Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine-homocysteine S-methyltransferase

Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Biochemical Journal (Impact Factor: 4.4). 05/2006; 395(2):363-71. DOI: 10.1042/BJ20051966
Source: PubMed


We have previously reported a positive correlation between the expression of BHMT (betaine-homocysteine S-methyltransferase) and ApoB (apolipoprotein B) in rat hepatoma McA (McArdle RH-7777) cells [Sowden, Collins, Smith, Garrow, Sparks and Sparks (1999) Biochem. J. 341, 639-645]. To examine whether a similar relationship occurs in vivo, hepatic BHMT expression was induced by feeding rats a Met (L-methionine)-restricted betaine-containing diet, and parameters of ApoB metabolism were evaluated. There were no generalized metabolic abnormalities associated with Met restriction for 7 days, as evidenced by control levels of serum glucose, ketones, alanine aminotransferase and L-homocysteine levels. Betaine plus the Met restriction resulted in lower serum insulin and non-esterified fatty acid levels. Betaine plus Met restriction induced hepatic BHMT 4-fold and ApoB mRNA 3-fold compared with Met restriction alone. No changes in percentage of edited ApoB mRNA were observed on the test diets. An increase in liver ApoB mRNA correlated with an 82% and 46% increase in ApoB and triacylglycerol production respectively using in vivo Triton WR 1339. Increased secretion of VLDL (very-low-density lipoprotein) with Met restriction plus betaine was associated with a 45% reduction in liver triacylglycerol compared with control. Nuclear run-off assays established that transcription of both bhmt and apob genes was also increased in Met-restricted plus betaine diets. No change in ApoB mRNA stability was detected in BHMT-transfected McA cells. Hepatic ApoB and BHMT mRNA levels were also increased by 1.8- and 3-fold respectively by betaine supplementation of Met-replete diets. Since dietary betaine increased ApoB mRNA, VLDL ApoB and triacylglycerol production and decreased hepatic triacylglycerol, results suggest that induction of apob transcription may provide a potential mechanism for mobilizing hepatic triacylglycerol by increasing ApoB available for VLDL assembly and secretion.

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Available from: Charles E Sparks, Oct 04, 2015
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    • "While choline is positively associated with fat mass, betaine is inversely associated. These nutrients are also related to energy expenditure and glucose, triglyceride and HDL levels (Konstantinova et al., 2008; Sparks et al., 2006; Teng et al., 2012). The positive association between HDL cholesterol and choline levels found in our study is consistent with previous observations, and may explain the low levels of HDL commonly observed in homocystinuria patients (Moat et al., 1999; Poloni et al., 2012). "
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    ABSTRACT: Classical homocystinuria is a rare genetic disease caused by cystathionine β-synthase deficiency, resulting in homocysteine accumulation. Growing evidence suggests that reduced fat mass in patients with classical homocystinuria may be associated with alterations in choline and homocysteine pathways. This study aimed to evaluate the body composition of patients with classical homocystinuria, identifying changes in body fat percentage and correlating findings with biochemical markers of homocysteine and choline pathways, lipoprotein levels and bone mineral density (BMD) T-scores. Nine patients with classical homocystinuria were included in the study. Levels of homocysteine, methionine, cysteine, choline, betaine, dimethylglycine and ethanolamine were determined. Body composition was assessed by bioelectrical impedance analysis (BIA) in patients and in 18 controls. Data on the last BMD measurement and lipoprotein profile were obtained from medical records. Of 9 patients, 4 (44%) had a low body fat percentage, but no statistically significant differences were found between patients and controls. Homocysteine and methionine levels were negatively correlated with body mass index (BMI), while cysteine showed a positive correlation with BMI (p<0.05). There was a trend between total choline levels and body fat percentage (r=0.439, p=0.07). HDL cholesterol correlated with choline and ethanolamine levels (r=0.757, p=0.049; r=0.847, p=0.016, respectively), and total cholesterol also correlated with choline levels (r=0.775, p=0.041). There was no association between BMD T-scores and body composition. These results suggest that reduced fat mass is common in patients with classical homocystinuria, and that alterations in homocysteine and choline pathways affect body mass and lipid metabolism.
    Gene 05/2014; 546(2). DOI:10.1016/j.gene.2014.05.015 · 2.14 Impact Factor
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    • "In Zucker diabetic fatty rats representing a type 2 diabetes model and in a type 1 diabetes animal model with streptozotocin an impaired insulin secretion and signaling and an increased hepatic gene expression of CBS and BHMT representing the branch-point enzymes of C1-metabolism have been reported [47], [48], [49], [50]. This is to some extent in line with our data suggesting increased Hcy remethylation and improved VLDL secretion due to increased BHMT expression in obese animals [51]. Furthermore, the implication of BHMT in lipid and PL metabolism of the liver and adipose tissue was recently shown by Teng et al. [52], [53]. "
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    ABSTRACT: Obesity is an underlying risk factor in the development of cardiovascular disease, dyslipidemia and non-alcoholic fatty liver disease (NAFLD). Increased hepatic lipid accumulation is a hallmark in the progression of NAFLD and impairments in liver phosphatidylcholine (PC) metabolism may be central to the pathogenesis. Hepatic PC biosynthesis, which is linked to the one-carbon (C1) metabolism by phosphatidylethanolamine N-methyltransferase, is known to be important for hepatic lipid export by VLDL particles. Here, we assessed the influence of a high-fat (HF) diet and NAFLD status in mice on hepatic methyl-group expenditure and C1-metabolism by analyzing changes in gene expression, protein levels, metabolite concentrations, and nuclear epigenetic processes. In livers from HF diet induced obese mice a significant downregulation of cystathionine β-synthase (CBS) and an increased betaine-homocysteine methyltransferase (BHMT) expression were observed. Experiments , using hepatoma cells stimulated with peroxisome proliferator activated receptor alpha (PPARα) agonist WY14,643, revealed a significantly reduced Cbs mRNA expression. Moreover, metabolite measurements identified decreased hepatic cystathionine and L-α-amino-n-butyrate concentrations as part of the transsulfuration pathway and reduced hepatic betaine concentrations, but no metabolite changes in the methionine cycle in HF diet fed mice compared to controls. Furthermore, we detected diminished hepatic gene expression of DNA methyltransferase 3b but no effects on hepatic global genomic DNA methylation or hepatic DNA methylation in the Cbs promoter region upon HF diet. Our data suggest that HF diet induces a PPARα-mediated downregulation of key enzymes in the hepatic transsulfuration pathway and upregulates BHMT expression in mice to accommodate to enhanced dietary fat processing while preserving the essential amino acid methionine.
    PLoS ONE 10/2013; 8(3):e57387. DOI:10.1371/journal.pone.0057387 · 3.23 Impact Factor
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    • "A further enzyme up-regulated in winter compared with fall is betaine-homocysteine methyltransferase (BHMT), which converts homocysteine to methionine. Induction of BHMT in rat hepatoma cells increases apolipoprotein B mRNA levels, which in turn leads to greater secretion of triacylglycerol and apolipoprotein B-based lipoproteins from hepatocytes (Sparks et al. 2006). Thus, considerable modulation of lipid and triacylglycerol synthesis and transport appear to take place during winter in smelt liver, consistent with the response of carp liver to low temperature (Gracey et al. 2004;G r a c e y2007). "
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    ABSTRACT: Rainbow smelt (Osmerus mordax) are freeze-resistant fish that accumulate glycerol and produce an antifreeze protein during winter. Quantitative reverse transcription PCR (qPCR) and subtractive hybridization studies have previously revealed five genes in rainbow smelt liver to be differentially regulated in winter in comparison with the fall when water temperatures are warmer. In order to further define the suite of processes that are regulated seasonally, we undertook a large-scale analysis of gene expression by hybridization of smelt cDNA to the salmonid 16K cGRASP microarray. In total, 69 genes were identified as up-regulated and 14 genes as down-regulated under winter conditions. A subset of these genes was examined for differential regulation by qPCR in the individual cDNA samples that were pooled for microarray analysis. Ten of the 15 genes tested showed significant change in the same direction as microarray results, whereas one showed significant change in the opposite direction. Fructose-bisphosphate aldolase B and the cytosolic NAD-dependent glycerol-3-phosphate dehydrogenase were among the most highly up-regulated genes, a result supporting a metabolic focus on glycerol synthesis during winter. Modulation of other processes, including endoplasmic reticulum stress, lipid metabolism and transport, and protein synthesis, was also suggested by the qPCR analysis of array-identified genes. The 15 genes were subsequently examined by qPCR for seasonal variation in expression over five sampling times between October and March, and ten showed significant variation in expression over the sampling period. Taken together, these results provide new understanding of the biochemical adaptations of vertebrates to an extremely low seasonal temperature.
    Marine Biotechnology 11/2010; 12(6):650-63. DOI:10.1007/s10126-009-9252-8 · 3.27 Impact Factor
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