Research Article Details
| Article ID: | A25800 |
| PMID: | 21446920 |
| Source: | Clin Sci (Lond) |
| Title: | Methionine and protein metabolism in non-alcoholic steatohepatitis: evidence for lower rate of transmethylation of methionine. |
| Abstract: | Hepatic metabolism of methionine is the source of cysteine, the precursor of glutathione, the major intracellular antioxidant in the body. Methionine also is the immediate precursor of SAM (S-adenosylmethionine) the key methyl donor for phosphatidylcholine synthesis required for the export of VLDL (very-low-density lipoprotein) triacylglycerols (triglycerides) from the liver. We have examined the kinetics of methionine, its transmethylation and trans-sulfuration with estimates of whole body rate of protein turnover and urea synthesis in clinically stable biopsy-confirmed subjects with NASH (non-alcoholic steatohepatitis). Subjects with NASH were more insulin-resistant and had significantly higher plasma concentrations of usCRP (ultrasensitive C-reactive protein), TNFα (tumour necrosis factor α) and other inflammatory cytokines. There was no significant effect of insulin resistance and NASH on whole body rate of protein turnover [phenylalanine Ra (rate of appearance)] and on the rate of urea synthesis. The rates of methylation of homocysteine and transmethylation of methionine were significantly lower in NASH compared with controls. There was no difference in the rate of trans-sulfuration of methionine between the two groups. Enteric mixed nutrient load resulted in a significant increase in all the measured parameters of methionine kinetics. Heterozygosity for MTHFR (5,10-methylene-tetrahydrofolate reductase) (677C→T) did not have an impact on methionine metabolism. We speculate that, as a result of oxidant stress possibly due to high fatty acid oxidation, the activity of methionine adenosyltransferase is attenuated resulting in a lower rate of transmethylation of methionine and of SAM synthesis. These results are the first evidence for perturbed metabolism of methionine in NASH in humans and provide a rationale for the development of targeted intervention strategies. |
| DOI: | 10.1042/CS20110060 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D545 | Pig placenta extract | Biological extract | -- | -- | -- | Under clinical trials | Details |
| D199 | L-alanine | Chemical drug | DB00160 | KYNU | -- | Failed in clinical trials | Details |
| D075 | Choline | Supplement | DB00122 | PLD2 product of; PLD1 product of | -- | Under clinical trials | Details |
| D140 | Folic acid | Supplement | DB00158 | FOLR2 binder | -- | Under clinical trials | Details |
| D273 | Phosphatidylcholine | Chemical drug | DB15834 | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D094 | Cysteamine | Chemical drug | DB00847 | GSS stimulant | Renal drug | Under clinical trials | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | Under clinical trials | Details |
| D158 | Glutathione | Chemical drug | DB00143 | MGST3; HPGDS; GSTM2; GSTM5; GPX7 cofactor; MGST2; GSS; GSTM1; GSTK1; GSTM3; GSTM4; GPX1 cofactor; GPX2 cofactor; GPX3 cofactor | -- | Under clinical trials | Details |
| D095 | Cysteamine bitartrate | Chemical drug | DB00847 | -- | -- | Under clinical trials | Details |