Betaine alleviates nonalcoholic fatty liver disease (NAFLD) via a manner involving BHMT/FTO/m6A/ PGC1α signaling.

Nonalcoholic fatty liver disease (NAFLD) has emerged as a major public health crisis with significant health threats and economic burdens worldwide in the past decades. Betaine, a naturally occurring alkaloid compound present in various dietary sources including spinach and beets, has been shown to ameliorate hepatic lipid metabolism and attenuate (NAFLD), while the underlying mechanism remains elusive. Here, we propose a novel mechanism through which betaine exerts its protective effects against hepatic lipid accumulation and (NAFLD) from an epigenetics perspective. Specifically, we discover that betaine upregulates betaine homocysteine S-methyltransferase (BHMT) expression, leading to increased nicotinamide adenine dinucleotide phosphate (NADPH) production and subsequent upregulation of fat mass and obesity-associated protein (FTO) expression. Increased abundance of FTO targets peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) mRNA and reduces the N6-methyladenosine (m6A) level in the CDS of Ppargc1α transcript, which positively regulates PGC1α expression and subsequently inhibits hepatic lipid accumulation. Overall, our works demonstrate that betaine may be a promising therapeutic strategy for treating (NAFLD) and improving liver function through the regulation of (NADPH) and m6A-mediated pathways.

Regulation of Betaine Homocysteine Methyltransferase by Liver Receptor Homolog-1 in the Methionine Cycle.

Betaine-homocysteine S-methyltransferase (BHMT) is one of the most abundant proteins in the liver and regulates homocysteine metabolism. However, the molecular mechanisms underlying Bhmt transcription have not yet been elucidated. This study aimed to assess the molecular mechanisms underlying Bhmt transcription and the effect of BHMT deficiency on metabolic functions in the liver mediated by liver receptor homolog-1 (LRH-1). During fasting, both Bhmt and Lrh-1 expression increased in the liver of Lrh-1f/f mice; however, Bhmt expression was decreased in LRH-1 liver specific knockout mice. Promoter activity analysis confirmed that LRH-1 binds to a specific site in the Bhmt promoter region. LRH-1 deficiency was associated with elevated production of reactive oxygen species (ROS), lipid peroxidation, and mitochondrial stress in hepatocytes, contributing to hepatic triglyceride (TG) accumulation. In conclusion, this study suggests that the absence of an LRH-1-mediated decrease in Bhmt expression promotes TG accumulation by increasing ROS levels and inducing mitochondrial stress. Therefore, LRH-1 deficiency not only leads to excess ROS production and mitochondrial stress in hepatocytes, but also disrupts the methionine cycle. Understanding these regulatory pathways may pave the way for novel therapeutic interventions against metabolic disorders associated with hepatic lipid accumulation.

Deficiency of betaine-homocysteine methyltransferase activates glucose-6-phosphate dehydrogenase (G6PD) by decreasing arginine methylation of G6PD in hepatocellular carcinogenesis.

Betaine-homocysteine methyltransferase (BHMT) regulates protein methylation and is correlated with tumorigenesis; however, the effects and regulation of BHMT in hepatocarcinogenesis remain largely unexplored. Here, we determined the clinical significance of BHMT in the occurrence and progression of hepatocellular carcinoma (HCC) using tissue samples from 198 patients. BHMT was to be frequently found (86.6%) expressed at relatively low levels in HCC tissues and was positively correlated with the overall survival of patients with HCC. Bhmt overexpression effectively suppressed several malignant phenotypes in hepatoma cells in vitro and in vivo, whereas complete knockout of Bhmt (Bhmt-/-) produced the opposite effect. We combined proteomics, metabolomics, and molecular biological strategies and detected that Bhmt-/- promoted hepatocarcinogenesis and tumor progression by enhancing the activity of glucose-6-phosphate dehydrogenase (G6PD) and PPP metabolism in DEN-induced HCC mouse and subcutaneous tumor-bearing models. In contrast, restoration of Bhmt with an AAV8-Bhmt injection or pharmacological inhibition of G6PD attenuated hepatocarcinogenesis. Additionally, coimmunoprecipitation identified monomethylated modifications of the G6PD, and BHMT regulated the methylation of G6PD. Protein sequence analysis, generation and application of specific antibodies, and site-directed mutagenesis indicated G6PD methylation at the arginine residue 246. Furthermore, we established bidirectionally regulated BHMT cellular models combined with methylation-deficient G6PD mutants to demonstrate that BHMT potentiated arginine methylation of G6PD, thereby inhibiting G6PD activity, which in turn suppressed hepatocarcinogenesis. Taken together, this study reveals a new methylation-regulatory mechanism in hepatocarcinogenesis owing to BHMT deficiency, suggesting a potential therapeutic strategy for HCC treatment.

Homocysteine-induced endoplasmic reticulum stress activates FGF21 and is associated with browning and atrophy of white adipose tissue in Bhmt knockout mice.

Betaine-homocysteine methyltransferase (BHMT) catalyzes the transfer of methyl groups from betaine to homocysteine (Hcy), producing methionine and dimethylglycine. In this work, we characterize Bhmt wild type (Bhmt-WT) and knockout (Bhmt-KO) mice that were fully backcrossed to a C57Bl6/J background. Consistent with our previous findings, Bhmt-KO mice had decreased body weight, fat mass, and adipose tissue weight compared to WT. Histological analyses and gene expression profiling indicate that adipose browning was activated in KO mice and contributed to the adipose atrophy observed. BHMT is not expressed in adipose tissue but is abundant in liver; thus, a signal must originate from the liver that modulates adipose tissue. We found that, in Bhmt-KO mice, homocysteine-induced endoplasmic reticulum (ER) stress is associated with activation of the hepatic transcription factor cyclic AMP response element binding protein (CREBH), and an increase in hepatic and plasma concentrations of fibroblast growth factor 21 (FGF21), which is known to induce adipose browning. Our data indicate that the deletion of a single gene in one-carbon metabolism modifies adipose biology and energy metabolism. Future studies could focus on identifying if functional polymorphisms in BHMT result in a similar adipose atrophy phenotype.

Betaine consumption as a new clinical approach to treatment and prophylaxis of folate-related pathologies.

The most important pathway in the development of folate-related pathologies is an increase in the level of homocysteine (HC). HC, a cytotoxic and neurotoxic amino acid (when its level is ≥12 µmol/L), is 1 of the most widely studied compounds in cardiology, neurobiology, oncology, and embryology for the last 20 years. Given its toxicity, the processes of endogenous detoxification of HC are of particular interest to medicine. To date, the most studied pathway is that of remethylation (the conversion of HC to methionine), with the participation of B12- and B9-dependent methionine synthase. Less studied is remethylation with the participation of the choline derivatives betaine and betaine-HC-S-methyltransferase (BHMT). Therefore, the aim of this review was to conduct a theoretical analysis of available information regarding the contribution of betaine metabolism, its enzyme, and its genetic polymorphism to folate metabolism disturbances, and the development of folate-related pathologies. This review emphasizes the potential clinical significance of 2 factors that can influence the remethylation reaction of HC: the use of betaine and identifying the BHMT gene variants and their impact on the risk for developing certain folate-related pathologies, and treatment options. Moreover, with a high level of methylation of the BHMT gene and in the presence of its low-function variants (eg, rs3733890), it is necessary to use betaine as an additional methyl donor, especially during folate therapy. More clinical research is needed to identify the effects of the different BHMT gene variants on the individual risk for folate-related pathologies to better assess the clinical significance, the need for genetic testing, and betaine consumption.

Association of Maternal Betaine-Homocysteine Methyltransferase (BHMT) and BHMT2 Genes Polymorphisms with Congenital Heart Disease in Offspring.

To systematically explore the association of single nucleotide polymorphisms (SNPs) of maternal BHMT and BHMT2 genes with the risk of congenital heart disease (CHD) and its three subtypes including atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus (PDA) in offspring. A hospital-based case-control study involving 683 mothers of CHD children and 740 controls was performed. Necessary exposure information was captured through epidemiological investigation. Totally twelve SNPs of maternal BHMT and BHMT2 genes were detected and analyzed systematically. The study showed that maternal BHMT gene polymorphisms at rs1316753 (CG vs. CC: OR = 1.96 [95% CI 1.41-2.71]; GG vs. CC: OR = 1.99 [95% CI 1.32-3.00]; dominant model: OR = 1.97 [95% CI 1.44-2.68]) and rs1915706 (TC vs. TT: OR = 1.93 [95% CI 1.44-2.59]; CC vs. TT: OR = 2.55 [95% CI 1.38-4.72]; additive model: OR = 1.77 [95% CI 1.40-2.24]) were significantly associated with increased risk of total CHD in offspring. And two haplotypes were observed to be significantly associated with risk of total CHD, including C-C haplotype involving rs1915706 and rs3829809 in BHMT gene (OR = 1.30 [95% CI 1.07-1.58]) and C-A-A-C haplotype involving rs642431, rs592052, rs626105, and rs682985 in BHMT2 gene (OR = 0.71 [95% CI 0.58-0.88]). Besides, a three-locus model involving rs1316753 (BHMT), rs1915706 (BHMT), and rs642431 (BHMT2) was identified through gene-gene interaction analyses (P < 0.01). As for three subtypes including ASD, VSD, and PDA, significant SNPs and haplotypes were also identified. The results indicated that maternal BHMT gene polymorphisms at rs1316753 and rs1915706 are significantly associated with increased risk of total CHD and its three subtypes in offspring. Besides, significant interactions between different SNPs do exist on risk of CHD. Nevertheless, studies with larger sample size in different ethnic populations and involving more SNPs in more genes are expected to further define the genetic contribution underlying CHD and its subtypes.

Pathogenesis of Alcohol-Associated Liver Disease.

Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease.

Profiling the Influence of Gene Variants Related to Folate-Mediated One-Carbon Metabolism on the Outcome of In Vitro Fertilization (IVF) with Donor Oocytes in Recipients Receiving Folic Acid Fortification.

Nutritional status and gene polymorphisms of one-carbon metabolism confer a well-known interaction that in pregnant women may affect embryo viability and the health of the newborn. Folate metabolism directly impacts nucleotide synthesis and methylation, which is of increasing interest in the reproductive medicine field. Studies assessing the genetic influence of folate metabolism on IVF treatments have currently been performed in women using their own oocytes. Most of these patients seeking to have a child or undergoing IVF treatments are advised to preventively intake folate supplies that restore known metabolic imbalances, but the treatments could lead to the promotion of specific enzymes in specific women, depending on their genetic variance. In the present study, we assess the influence of candidate gene variants related to folate metabolism, such as Serine Hydroxymethyltransferase 1 SHMT1 (rs1979276 and rs1979277), Betaine-Homocysteine S-Methyltransferase BHMT (rs3733890), Methionine synthase reductase MTRR (rs1801394), Methylenetetrahydrofolate reductase MTHFR (rs1801131 and rs1801133), methionine synthase MTR (rs12749581), ATP Binding Cassette Subfamily B Member 1 ABCB1 (rs1045642) and folate receptor alpha FOLR1 (rs2071010) on the success of IVF treatment performed in women being recipients of donated oocytes. The implication of such gene variants seems to have no direct impact on pregnancy consecution after IVF; however, several gene variants could influence pregnancy loss events or pregnancy maintenance, as consequence of folic acid fortification.

Identification and Evolution Analysis of the Complete Methyl Farnesoate Biosynthesis and Related Pathway Genes in the Mud Crab, Scylla paramamosain.

The sesquiterpenoid hormone methyl farnesoate (MF) plays a vital role during crustacean development, which is mainly evidenced by its varied titers during different developmental stages. However, the biosynthesis pathways of MF remain obscure to some extent. In this study, we identified the complete MF biosynthesis and related pathway genes in Scylla paramamosain, including three involved in acetyl-CoA metabolism, eight in the mevalonate pathway, five in the sesquiterpenoids synthesis pathway, and five in the methionine cycle pathway. Bioinformatics, genomic structure, and phylogenetic analysis indicated that the JH biosynthesis genes might have experienced evolution after species differentiation. The mRNA tissue distribution analysis revealed that almost all genes involving in or relating to MF syntheses were highly expressed in the mandibular organ (MO), among which juvenile hormone acid methyltransferase was exclusively expressed in the MO, suggesting that most of these genes might mainly function in MF biosynthesis and that the methionine cycle pathway genes might play a crucial regulatory role during MF synthesis. In addition, the phylogenetic and tissue distribution analysis of the cytochrome P450 CYP15-like gene suggested that the epoxidized JHs might exist in crustaceans, but are mainly synthesized in hepatopancreas rather than the MO. Finally, we also found that betaine-homocysteine S-methyltransferase genes were lost in insects while methionine synthase was probably lost in most insects except Folsomia candida, indicating a regulatory discrepancy in the methionine cycle between crustaceans and insects. This study might increase our understanding of synthetic metabolism tailored for sesquiterpenoid hormones in S. paramamosain and other closely related species.

Association and Interaction Effect of BHMT Gene Polymorphisms and Maternal Dietary Habits with Ventricular Septal Defect in Offspring.

This study attempted to learn the association between maternal betaine-homocysteine methyltransferase (BHMT) gene polymorphisms, maternal dietary habits, and their interactions with the risk of ventricular septal defects (VSD) in offspring. A total of 426 mothers of VSD children and 740 control mothers were included in the study. Logistic regression was used to evaluate the level of associations and interaction effects. Our study suggested that mothers reporting excessive intake of smoked foods (aOR = 2.44, 95%CI: 1.89-3.13), barbecued foods (aOR = 1.86, 95%CI: 1.39-2.48), fried foods (aOR = 1.93, 95%CI: 1.51-2.46), and pickled vegetables (aOR = 2.50, 95%CI: 1.92-3.25) were at a significantly higher risk of VSD in offspring, instead, mothers reporting regular intake of fresh fruits (aOR = 0.47, 95%CI: 0.36-0.62), fish and shrimp (aOR = 0.35, 95%CI: 0.28-0.44), fresh eggs, (aOR = 0.56, 95%CI: 0.45-0.71), beans (aOR = 0.68, 95%CI: 0.56-0.83), and milk products (aOR = 0.67, 95%CI: 0.56-0.80) were at a lower risk of VSD in offspring. In addition, maternal BHMT gene polymorphisms at rs1316753 (CG vs. CC: aOR = 2.01, 95%CI: 1.43-2.83) and rs1915706 (CT vs. TT: (aOR = 1.81, 95%CI: 1.33-2.46) were significantly associated with increased risk of VSD in offspring. Furthermore, a significant interaction between BHMT polymorphisms and maternal bean intake was identified in the study. In conclusion, Maternal BHMT polymorphisms at rs1316753 and rs1915706, dietary habits as well as their interaction were observed to be significantly associated with the risk of VSD in offspring.

How Different Dietary Methionine Sources Could Modulate the Hepatic Metabolism in Rainbow Trout?

In aquafeeds in which plant proteins are used to replace fishmeal, exogenous methionine (Met) sources are demanded to balance the amino acid composition of diets and meet the metabolic fish requirements. Nonetheless, since different synthetic Met sources are commercially available, it is important to determine their bioavailability and efficacy. To address this issue, we conducted a two-month feeding trial with rainbow trout (Oncorhynchus mykiss), which were fed diets supplemented with five different forms of Met: Met-Met, L-Met, HMTBa, DL-Met, and Co DL-Met. No differences in growth performance were found in trout fed with different Met forms, but changes in the whole-body composition were found. In particular, Met-Met and L-Met promoted a significant body lipid reduction, whereas the protein retention was significantly increased in fish fed with HMTBa and Co DL-Met. The latter affected the hepatic Met metabolism promoting the trans-sulfuration pathway through the upregulation of CBS gene expression. Similarly, the L-Met enhanced the remethylation pathway through an increase in BHMT gene expression to maintain the cellular demand for Met. Altogether, our findings suggest an optimal dietary intake of all tested Met sources with similar promoting effects on fish growth and hepatic Met metabolism. Nevertheless, the mechanisms underlying these effects warrant further investigation.

Repair mechanism of Wuwei Fuzheng Yijing formula in di-2-ethylhexyl phthalate-induced sperm DNA fragmentation in mice.

CONTEXT: Di-2-ethylhexyl phthalate (DEHP), a known persistent organic pollutant, can increase the sperm DNA fragmentation index (DFI). OBJECTIVE: To investigate the mechanism underlying the repair of DEHP-induced sperm DNA damage in mice by Wuwei Fuzheng Yijing (WFY) formula. MATERIALS AND METHODS: The potential targets of WFY and sperm DNA fragment (SDF) were obtained from the TCMSP, BATMAN-TCM, OMIM and GeneCards. The protein-protein interaction (PPI) network, GO and KEGG pathway analyses of WFY-SDF were constructed. An animal model of DEHP-induced sperm DNA damage was replicated by gavage of SPF ICR (CD1) mice DEHP at 1 g/kg/d and treated with WFY at 8.92, 17.84 and 35.67 g/kg, respectively, for 60 d. Sperm DFI of each group was detected and compared. The target genes of WFY identified by transcriptomic and proteomic analyses were validated by qRT-PCR and Western blotting. RESULTS: Network pharmacology pathway analysis indicated that PI3K/Akt was the potential target of WFY on SDF. The DFI of the DEHP group (25.48%) was significantly higher than that of the control group (4.02%). The high-dose WFY group (19.05%) exhibited the most significant repairing effect. The related pathways were PI3K/Akt and metabolic. Aass, Aldh1a7, GSTA3, betaine homocysteine S-methyltransferase (Bhmt), Mug2 and Svs1 were screened and Bhmt was validated. DISCUSSION AND CONCLUSIONS: WFY can repair sperm DNA damage caused by DEHP, and the mechanism may be related to PI3K/Akt and metabolic pathways, and Bhmt. This provides a new direction for using traditional Chinese medicine to prevent and repair reproductive system injury caused by pollutants.

Concurrent medial and lateral bucket handle meniscal tear repair in a chronic anterior cruciate ligament-deficient knee: a case report.

Bucket handle meniscus tears (BHMTs) are seen in the active population, especially young athletes. They often occur with anterior cruciate ligament (ACL) injury, causing significant knee symptoms and affecting the patients' quality of life. All-inside meniscus repair can be effective in the treatment for BHMT to improve symptoms and to preserve the native meniscus. We report a case of a 25-year-old female retired soccer player who presented with a three-year history of right knee pain, swelling and instability. She was diagnosed with BHMT of medial and lateral menisci and complete tear of the ACL on magnetic resonance imaging (MRI). She underwent arthroscopic medial and lateral meniscus repair with concomitant ACL reconstruction. Both the medial and lateral BHMT were reduced and repaired using an all-inside meniscus repair. We present her examination findings, functional outcomes and radiological imaging pre-operatively and 6 years post-operatively, which show an intact and stable ACL graft and repaired medial and lateral menisci with minimal progression to knee osteoarthritis. This shows that with good reduction and fixation, all-inside meniscus repair can achieve good mid-term results for the repair of bicompartmental chronic bucket handle tears.

Combined Analysis of Expression Profiles in a Mouse Model and Patients Identified BHMT2 as a New Regulator of Lipid Metabolism in Metabolic-Associated Fatty Liver Disease.

Metabolic associated fatty liver disease (MAFLD) is associated with obesity, type 2 diabetes mellitus, and other metabolic syndromes. Farnesoid X receptor (FXR, NR1H4) plays a prominent role in hepatic lipid metabolism. This study combined the expression of liver genes in FXR knockout (KO) mice and MAFLD patients to identify new pathogenic pathways for MAFLD based on genome-wide transcriptional profiling. In addition, the roles of new target genes in the MAFLD pathogenic pathway were also explored. Two groups of differentially expressed genes were obtained from FXR-KO mice and MAFLD patients by transcriptional analysis of liver tissue samples. The similarities and differences between the two groups of differentially expressed genes were analyzed to identify novel pathogenic pathways and target genes. After the integration analysis of differentially expressed genes, we identified 134 overlapping genes, many of which have been reported to play an important role in lipid metabolism. Our unique analysis method of comparing differential gene expression between FXR-KO mice and patients with MAFLD is useful to identify target genes and pathways that may be strongly implicated in the pathogenesis of MAFLD. The overlapping genes with high specificity were screened using the Gene Expression Omnibus (GEO) database. Through comparison and analysis with the GEO database, we determined that BHMT2 and PKLR could be highly correlated with MAFLD. Clinical data analysis and RNA interference testing in vitro confirmed that BHMT2 may a new regulator of lipid metabolism in MAFLD pathogenesis. These results may provide new ideas for understanding the pathogenesis of MAFLD and thus provide new targets for the treatment of MAFLD.

Effects of Partially Defatted Hermetia illucens Meal in Rainbow Trout Diet on Hepatic Methionine Metabolism.

This study investigated, for the first time, the effects of replacement of fishmeal (FM) with insect meal from Hermetia illucens (HI) on the transcript levels of three genes involved in methionine (Met) metabolism in rainbow trout (Oncorhynchus mykiss) liver. Two target genes-betaine-homocysteine S-methyltransferase (BHMT) and S-adenosylhomocysteine hydrolase (SAHH)-are involved in Met resynthesis and the third one-cystathionine ß synthase (CBS)-is involved in net Met loss (taurine synthesis). We also investigated the levels of two Met metabolites involved in the maintenance of methyl groups and homocysteine homeostasis in the hepatic tissue: S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). Three diets were formulated, an FM-based diet (HI0) and two diets in which 25% (HI25) and 50% (HI50) of FM was replaced with HI larvae meal. A 78-day feeding trial involved 360 rainbow trout with 178.9 ± 9.81 g initial average weight. Dietary replacement of up to 50% of FM with HI larvae meal, without any Met supplementation, did not negatively affect rainbow trout growth parameters and hepatic Met metabolism. In particular, Met availability from the insect-based diets directly modulated the transcript levels of two out of three target genes (CBS, SAHH) to maintain an optimal level of one-carbon metabolic substrates, i.e., the SAM:SAH ratio in the hepatic tissue.

Methylation map genes can be critical in determining the methylome of intracranial aneurysm patients.

Aim: Intracranial aneurysm is often asymptomatic until the time of rupture. Elevated homocysteine is reported in vascular diseases. Identifying early events in homocysteine metabolism through methylation map genes may prevent fatality. Materials & methods: In the present study, we investigated the role of variants in methylation map genes in ethnically matched 480 individuals that can influence the homocysteine levels and promote development of aneurysm. Results: The study demonstrates that the genetic variants in folate cycle and methionine cycle genes such as MTHFR, MTRR, MTR, BHMT and DNMT1 are associated with the risk of aneurysm. Conclusion: The associated allelic variants in these genes have functional relevance and are predictive of decreased expression indicative of altered methylation levels that may result in elevated homocysteine.

Mtrr hypomorphic mutation alters liver morphology, metabolism and fuel storage in mice.

Nonalcoholic fatty liver disease (NAFLD) is associated with dietary folate deficiency and mutations in genes required for one­carbon metabolism. However, the mechanism through which this occurs is unclear. To improve our understanding of this link, we investigated liver morphology, metabolism and fuel storage in adult mice with a hypomorphic mutation in the gene methionine synthase reductase (Mtrr gt ). MTRR enzyme is a key regulator of the methionine and folate cycles. The Mtrr gt mutation in mice was previously shown to disrupt one­carbon metabolism and cause a wide-spectrum of developmental phenotypes and late adult-onset macrocytic anaemia. Here, we showed that livers of Mtrr gt/gt female mice were enlarged compared to control C57Bl/6J livers. Histological analysis of these livers revealed eosinophilic hepatocytes with decreased glycogen content, which was associated with down-regulation of genes involved in glycogen synthesis (e.g., Ugp2 and Gsk3a genes). While female Mtrr gt/gt livers showed evidence of reduced ß-oxidation of fatty acids, there were no other associated changes in the lipidome in female or male Mtrr gt/gt livers compared with controls. Defects in glycogen storage and lipid metabolism often associate with disruption of mitochondrial electron transfer system activity. However, defects in mitochondrial function were not detected in Mtrr gt/gt livers as determined by high-resolution respirometry analysis. Overall, we demonstrated that adult Mtrr gt/gt female mice showed abnormal liver morphology that differed from the NAFLD phenotype and that was accompanied by subtle changes in their hepatic metabolism and fuel storage.

Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis.

Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programmes. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate gene expression that supports neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability.

Association of Betaine-Homocysteine S-Methyl Transferase (rs3797546 and rs3733890) polymorphisms with non-syndromic cleft lip/palate: A meta-analysis.

OBJECTIVE: Non-syndromic cleft lip/palate (NSCL/P) has a multifactorial and polygenic aetiology. The role of genetics in its occurrence has not been fully clarified. The present meta-analysis aimed to evaluate the association of betaine-homocysteine S-methyltransferase (BHMT) polymorphisms (rs3797546 and rs3733890) with the risk of NSCL/P. MATERIALS AND METHODS: PubMed/Medline, Scopus, Cochrane Library, and Web of Science databases were systematically searched for articles published up until December 2018 with no language restriction. Quality evaluation of each study was performed by the Newcastle-Ottawa Scale (NOS). The crude odds ratio (OR) and 95% confidence interval (CI) were calculated for each study by RevMan 5.3 software, and a funnel plot analysis was performed by the CMA 2.0 software using the Egger's and Begg's tests. RESULTS: Review of the four selected studies revealed that the CC genotype of rs3797546 polymorphism significantly increased the risk of NSCL/P. No association was noted between NSCL/P risk and rs3733890 polymorphism except in Chinese (elevated risk of NSCL/P) and Polish (decreased risk of NSCL/P) populations. CONCLUSIONS: According to the present meta-analysis, rs3733890 polymorphism does not play a role in susceptibility to NSCL/P; whereas, rs3797546 polymorphism may play a role in susceptibility to NSCL/P. Future studies are required to examine the association between BHMT polymorphisms and the NSCL/P risk in different ethnicities with a larger sample size.

Long non-coding RNA Bhmt-AS attenuates hepatic gluconeogenesis via modulation of Bhmt expression.

Dysregulation of gluconeogenesis contributes to the pathogenesis of metabolic disease, such as type-2 diabetes. The role of long non-coding RNAs (lncRNAs) in the pathogenesis of diabetes has recently received increased attention. In the present study, we identified a novel lncRNA, betaine-homocysteine methyltransferase-antisense (Bhmt-AS), and examined its expression patterns under pathophysiological conditions. Our results revealed that the expression of Bhmt-AS was significantly increased in the livers of fasted and db/db mice and was induced by gluconeogenic hormonal stimuli. The Bhmt-AS was also shown to be a concordant regulator of Bhmt expression. Functionally, depletion of Bhmt-AS suppressed hepatic glucose production both in vivo and in vitro. Adenovirus-mediated hepatic knockdown of Bhmt-AS improved pyruvate tolerance, glucose tolerance, and insulin sensitivity. Furthermore, overexpression of Bhmt restored the decreased glucose production caused by knockdown of Bhmt-AS in primary hepatocytes. Taken together, we uncovered a novel antisense lncRNA (Bhmt-AS) that is co-expressed with Bhmt and concordantly and specifically regulates Bhmt expression both in vitro and in vivo to regulate hepatic gluconeogenesis.