Folic acid supplementation alters the DNA methylation profile and improves insulin resistance in high-fat-diet-fed mice

Diets high in saturated fat and cholesterol facilitate weight gain, a predisposing factor that contributes to the onset of obesity and metabolic disorders. Hepatic oxidative stress is commonly reported in various animal models of obesity and has been associated with enhanced expression of NADPH oxidase. We have previously reported several antioxidant mechanisms through which folic acid confers protection during hyperhomocysteinemia-induced oxidative stress. The objective of the present study was to investigate whether folic acid supplementation ameliorates high-fat diet induced oxidative stress in the liver, and to identify the underlying mechanisms. Male C57BL/6J mice were fed a control diet, a high-fat diet, or a high-fat diet supplemented with folic acid for 12 weeks. A high-fat diet led to increased body mass, hepatic lipid peroxidation, and liver injury. There was a significant increase in hepatic NADPH oxidase activity, which was associated with enhanced expression of several NADPH-oxidase subunits. Folic acid supplementation had a protective effect against high-fat diet induced hepatic oxidative stress and liver injury. Further analysis revealed that the antioxidant effect of folic acid was attributed, in part, to transcriptional regulation of NADPH oxidase. These results suggested that folic acid supplementation may be hepatoprotective from liver injury associated with a high-fat diet.

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Folic acid supplementation during high-fat diet feeding restores AMPK activation via an AMP-LKB1-dependent mechanism

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00260.2015 ◽

2015 ◽

Vol 309 (10) ◽

pp. R1215-R1225 ◽

Cited By ~ 19

Author(s):

Victoria Sid ◽

Nan Wu ◽

Lindsei K. Sarna ◽

Yaw L. Siow ◽

James D. House ◽

...

Keyword(s):

Oxidative Stress ◽

Folic Acid ◽

Glucose Metabolism ◽

High Fat Diet ◽

Folic Acid Supplementation ◽

Ampk Activation ◽

Hepatic Cholesterol ◽

High Fat ◽

Acid Supplementation ◽

Ampk Phosphorylation

AMPK is an endogenous energy sensor that regulates lipid and carbohydrate metabolism. Nonalcoholic fatty liver disease (NAFLD) is regarded as a hepatic manifestation of metabolic syndrome with impaired lipid and glucose metabolism and increased oxidative stress. Our recent study showed that folic acid supplementation attenuated hepatic oxidative stress and lipid accumulation in high-fat diet-fed mice. The aim of the present study was to investigate the effect of folic acid on hepatic AMPK during high-fat diet feeding and the mechanisms involved. Male C57BL/6J mice were fed a control diet (10% kcal fat), a high-fat diet (60% kcal fat), or a high-fat diet supplemented with folic acid (26 mg/kg diet) for 5 wk. Mice fed a high-fat diet exhibited hyperglycemia, hepatic cholesterol accumulation, and reduced hepatic AMPK phosphorylation. Folic acid supplementation restored AMPK phosphorylation (activation) and reduced blood glucose and hepatic cholesterol levels. Activation of AMPK by folic acid was mediated through an elevation of its allosteric activator AMP and activation of its upstream kinase, namely, liver kinase B1 (LKB1) in the liver. Consistent with in vivo findings, 5-methyltetrahydrofolate (bioactive form of folate) restored phosphorylation (activation) of both AMPK and LKB1 in palmitic acid-treated HepG2 cells. Activation of AMPK by folic acid might be responsible for AMPK-dependent phosphorylation of HMG-CoA reductase, leading to reduced hepatic cholesterol synthesis during high-fat diet feeding. These results suggest that folic acid supplementation may improve cholesterol and glucose metabolism by restoration of AMPK activation in the liver.

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Analysis of Locus‐Specific DNA Methylation in Response to Chronic Folic Acid Supplementation and Withdrawal in Chinese Women

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.689.4 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Jason O Brant ◽

Jiang‐Hui Zhu ◽

Krista Crider ◽

R J Berry ◽

Ling Hao ◽

...

Keyword(s):

Dna Methylation ◽

Folic Acid ◽

Chinese Women ◽

Folic Acid Supplementation ◽

Acid Supplementation

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No Effect of Folic Acid Supplementation on Global DNA Methylation in Men and Women with Moderately Elevated Homocysteine

PLoS ONE ◽

10.1371/journal.pone.0024976 ◽

2011 ◽

Vol 6 (9) ◽

pp. e24976 ◽

Cited By ~ 31

Author(s):

Audrey Y. Jung ◽

Yvo Smulders ◽

Petra Verhoef ◽

Frans J. Kok ◽

Henk Blom ◽

...

Keyword(s):

Dna Methylation ◽

Folic Acid ◽

Folic Acid Supplementation ◽

Global Dna Methylation ◽

Men And Women ◽

Acid Supplementation

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Folic acid attenuates homocysteine and enhances antioxidative capacity in atherosclerotic rats

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2017-0158 ◽

2017 ◽

Vol 42 (10) ◽

pp. 1015-1022 ◽

Cited By ~ 6

Author(s):

Shanshan Cui ◽

Wen Li ◽

Xin Lv ◽

Pengyan Wang ◽

Guowei Huang ◽

...

Keyword(s):

Folic Acid ◽

Antioxidant Capacity ◽

Wistar Rats ◽

Folic Acid Supplementation ◽

Plasma Homocysteine ◽

Serum Folate ◽

Antioxidative Capacity ◽

High Fat ◽

Acid Supplementation ◽

Atherosclerotic Lesions

Atherosclerosis is a chronic disease that can seriously endanger human life. Folic acid supplementation modulates several disorders, including atherosclerosis, via its antiapoptotic and antioxidative properties. This study investigated whether folic acid alleviates atherogenesis by restoring homocysteine levels and antioxidative capacity in atherosclerosis Wistar rats. To this end, 28 Wistar rats were randomly divided into 4 groups (7 rats/group) as follows: (i) wild-type group, fed only the AIN-93 semi-purified rodent diet (folic acid: 2.1 mg/kg); (ii) high-fat + folic acid-deficient group (HF+DEF) (folic acid: 0.2 mg/kg); (iii) high-fat + normal folic acid group (folic acid: 2.1 mg/kg); and (iv) high-fat + folic acid-supplemented group (folic acid: 4.2 mg/kg). After 12 weeks, histopathological changes in the atherosclerotic lesions of the aortic arch were determined. In addition, serum folate levels, plasma homocysteine levels, plasma S-adenosyl-homocysteine levels, antioxidant status, oxidant status, and lipid profiles were evaluated. The results show aggravated atherosclerotic lesions in the HF+DEF group. Folic acid supplementation increased concentrations of serum folate. Further, folic acid supplementation increased high-density lipoprotein-cholesterol, decreased plasma homocysteine levels, and improved antioxidant capacity in atherogenic rats. These findings are consistent with the hypothesis that folic acid alleviates atherogenesis by reducing plasma homocysteine levels and improving antioxidant capacity in rats fed a high-fat diet.

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