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Effect of folate deficiency and over-supplementation on serum and liver tissue folate of DEN treated rats a Serum folate, b Total folate, c Conjugated folate, d Free folate
Source publication
The present study evaluated the role of dietary folate modulations in the development of hepatocellular carcinoma (HCC) in a rat model. Male Wistar rats were given diethylnitrosamine (DEN) carcinogen for a period of 18 weeks in addition to different folate modulations. Biochemical parameters were assayed and liver tissues were examined using variou...
Citations
... However, studies have shown to the contrary that mice fed a diet deficient in carcinogenic methionine and choline develop significant liver fibrosis due to HSC activation and collagen deposition. In addition, most HCC cells undergo cell cycle arrest and severe DNA damage responses after acute methionine deprivation [63]. MAT2A is a rate-limiting enzyme in the methionine cycle that catalyzes the synthesis of SAM from methionine and adenosine triphosphate (ATP). ...
Folate is a water-soluble B vitamin involved in the synthesis of purines and pyrimidines and is one of the essential vitamins for human growth and reproduction. Folate deficiency due to low dietary intake, poor absorption of folate, and alterations in folate metabolism due to genetic defects or drug interactions significantly increases the risk of diseases such as neural tube defects, cardiovascular disease, cancer, and cognitive dysfunction. Recent studies have shown that folate deficiency can cause hyperhomocysteinemia, which increases the risk of hypertension and cardiovascular disease, and that high homocysteine levels are an independent risk factor for liver fibrosis and cirrhosis. In addition, folate deficiency results in increased secretion of pro-inflammatory factors and impaired lipid metabolism in the liver, leading to lipid accumulation in hepatocytes and fibrosis. There is substantial evidence that folate deficiency contributes to the development and progression of a variety of liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), viral hepatitis, hepatic fibrosis, and liver cancer. Here we review key studies on the role of folate in the pathophysiology of liver diseases, summarize the current status of studies on folate in the treatment of liver diseases, and speculate that folate may be a potential therapeutic target for liver diseases.
... Numerous studies indicate that FA is beneficial in preventing the initiation phase of cancer, it may paradoxically foster the progression and development of preexisting tumours and subclinical carcinomas. [98][99][100][101][102][103] For certain cancers, including rectal, 104 cervical, 105 lung 106 and esophageal cancer, 107 an inverse relationship has been observed between disease incidence and FA levels. A 2016 study among 312 HCC patients and 325 healthy controls reported significant reductions in FA levels in the HCC group. ...
... 116 Diets abundant in FA significantly accelerated the progression of HCC in animals subjected to various carcinogens, such as diethylnitrosamine (DEN), an HFD, and carbon tetrachloride (CCl 4 ). 102,117,118 Animal studies have demonstrated that an FA-deficient diet lowers HCC incidence but raises the risk of liver fibrosis, suggesting a delay in HCC progression. 102 FA assists in the integration of methionine and 1C metabolism, leading to HCC development through the methionine adenylyltransferase 2A (MTIα) metabolic pathway. ...
... 102,117,118 Animal studies have demonstrated that an FA-deficient diet lowers HCC incidence but raises the risk of liver fibrosis, suggesting a delay in HCC progression. 102 FA assists in the integration of methionine and 1C metabolism, leading to HCC development through the methionine adenylyltransferase 2A (MTIα) metabolic pathway. Several metabolites produced in the FA cycle are vital for HCC growth. ...
In recent years, the incidence of non‐alcoholic fatty liver disease (NAFLD) has been increasing, which has become an explosive interest because of the growing impact on world health. NAFLD is the hepatic manifestation of systemic metabolic syndrome (MS), and the umbrella term that comprises a continuum of liver conditions, from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and hepatocellular carcinoma (HCC). currently, there is no pharmacological agent that is therapeutically approved for the treatment of this disease. Folic acid (FA) was one of a water‐soluble B vitamins, entirely absorbed from the diet. Numbers of clinical studies have confirmed that patients with NAFLD and insulin resistance are often accompanied by abnormal FA. We investigated the potential effects of FA on NAFLD through the metabolic pathways, DNA synthesis and methylation, oxidative stress in liver and intestinal flora. In addition, FA has an effect on HCC or other cancer. Therefore, FA might be a safe and economical potential treatment method for NAFLD.
... Deghan Manshadi et al., in a study of mammary tumors initiated in female rats at puberty, demonstrated accelerated tumor progression and greater tumor weight/volume associated with folic acid supplementation 2.5x the control concentration [36]. Sharma et al. discovered that high folate progressed the development of hepatocellular carcinoma among rats given diethylnitrosamine carcinogen [45]. In a previous study also investigating nerve sheath tumors, mice carrying the human T-lymphotropic virus type 1 transactivator gene and provided high folate developed tumors significantly sooner than carrier mice assigned to low folate [35]. ...
... The inconsistency could also be due to differences in administered folate concentrations. In the current study, deficient, control, and supplemented diets contained 0.3, 2.0, and 8.0 mg/kg folic acid whereas the high folate group in Lawrance et al. received 20 mg/kg folic acid [33], and Sharma et al. provided low and high folate groups with 0 mg/kg folate and 20 mg/kg folate, respectively [45]. The higher concentration of administered folate in supplemented groups and/or wider range of dietary consumption in other studies could help explain the inconsistency of our results. ...
Objective
In epidemiological and experimental research, high folic acid intake has been demonstrated to accelerate tumor development among populations with genetic and/or molecular susceptibility to cancer. Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder predisposing affected individuals to tumorigenesis, including benign plexiform neurofibromas; however, understanding of factors associated with tumor risk in NF1 patients is limited. Therefore, we investigated whether pregestational folic acid intake modified plexiform-like peripheral nerve sheath tumor risk in a transgenic NF1 murine model.
Results
We observed no significant differences in overall survival according to folate group. Relative to controls (180 days), median survival did not statistically differ in deficient (174 days, P = 0.56) or supplemented (177 days, P = 0.13) folate groups. Dietary folate intake was positively associated with RBC folate levels at weaning, (P = 0.023, 0.0096, and 0.0006 for deficient vs. control, control vs. supplemented, and deficient vs. supplemented groups, respectively). Dorsal root ganglia (DRG), brachial plexi, and sciatic nerves were assessed according to folate group. Mice in the folate deficient group had significantly more enlarged DRG relative to controls (P = 0.044), but no other groups statistically differed. No significant differences for brachial plexi or sciatic nerve enlargement were observed according to folate status.
... But the role of folate and its synthetic form, folic acid, in cancer development and progression is highly controversial. 7,[13][14][15][16] To explore how folate influence the development of HCC in vivo, we fed DEN-injected mice with purified HFD containing standard level of folate (1×), high level of folate (10×) or folate free (0×) as indicated, respectively, because diet is the main source of folate in the body (Fig. 1a). 5 months after DEN injection, high folate diet significantly promoted HFDinduced HCC development (Fig. 1b). ...
... Non-alcoholic steatohepatitis (NASH) is the most severe form of non-alcoholic fatty liver disease (NAFLD) and supposed as a potential precursor of HCC. 28 16 weeks after HFD feeding, fasting serum glucose and insulin levels were significantly decreased in Mat2a LKO mice ( Supplementary Fig. S3d, e). Furthermore, glucose and insulin c-e Quantification of the ratio of liver weight to body weight (c), the number of tumors (d), and the size of the largest tumor per mouse (e). ...
Folic acid, served as dietary supplement, is closely linked to one-carbon metabolism and methionine metabolism. Previous clinical evidence indicated that folic acid supplementation displays dual effect on cancer development, promoting or suppressing tumor formation and progression. However, the underlying mechanism remains to be uncovered. Here, we report that high-folate diet significantly promotes cancer development in mice with hepatocellular carcinoma (HCC) induced by DEN/high-fat diet (HFD), simultaneously with increased expression of methionine adenosyltransferase 2A (gene name, MAT2A; protein name, MATIIα), the key enzyme in methionine metabolism, and acceleration of methionine cycle in cancer tissues. In contrast, folate-free diet reduces MATIIα expression and impedes HFD-induced HCC development. Notably, methionine metabolism is dynamically reprogrammed with valosin-containing protein p97/p47 complex-interacting protein (VCIP135) which functions as a deubiquitylating enzyme to bind and stabilize MATIIα in response to folic acid signal. Consistently, upregulation of MATIIα expression is positively correlated with increased VCIP135 protein level in human HCC tissues compared to adjacent tissues. Furthermore, liver-specific knockout of Mat2a remarkably abolishes the advocating effect of folic acid on HFD-induced HCC, demonstrating that the effect of high or free folate-diet on HFD-induced HCC relies on Mat2a. Moreover, folate and multiple intermediate metabolites in one-carbon metabolism are significantly decreased in vivo and in vitro upon Mat2a deletion. Together, folate promotes the integration of methionine and one-carbon metabolism, contributing to HCC development via hijacking MATIIα metabolic pathway. This study provides insight into folate-promoted cancer development, strongly recommending the tailor-made folate supplement guideline for both sub-healthy populations and patients with cancer expressing high level of MATIIα expression.
Scope
Disturbances in one‐carbon metabolism contribute to nonalcoholic fatty liver disease (NAFLD) which encompasses steatosis, steatohepatitis, fibrosis, and cirrhosis. The goal is to examine impact of folate deficiency and the Mthfr 677C >T variant on NAFLD.
Methods and results
This study uses the new Mthfr 677C >T mouse model for the human MTHFR 677C >T variant. Mthfr 677CC and Mthfr 677TT mice were fed control diet (CD) or folate‐deficient (FD) diets for 4 months. FD and Mthfr 677TT alter choline/methyl metabolites in liver and/or plasma (decreased S‐adenosylmethionine (SAM):S‐adenosylhomocysteine (SAH) ratio, methyltetrahydrofolate, and betaine; increased homocysteine [Hcy]). FD, with contribution from Mthfr 677TT , provokes fibrosis in males. Studies of normal livers reveal alterations in plasma markers and gene expression that suggest an underlying predisposition to fibrosis induced by FD and/or Mthfr 677TT in males. These changes are absent or reverse in females, consistent with the sex disparity of fibrosis. Sex‐based differences in methylation potential, betaine, sphingomyelin, and trimethylamine‐ N ‐oxide (TMAO) levels may prevent fibrogenesis in females. In contrast, Mthfr 677TT alters choline metabolism, dysregulates expression of lipid metabolism genes, and promotes steatosis in females.
Conclusion
This study suggests that folate deficiency predisposes males to fibrosis, which is exacerbated by Mthfr 677TT , whereas Mthfr 677TT predisposes females to steatosis, and reveal novel contributory mechanisms for these NAFLD‐related disorders.
