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.
Original language | English |
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Pages (from-to) | 352-363 |
Number of pages | 12 |
Journal | Free Radical Biology and Medicine |
Volume | 51 |
Issue number | 2 |
DOIs | |
State | Published - 15 Jul 2011 |
Bibliographical note
Funding Information:This work was supported by an operating grant from the Canadian Diabetes Association and CIHR. Prasanth Puthanveetil, Fang Wang, and Min Suk Kim are the recipients of Doctoral Student Research Awards from the Canadian Diabetes Association.
Keywords
- Cardiac triglycerides
- CD36
- FoxO1
- Free radicals
- iNOS
- Lipid excess
- Saturated fatty acids