title: Folic acid supplementation during high-fat diet feeding restores AMPK activation via an AMP-LKB1-dependent mechanism.
abstract: 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.
authors.affiliation: St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada; Department of Physiology and Pathophysiology, Winnipeg, Manitoba, Canada;
authors.forename: Victoria
authors.initials: V
authors.lastname: Sid
authors.affiliation: St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada; Department of Physiology and Pathophysiology, Winnipeg, Manitoba, Canada;
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.affiliation: St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada; Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Lindsei K
authors.initials: LK
authors.lastname: Sarna
authors.affiliation: St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada; Department of Physiology and Pathophysiology, Winnipeg, Manitoba, Canada; Agriculture and Agri-Food Canada, Winnipeg, Manitoba, Canada; and.
authors.forename: Yaw L
authors.initials: YL
authors.lastname: Siow
authors.affiliation: Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Human Nutritional Science, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: James D
authors.initials: JD
authors.lastname: House
authors.affiliation: St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada; Department of Physiology and Pathophysiology, Winnipeg, Manitoba, Canada; Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada; karmino@sbrc.ca.
authors.forename: Karmin
authors.initials: K
authors.lastname: O
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage* / Q000009:adverse effects; D019587:Dietary Supplements; D004789:Enzyme Activation / Q000187:drug effects*; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain
chemical_list: D004041:Dietary Fats; D000249:Adenosine Monophosphate; D005492:Folic Acid; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: AMP; AMP-activated protein kinase; folic acid; liver kinase B1; nonalcoholic fatty liver disease