Hyperhomocysteinemia due to cystathionine beta synthase deficiency induces dysregulation of genes involved in hepatic lipid homeostasis in mice

Hamelet, Julien; Demuth, Karine; Paul, Jean–Louis; Delabar, Jean–Maurice; Janel, Nathalie

doi:10.1016/j.jhep.2006.07.028

Cited by 106 publications

(64 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We find that dCBS and TSP activity promote fat deposition in flies. This is reminiscent of the metabolic consequences of transsulfuration in mammals, in which hepatic CBS enzyme activity was significantly reduced when mice were fed a high-fat/high-sucrose diet (43) and CBS deficiency induced dysregulation of genes involved in hepatic lipid homeostasis (44,45).…”

Section: Discussionmentioning

confidence: 99%

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Kabil

Banerjee

et al. 2011

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

133

154

View full text Add to dashboard Cite

The mechanisms through which dietary restriction enhances health and longevity in diverse species are unclear. The transsulfuration pathway (TSP) is a highly conserved mechanism for metabolizing the sulfur-containing amino acids, methionine and cysteine. Here we show that Drosophila cystathionine β-synthase (dCBS), which catalyzes the rate-determining step in the TSP, is a positive regulator of lifespan in Drosophila and that the pathway is required for the effects of diet restriction on animal physiology and lifespan. dCBS activity was up-regulated in flies exposed to reduced nutrient conditions, and ubiquitous or neuron-specific transgenic overexpression of dCBS enhanced longevity in fully fed animals. Inhibition of the TSP abrogated the changes in lifespan, adiposity, and protein content that normally accompany diet restriction. RNAi-mediated knockdown of dCBS also limited lifespan extension by diet. Diet restriction reduced levels of protein translation in Drosophila, and we show that this is largely caused by increased metabolic commitment of methionine cycle intermediates to transsulfuration. However, dietary supplementation of methionine restored normal levels of protein synthesis to restricted animals without affecting lifespan, indicating that global reductions in translation alone are not required for diet-restriction longevity. Our results indicate a mechanism by which dietary restriction influences physiology and aging.hydrogen sulfide | essential amino acids | metabolism | healthspan F or a broad range of taxonomically diverse organisms, the quality of their diet acts as a powerful modulator of health and longevity through molecular mechanisms that are largely unknown. Lifespan is extended, for example, when food is restricted to an extent that falls short of inducing starvation. In mammals, this manipulation, which is often called dietary restriction (DR), not only increases lifespan but also imparts a broad-spectrum improvement in health during aging. In humans, for example, DR reduces risk factors for diabetes, cardiovascular disease, and cancer (1).Transsulfuration is an evolutionarily ancient metabolic process that involves a network of enzymes responsible for the metabolism of sulfur-containing amino acids. The transsulfuration pathway (TSP) has been studied extensively in mammals, in which it has been shown to direct the conversion of homocysteine to cysteine following the breakdown of methionine, an essential amino acid. Flux through the TSP is known to affect overall cellular metabolism by directly influencing cysteine and methionine levels. Methionine availability affects protein synthesis and methylation, and it has been implicated in murine aging (2). Cysteine availability controls the synthesis of glutathione (GSH), which is the chief regulator of cellular redox homeostasis and an important agent in xenobiotic detoxification (Fig. 1A). Patients with genetic defects in the TSP are characterized by high levels of homocysteine, low levels of GSH, and increased incidence of age-related path...

show abstract

Section: Discussionmentioning

confidence: 99%

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Kabil

Banerjee

et al. 2011

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

133

154

View full text Add to dashboard Cite

show abstract

“…In classical homocystinuria produced by mutations in the CBS gene, fatty liver disease is a common finding (6,8,34,35). However, fatty liver disease is also associated with nongene-induced hyperhomocysteinemia (36 -40).…”

Section: Discussionmentioning

confidence: 99%

The Nutrigenetics of Hyperhomocysteinemia

DiBello

Dayal

Kaveti

et al. 2010

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

Hyperhomocysteinemia has long been associated with atherosclerosis and thrombosis and is an independent risk factor for cardiovascular disease. Its causes include both genetic and environmental factors. Although homocysteine is produced in every cell as an intermediate of the methionine cycle, the liver contributes the major portion found in circulation, and fatty liver is a common finding in homocystinuric patients. To understand the spectrum of proteins and associated pathways affected by hyperhomocysteinemia, we analyzed the mouse liver proteome of gene-induced (cystathionine ␤-synthase (CBS)) and diet-induced (high methionine) hyperhomocysteinemic mice using two-dimensional difference gel electrophoresis and Ingenuity Pathway Analysis. Nine proteins were identified whose expression was significantly changed by 2-fold (p < 0.05) as a result of genotype, 27 proteins were changed as a result of diet, and 14 proteins were changed in response to genotype and diet. Importantly, three enzymes of the methionine cycle were upregulated. S-Adenosylhomocysteine hydrolase increased in response to genotype and/or diet, whereas glycine Nmethyltransferase and betaine-homocysteine methyltransferase only increased in response to diet. The antioxidant proteins peroxiredoxins 1 and 2 increased in wild-type mice fed the high methionine diet but not in the CBS mutants, suggesting a dysregulation in the antioxidant capacity of those animals. Furthermore, thioredoxin 1 decreased in both wild-type and CBS mutants on the diet but not in the mutants fed a control diet. Several urea cycle proteins increased in both diet groups; however, arginase 1 decreased in the CBS ؉/؊ mice fed the control diet. Pathway analysis identified the retinoid X receptor signaling pathway as the top ranked network associated with the CBS ؉/؊ genotype, whereas xenobiotic metabolism and the NRF2-mediated oxidative stress response were associated with the high methionine diet. Our results show that hyperhomocysteinemia, whether caused by a genetic mutation or diet, alters the abundance of several liver proteins involved in homocysteine/methionine metabolism, the urea cycle, and antioxidant defense. Molecular & Cellular Proteomics 9:471-485, 2010.

show abstract

“…High fat diet could be used to induce significant oxygen-centered free radicals and ROS generation in the mice. The liver plays a central role in the maintenance of systemic lipid homeostasis and it is especially susceptible to reactive oxygen species (ROSs) damage (Hamelet et al, 2007). Free radicals can diffuse intracellularly and result in mitochondrial enzyme damage and DNA breaks, impair cellular function (Bonnefont-Rousselot et al, 2000).…”

Section: Groupmentioning

confidence: 99%

Antioxidant Therapies for Hypolipidemia and Hyperglycemia

Gao¹

2012

Antioxidant Enzyme

View full text Add to dashboard Cite

Hyperhomocysteinemia due to cystathionine beta synthase deficiency induces dysregulation of genes involved in hepatic lipid homeostasis in mice

Cited by 106 publications

References 46 publications

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

The Nutrigenetics of Hyperhomocysteinemia

Antioxidant Therapies for Hypolipidemia and Hyperglycemia

Contact Info

Product

Resources

About