. Conclusion: These results indicate that repression of targets of Bmi1 other than the Ink4a/Arf locus plays a crucial role in the oncogenic transformation of hepatic stem/progenitor cells. Functional analyses of Bmi1 target genes would be of importance to elucidate the molecular machinery underlying hepatic stem cell system and explore therapeutic approaches for the eradication of liver cancer stem cells.

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Section: Discussionmentioning

confidence: 99%

Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

et al. 2010

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“…Studies by Mato and colleagues showed that MAT1A − /− mice, which are deficient in SAM, spontaneously develop steatohepatitis and hepatocellular carcinoma demonstrating that SAM depletion primes the liver for progression to more severe injury [184,185]. Mitochondria isolated from liver of MAT1A − /− mice also have decreased levels of the mitochondrial encoded subunits for cytochrome c oxidase and reduced membrane potential [186].…”

Section: Are Antioxidants Feasible Treatments For Fatty Liver Disease?mentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

381

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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“…To more clearly interrogate the role of AdoMet in regulating CBS levels, we used the transgenic murine model in which the gene for MAT1A (encoding the MATI͞III isoenzyme) is disrupted (11). This knockout induces expression of the MATII isoenzyme in liver with a consequent lowering of hepatic AdoMet and glutathione levels by 4-and 2.5-fold, respectively, and results in an Ϸ8-fold increase in plasma methionine levels (11). Chronic hepatic insufficiency of AdoMet in the MAT1A knockout mice predisposes them to spontaneous steatohepatitis and hepatocellular carcinoma (11,12).…”

Section: Cbs Is Repressed In Mat1a Knockout Mice With High Methioninementioning

confidence: 99%

S -adenosylmethionine stabilizes cystathionine β-synthase and modulates redox capacity

Prudova

Bauman

Braun

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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214

202

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The transsulfuration pathway converts homocysteine to cysteine and represents the metabolic link between antioxidant and methylation metabolism. The first and committing step in this pathway is catalyzed by cystathionine ␤-synthase (CBS), which is subject to complex regulation, including allosteric activation by the methyl donor, S-adenosylmethionine (AdoMet). In this study, we demonstrate that methionine restriction leads to a >10-fold decrease in CBS protein levels, and pulse proteolysis studies reveal that binding of AdoMet stabilizes the protein against degradation by Ϸ12 kcal͞mol. These observations predict that under pathological conditions where AdoMet levels are diminished, CBS, and therefore glutathione levels, will be reduced. Indeed, we demonstrate this to be the case in a mouse model for spontaneous steatohepatitis in which the gene for the MAT1A isoenzyme encoding AdoMet synthetase has been disrupted, and in human hepatocellular carcinoma, where MAT1A is silenced. Furthermore, diminished CBS levels are associated with reduced cell viability in hepatoma cells challenged with tert-butyl hydroperoxide. This study uncovers a mechanism by which CBS is allosterically activated by AdoMet under normal conditions but is destabilized under pathological conditions, for redirecting the metabolic flux toward methionine conservation. A mechanistic basis for the coordinate changes in redox and methylation metabolism that are a hallmark of several complex diseases is explained by these observations. glutathione ͉ liver disease C ellular methylation and antioxidant metabolism are linked by the transsulfuration pathway, which converts the methionine cycle intermediate, homocysteine, to cysteine, the limiting reagent in glutathione synthesis. The balance between conserving methionine via transmethylation under conditions of methionine restriction and committing it to transsulfuration under conditions of plenty is regulated at two key control points, methionine adenosyltransferase (MAT) and cystathionine ␤-synthase (CBS) (Fig. 1). Aberrations in methylation and redox homeostasis are common to a number of chronic diseases including pathologies of the liver. In alcoholic liver disease and in hepatocellular carcinoma an increase in markers of oxidative stress is observed (1, 2). Furthermore, there is a switch in the expression of MAT genes from MAT1A to MAT2A in liver cancer, which correlates with lower S-adenosylmethionine (AdoMet) levels (3).Under normal conditions, coordinate regulation of methylation and antioxidant metabolism is achieved by the allosteric activation of CBS by AdoMet (Fig. 1). AdoMet is a V-type allosteric effector that increases CBS activity 2-to 3-fold (4, 5). Under conditions of plenty, methionine is directed toward cysteine synthesis via the transsulfuration pathway for use in glutathione and other cellular functions or directed toward catabolism. Cysteine is the limiting reagent in glutathione synthesis and in liver; Ϸ50% of the cysteine in glutathione is derived from methionine via the transsulf...

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Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation

Cited by 408 publications

References 46 publications

Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

S -adenosylmethionine stabilizes cystathionine β-synthase and modulates redox capacity

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