Abstract
GPIHBP1 is a protein localized at the endothelial cell surface that facilitates triglyceride (TG) lipolysis by binding lipoprotein lipase (LPL). Whether Glycosyl Phosphatidyl Inositol high density lipoprotein binding protein 1 (GPIHBP1) function is impaired and may underlie the hyperTG phenotype observed in type 2 diabetes is not yet established. To elucidate the mechanism underlying impaired TG homeostasis in insulin resistance state we studied the effect of insulin on GPIHBP1 protein expression in human microvascular endothelial cells (HMVEC) under flow conditions. Next, we assessed visceral adipose tissue GPIHBP1 protein expression in type 2 diabetes Lepr db/db mouse model as well as in subjects with ranging levels of insulin resistance. We report that insulin reduces the expression of GPIHBP1 protein in HMVECs. Furthermore, GPIHBP1 protein expression in visceral adipose tissue in Lepr db/db mice is significantly reduced as is the active monomeric form of GPIHBP1 as compared to Leprdb/m mice. A similar decrease in GPIHBP1 protein was observed in subjects with increased body weight. GPIHBP1 protein expression was negatively associated with insulin and HOMA-IR.In conclusion, our data suggest that decreased GPIHBP1 availability in insulin resistant state may hamper peripheral lipolysis capacity.
Highlights
In human visceral adipose tissue we observed a correlation with plasma insulin levels, suggesting that peripheral lipolysis capacity may be impaired
It has been generally accepted that insulin resistance is associated with the presence of the atherogenic dyslipidemia, which is defined by the presence of moderate elevated plasma TG levels and reduced HDL cholesterol levels [2]
GPIHBP1 has been recognized as the protein on the endothelial cell surface that binds lipoprotein lipase (LPL) and facilitates TG lipolysis in the peripheral tissues.[27]
Summary
Patients with the Metabolic Syndrome or type 2 diabetes (T2DM) are frequently characterized with atherogenic dyslipidemia, displayed by elevated plasma triglyceride (TG)-rich remnant. Abnormalities in TG homeostasis can occur through either increased hepatic VLDL secretion or via decreased TRL clearance. In this respect, lipoprotein lipase (LPL)-mediated lipolysis is the rate-limiting first step to hydrolyse TG in TRL allowing the uptake of free fatty acids (FFA) in peripheral tissues (adipose tissue, heart and skeletal muscle) for storage and energy [8]. To further understand the mechanism underlying the hyperTG phenotype we evaluated adipose tissue GPIHBP1 expression in a T2DM mouse model as well as in subjects with ranging levels of insulin resistance. GPIHBP1 protein in visceral adipose tissue is significantly decreased in an insulin resistant mouse model and in subjects with increased body weight. GPIHBP1 protein was negatively associated with insulin and HOMA-IR, suggesting that decreased GPIHBP1 protein availability may hamper peripheral lipolysis and affect plasma TG levels
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