Sulfur amino acids in methionine-restricted rats: Hyperhomocysteinemia

Elshorbagy, Amany K.; Valdivia-Garcia, Maria; Refsum, Helga; Smith, A.D.; Mattocks, Dwight A.L.; Perrone, Carmen E.

doi:10.1016/j.nut.2009.09.017

Cited by 85 publications

(87 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MR lowers serum levels of methionine and methionine-derived amino acids including cysteine [7]. In agreement with reports showing a positive association between cysteine levels and body mass index (BMI) in humans [8], the supplementation of the MR diet with cysteine was shown to reverse the MR-mediated effects on adiposity and serum parameters associated with adiposity suggesting that lowered cysteine levels contribute to MR’s effects on body composition [9].…”

Section: Introductionsupporting

confidence: 79%

“…As expected, MR decreased levels of sulfur-containing amino acids in serum, liver and quadriceps muscle, and induced hyperhomocysteinemia [7], effects that were reversed by the supplementation of the MR diet with cysteine. Data on gene and protein expression patterns of hepatic methionine pathway enzymes together with liver metabolomic data from both MR and MRC rats were utilized to potentially identify the cause of hyperhomocysteinemia by MR.…”

Section: Discussionmentioning

confidence: 57%

See 1 more Smart Citation

Genomic and Metabolic Responses to Methionine-Restricted and Methionine-Restricted, Cysteine-Supplemented Diets in Fischer 344 Rat Inguinal Adipose Tissue, Liver and Quadriceps Muscle

et al. 2012

Self Cite

View full text Add to dashboard Cite

Background/Aims: Methionine restriction (MR) is a dietary intervention that increases lifespan, reduces adiposity and improves insulin sensitivity. These effects are reversed by supplementation of the MR diet with cysteine (MRC). Genomic and metabolomic studies were conducted to identify potential mechanisms by which MR induces favorable metabolic effects, and that are reversed by cysteine supplementation. Methods: Gene expression was examined by microarray analysis and TaqMan quantitative PCR. Levels of selected proteins were measured by Western blot and metabolic intermediates were analyzed by mass spectrometry. Results: MR increased lipid metabolism in inguinal adipose tissue and quadriceps muscle while it decreased lipid synthesis in liver. In inguinal adipose tissue, MR not only caused the transcriptional upregulation of genes associated with fatty acid synthesis but also of Lpin1, Pc, Pck1 and Pdk1, genes that are associated with glyceroneogenesis. MR also upregulated lipolysis-associated genes in inguinal fat and led to increased oxidation in this tissue, as suggested by higher levels of methionine sulfoxide and 13-HODE + 9-HODE compared to control-fed (CF) rats. Moreover, MR caused a trend toward the downregulation of inflammation-associated genes in inguinal adipose tissue. MRC reversed most gene and metabolite changes induced by MR in inguinal adipose tissue, but drove the expression of Elovl6, Lpin1, Pc, and Pdk1 below CF levels. In liver, MR decreased levels of a number of long-chain fatty acids, glycerol and glycerol-3-phosphate corresponding with the gene expression data. Although MR increased the expression of genes associated with carbohydrate metabolism, levels of glycolytic intermediates were below CF levels. MR, however, stimulated gluconeogenesis and ketogenesis in liver tissue. As previously reported, sulfur amino acids derived from methionine were decreased in liver by MR, but homocysteine levels were elevated. Increased liver homocysteine levels by MR were associated with decreased cystathionine β-synthase (CBS) protein levels and lowered vitamin B6 and 5-methyltetrahydrofolate (5MeTHF) content. Finally, MR upregulated fibroblast growth factor 21 (FGF21) gene and protein levels in both liver and adipose tissues. MRC reversed some of MR’s effects in liver and upregulated the transcription of genes associated with inflammation and carcinogenesis such as Cxcl16, Cdh17, Mmp12, Mybl1, and Cav1 among others. In quadriceps muscle, MR upregulated lipid metabolism-associated genes and increased 3-hydroxybutyrate levels suggesting increased fatty acid oxidation as well as stimulation of gluconeogenesis and glycogenolysis in this tissue. Conclusion: Increased lipid metabolism in inguinal adipose tissue and quadriceps muscle, decreased triglyceride synthesis in liver and the downregulation of inflammation-associated genes are among the factors that could favor the lean phenotype and increased insulin sensitivity observed in MR rats.

show abstract

Section: Introductionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 57%

Genomic and Metabolic Responses to Methionine-Restricted and Methionine-Restricted, Cysteine-Supplemented Diets in Fischer 344 Rat Inguinal Adipose Tissue, Liver and Quadriceps Muscle

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…A recent report studying sulfur amino acids in MR rats using a similar diet to the rat chow that was used in our studies revealed a near 150% increase in serum homocysteine level [43]. It was suspected that there occurred a possible MRinduced inhibition of homocysteine trans-sulfuration due to the MR diet.…”

Section: Mr Effects On Clinical Patients With Crohn's Diseasementioning

confidence: 55%

Methionine Restriction and Modification of Epithelial Tight Junction Barrier Function and Permeability

Wang¹

2012

JEBP

View full text Add to dashboard Cite

Abstract:It is well known that caloric restriction leads to an increased longevity by forestalling age-related diseases. Dietary restriction of methionine also renders similar benefits. In this review, we report studies on the effect of methionine restriction on epithelial barrier function in a renal epithelial LLC-PK 1 cell, a rodent gastrointestinal model and a clinical trial using Crohn's patients. In LLC-PK 1 cell culture, a reduction of culture medium methionine by 80% resulted in altered tight junctional claudin composition with improved epithelial barrier function as exemplified by increased transepithelial electrical resistance and decreased paracellular leak to 14 C-D-mannitol. In addition to small but significant reductions in plasma and intracellular colonocyte methionine levels, dietary methionine restriction tightens intestinal epithelium and reduces mannitol permeability in rat colonic, but not ileal tissue. Crohn's patients on methionine-restricted diet reported improved symptoms as demonstrated by a reduced CDAI index, but this diet was not able to significantly reduce the plasma methionine level in patients recruited. An increased urinary lactulose/mannitol ratio was also the result of the regimen in Crohn's patients, suggesting an increased, rather than decreased ileal leakage. Overall, our results showed that reduction in dietary intake of methionine is promising in improving at least some epithelial barriers and this may be through altering tight junctional protein compositions. Methionine restriction might result in contrasting effects depending on the tissue type and possible disease conditions, thus wider range of studies are required.

show abstract

“…Despite the low SAA intake of our vegetarian patients [27], plasma Met concentrations disclosed noticeable stability allowing to maintain the synthesis and functioning of myriads of Metdependent molecular, structural and metabolic compounds described in detail elsewhere [30,44]. These clinical investigations have received strong support from recent mouse [45] and rat [46] experiments submitted to Met-restricted regimens. At the end of the Met-deprivation period, both animal species did manifest meaningful HHcy states (p 0.001) contrasting with significantly lower BW (p 0.001) reduced by 33 % [45] and 44 % [46] of control, respectively.…”

Section: Impairment Of the Transsulfuration Pathwaymentioning

confidence: 77%

“…These clinical investigations have received strong support from recent mouse [45] and rat [46] experiments submitted to Met-restricted regimens. At the end of the Met-deprivation period, both animal species did manifest meaningful HHcy states (p 0.001) contrasting with significantly lower BW (p 0.001) reduced by 33 % [45] and 44 % [46] of control, respectively. In comparison with all other indispensable AAs, the uniqueness of Met behavior stands in accordance with balance studies performed on large mammalian species showing that the complete withdrawal of Met from otherwise normal diets causes the greatest rate of body loss, nearly equal to that generated by protein-free regimens [47,48].…”

Section: Impairment Of the Transsulfuration Pathwaymentioning

confidence: 96%

The Oxidative Stress of Hyperhomocysteinemia Results from Reduced Bioavailability of Sulfur-Containing Reductants

Ingenbleek¹

2011

TOCCHEMJ

View full text Add to dashboard Cite

Vegetarian subjects consuming subnormal amounts of methionine (Met) are characterized by subclinical protein malnutrition causing reduction in size of their lean body mass (LBM) best identified by the serial measurement of plasma transthyretin (TTR). As a result, the transsulfuration pathway is depressed at cystathionine--synthase (C S) level triggering the upstream sequestration of homocysteine (Hcy) in biological fluids and promoting its conversion to Met. Maintenance of beneficial Met homeostasis is counterpoised by the drop of cysteine (Cys) and glutathione (GSH) values downstream to C S causing in turn declining generation of hydrogen sulfide (H 2 S) from enzymatic sources. The biogenesis of H 2 S via non-enzymatic reduction is further inhibited in areas where earth's crust is depleted in elemental sulfur (S 8 ) and sulfate oxyanions. Combination of subclinical malnutrition and S 8 -deficiency thus maximizes the defective production of Cys, GSH and H 2 S reductants, explaining persistence of unabated oxidative burden. The clinical entity increases the risk of developing cardiovascular diseases (CVD) and stroke in underprivileged plant-eating populations regardless of Framingham criteria and vitamin-B status. Although unrecognized up to now, the nutritional disorder is one of the commonest worldwide, reaching top prevalence in populated regions of Southeastern Asia. Increased risk of hyperhomocysteinemia and oxidative stress may also affect individuals suffering from intestinal malabsorption or westernized communities having adopted vegan dietary lifestyles.

show abstract

Sulfur amino acids in methionine-restricted rats: Hyperhomocysteinemia

Cited by 85 publications

References 34 publications

Genomic and Metabolic Responses to Methionine-Restricted and Methionine-Restricted, Cysteine-Supplemented Diets in Fischer 344 Rat Inguinal Adipose Tissue, Liver and Quadriceps Muscle

Genomic and Metabolic Responses to Methionine-Restricted and Methionine-Restricted, Cysteine-Supplemented Diets in Fischer 344 Rat Inguinal Adipose Tissue, Liver and Quadriceps Muscle

Methionine Restriction and Modification of Epithelial Tight Junction Barrier Function and Permeability

The Oxidative Stress of Hyperhomocysteinemia Results from Reduced Bioavailability of Sulfur-Containing Reductants

Contact Info

Product

Resources

About