title: Cardiac triglyceride accumulation following acute lipid excess occurs through activation of a FoxO1-iNOS-CD36 pathway.
abstract: Obesity due to nutrient excess leads to chronic pathologies including type 2 diabetes and cardiovascular disease. Related to nutrient excess, FoxO1 has a role in regulating fatty acid uptake and oxidation and triglyceride (TG) storage by mechanisms that are largely unresolved. We examined the mechanism behind palmitate (PA)-induced TG accumulation in cardiomyocytes. To mimic lipid excess, rat ventricular myocytes were incubated with albumin-bound PA (1 mM) or rats were administered Intralipid (20%). PA-treated cardiomyocytes showed a substantial increase in TG accumulation, accompanied by amplification of nuclear migration of phospho-p38 and FoxO1, iNOS induction, and translocation of CD36 to the plasma membrane. PA also increased Cdc42 protein and its tyrosine nitration, thereby rearranging the cytoskeleton and facilitating CD36 translocation. These effects were duplicated by TNF-α and reversed by the iNOS inhibitor 1400 W. PA increased the nuclear interaction between FoxO1 and NF-κB, reduced the nuclear presence of PGC-1α, and downregulated expression of oxidative phosphorylation proteins. In vivo a robust increase in cardiac TGs after Intralipid administration was also associated with augmentation of nuclear FoxO1 and iNOS expression. Impeding this FoxO1-iNOS-CD36 pathway could decrease cardiac lipid accumulation and oxidative/nitrosative stress and help ameliorate the cardiovascular complications associated with obesity and diabetes.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Prasanth
authors.initials: P
authors.lastname: Puthanveetil
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Min Suk
authors.initials: MS
authors.lastname: Kim
authors.forename: Sheila
authors.initials: S
authors.lastname: Innis
authors.forename: Thomas
authors.initials: T
authors.lastname: Pulinilkunnil
authors.forename: Ashraf
authors.initials: A
authors.lastname: Abrahani
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018955:CD36 Antigens / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000378:metabolism*; D000071161:Forkhead Box Protein O1
chemical_list: D018955:CD36 Antigens; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D052247:Nitric Oxide Synthase Type II; D014280:Triglycerides; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1