title: Dual effects of fructose on ChREBP and FoxO1/3α are responsible for AldoB up-regulation and vascular remodelling.
abstract: Increased production of methylglyoxal (MG) in vascular tissues is one of the causative factors for vascular remodelling in different subtypes of metabolic syndrome, including hypertension and insulin resistance. Fructose-induced up-regulation of aldolase B (AldoB) contributes to increased vascular MG production but the underlying mechanisms are unclear. Serum levels of MG and fructose were determined in diabetic patients with hypertension. MG level had significant positive correlations with blood pressure and fructose level respectively. C57BL/6 mice were fed with control or fructose-enriched diet for 3 months and ultrasonographic and histologic analyses were performed to evaluate arterial structural changes. Fructose-fed mice exhibited hypertension and high levels of serum MG with normal glucose level. Fructose intake increased blood vessel wall thickness and vascular smooth muscle cell (VSMC) proliferation. Western blotting and real-time PCR analysis revealed that AldoB level was significantly increased in both the aorta of fructose-fed mice and the fructose-treated VSMCs, whereas aldolase A (AldoA) expression was not changed. The knockdown of AldoB expression prevented fructose-induced MG overproduction and VSMC proliferation. Moreover, fructose significantly increased carbohydrate-responsive element-binding protein (ChREBP), phosphorylated FoxO1/3α and Akt1 levels. Fructose induced translocation of ChREBP from the cytosol to nucleus and activated AldoB gene expression, which was inhibited by the knockdown of ChREBP. Meanwhile, fructose caused FoxO1/3α shuttling from the nucleus to cytosol and inhibited its binding to AldoB promoter region. Fructose-induced AldoB up-regulation was suppressed by Akt1 inhibitor but enhanced by FoxO1/3α siRNA. Collectively, fructose activates ChREBP and inactivates FoxO1/3α pathways to up-regulate AldoB expression and MG production, leading to vascular remodelling.
authors.affiliation: Department of Health Sciences, Lakehead University, Thunder Bay, Canada P7B 5E1.|School of Chemistry and Pharmacy, Northwest A&F University, Yangling 712100, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.affiliation: Thunder Bay Regional Research Institute, Thunder Bay, Canada P7A 7T1.
authors.forename: Tuanjie
authors.initials: T
authors.lastname: Chang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiao-Qiang
authors.initials: XQ
authors.lastname: Li
authors.affiliation: Cardiovascular and Metabolic Research Unit, Lakehead University, Thunder Bay, Canada P7A 7T1.|Cardiovascular and Metabolic Research Unit, Laurentian University, Canada P3E 2C6.|Department of Biology, Laurentian University, Canada P3E 2C6.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Health Sciences, Lakehead University, Thunder Bay, Canada P7B 5E1 lwu@lakeheadu.ca.|Cardiovascular and Metabolic Research Unit, Laurentian University, Canada P3E 2C6.|Health Sciences North Research Institute, Sudbury, Canada P3E 5J1.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D005632:Fructose / Q000097:blood / Q000494:pharmacology*; D005634:Fructose-Bisphosphate Aldolase / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000209:etiology; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000097:blood; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D066253:Vascular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D005632:Fructose; D011765:Pyruvaldehyde; D005634:Fructose-Bisphosphate Aldolase
keywords: FoxO1/3α; aldolase B; carbohydrate-responsive element-binding protein (ChREBP); fructose; hypertension