Jean-Pierre Bronowicki

Vascular and cellular stress in inflammatory bowel disease: revisiting the role of homocysteine.

Moderate hyperhomocysteinemia is a complex trait commonly associated with inflammatory bowel disease (IBD). Nutritional deficiencies and genetic determinants have been identified as risk factors for moderate hyperhomocysteinemia, such as folate and vitamin B12 deprivation and polymorphisms in the 5,10 methylenetetrahydrofolate reductase (MTHFR) encoding gene, respectively. Homocysteine has a crucial role in cellular stress, epigenetic events, inflammatory processes, and host-microbial interactions. Hyperhomocysteinemia might therefore influence the clinical history of IBD, including disease severity, susceptibility to particular enteric infections, and the risk for the development of colorectal cancer. In contrast, homocysteine metabolism does not seem to contribute to the greater risk of thrombosis in IBD subjects. Herein, we review the evidence linking homocysteine metabolism to the pathophysiology of IBD. Furthermore, we discuss the relevance of screening and treating folate and vitamin B12 deficiencies in IBD subjects. Given the peculiar frequency of such deficiencies in IBD, normalizing vitamin levels should be an integral part of the management of these patients, especially those with active disease, history of intestinal resection, and/or treated with methotrexate.

Methionine synthase A2756G polymorphism may predict ulcerative colitis and methylenetetrahydrofolate reductase C677T pancolitis, in Central China

BackgroundThe association of genetic polymorphisms related to metabolism of homocysteine with inflammatory bowel disease has been evidenced in Crohn disease and remains an open question in ulcerative colitis. We evaluated the association of the polymorphisms of MTHFR, MTR, MTRR and TCN2 genes with ulcerative colitis in Central China.Methods168 patients were genotyped for these polymorphisms and compared to 219 matched controls.ResultsMethionine synthase 2756G allele frequency was higher in ulcerative colitis than in controls 0.15 (95% C.I. 0.11–0.19) vs 0.09 (95% C.I. 0.07 – 0.12), (P = 0.0137) and predicted ulcerative colitis risk in logistic regression, with an Odds ratio at 1.8 (95% C.I. 1.15–2.84). Methylenetetrahydrofolate reductase 677TT genotype was 2.7-fold more prevalent in individuals with pancolitis than in those with left colitis or proctitis, with respective percentages of 27.3 (95% C.I.16.4–42.0) and 10.5 (95% C.I. 6.3–17.1) (P = 0.0123). The carriage of 677TT or 677CT/1298AC genotypes of methylenetetrahydrofolate reductase was more frequent in cases with pancolitis than in subjects with left colitis or proctitis (P = 0.0048), with an Odds ratio adjusted by age and sex at 3.3 (95% C.I. 1.4–7.9), P = 0.0084) in logistic regression.ConclusionMethionine synthase and methylenetetrahydrofolate reductase are genes of vitamin B12 and folate cellular metabolism associated respectively with risk and extent of ulcerative colitis, at least in Central China. This finding may open new insights, particularly for the potential interest in treating patients carrying the 677TT MTHFR genetic trait and a deficit in folate.

A splicing variant leads to complete loss of function of betaine-homocysteine methyltransferase (BHMT) gene in hepatocellular carcinoma.

The remethylation of homocyteine into methionine is catalyzed either by methionine synthase (MTR) or by betaine-homocysteine methyltransferase (BHMT), in the liver. Choline/betaine deficiency and impaired BHMT pathway have been associated with hepatocellular carcinogenesis, in animal models. The molecular mechanisms that impair the BHMT pathway are unknown. We aimed to investigate BHMT, BHMT2, and MTR expression in HepG2 cells and human hepatocarcinoma tissues. Transcripts were quantified by RT-qPCR and splicing was assessed by analysis of exon junctions and sequencing of variants. Protein expression was studied by Western Blot, immunohistochemistry and enzyme activity. Tumor tissue was compared with surrounding healthy tissue. RT-qPCR of HepG2 cells and of tumor samples showed a strong decrease of transcripts of BHMT and BHMT2, compared to normal. MTR transcript levels were not different. The decreased BHMT expression resulted from the transcription of a splicing variant that produced a frameshift in exon 4, with a premature termination codon in exon 5 and a loss of function of the gene. This splicing variant did not fit with any mechanism resulting from known splicing consensus sequences and was not detected in normal adult and fetal liver. Consistently, BHMT activity was abolished in HepG2 and protein expression was not detectable in HepG2 and in 5 of the 6 tumor samples, compared to normal tissues. In conclusion, a transcription variant of exon 4 produces a loss of function of BHMT in human hepatocarcinoma. Whether this abnormal transcription of BHMT is part or consequence of liver carcinogenesis should deserve further investigations.