TY - JOUR
T1 - Cardiac triglyceride accumulation following acute lipid excess occurs through activation of a FoxO1-iNOS-CD36 pathway
AU - Puthanveetil, Prasanth
AU - Wang, Ying
AU - Zhang, Dahai
AU - Wang, Fang
AU - Kim, Min Suk
AU - Innis, Sheila
AU - Pulinilkunnil, Thomas
AU - Abrahani, Ashraf
AU - Rodrigues, Brian
N1 - 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.
PY - 2011/7/15
Y1 - 2011/7/15
N2 - 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.
AB - 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.
KW - Cardiac triglycerides
KW - CD36
KW - FoxO1
KW - Free radicals
KW - iNOS
KW - Lipid excess
KW - Saturated fatty acids
UR - http://www.scopus.com/inward/record.url?scp=79959365710&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2011.04.009
DO - 10.1016/j.freeradbiomed.2011.04.009
M3 - Article
C2 - 21545834
AN - SCOPUS:79959365710
SN - 0891-5849
VL - 51
SP - 352
EP - 363
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 2
ER -