Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promote monocyte adhesion and impair insulin transcytosis.

Abstract

Obesity is associated with inflammation and immune cell recruitment to adipose tissue, muscle and intima of atherosclerotic blood vessels. Obesity and hyperlipidemia are also associated with tissue insulin resistance and can compromise insulin delivery to muscle. The muscle/fat microvascular endothelium mediates insulin delivery and facilitates monocyte transmigration, yet its contribution to the consequences of hyperlipidemia is poorly understood. Using primary endothelial cells from human adipose tissue microvasculature (HAMEC), we investigated the effects of physiological levels of fatty acids on endothelial inflammation and function. Expression of cytokines and adhesion molecules was measured by RT-qPCR. Signaling pathways were evaluated by pharmacological manipulation and immunoblotting. Surface expression of adhesion molecules was determined by immunohistochemistry. THP1 monocyte interaction with HAMEC was measured by cell adhesion and migration across transwells. Insulin transcytosis was measured by total internal reflection fluorescence microscopy. Palmitate, but not palmitoleate, elevated the expression of IL-6, IL-8, TLR2 (Toll-like receptor 2), and intercellular adhesion molecule 1 (ICAM-1). HAMEC had markedly low fatty acid uptake and oxidation, and CD36 inhibition did not reverse the palmitate-induced expression of adhesion molecules, suggesting that inflammation did not arise from palmitate uptake/metabolism. Instead, inhibition of TLR4 to NF-κB signaling blunted palmitate-induced ICAM-1 expression. Importantly, palmitate-induced surface expression of ICAM-1 promoted monocyte binding and transmigration. Conversely, palmitate reduced insulin transcytosis, an effect reversed by TLR4 inhibition. In summary, palmitate activates inflammatory pathways in primary microvascular endothelial cells, impairing insulin transport and increasing monocyte transmigration. This behavior may contribute in vivo to reduced tissue insulin action and enhanced tissue infiltration by immune cells.

• Authors: Nicolas J Pillon, Paymon M Azizi, Yujin E Li, Jun Liu, Changsen Wang, Kenny L Chan, Kathryn E Hopperton, Richard P Bazinet, Bryan Heit, Philip J Bilan, Warren L Lee, Amira Klip
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 309 Issue 1 Pg. E35-44 (Jul 01 2015) ISSN: 1522-1555 [Electronic] United States
• PMID: 25944880 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• Insulin
• Palmitic Acid

Topics

• Adipose Tissue (blood supply, cytology, drug effects)
• Cell Adhesion (drug effects)
• Cells, Cultured
• Endothelial Cells (drug effects, metabolism)
• Human Umbilical Vein Endothelial Cells
• Humans
• Inflammation (chemically induced, metabolism)
• Insulin (metabolism)
• Microvessels (cytology)
• Monocytes (drug effects, physiology)
• Palmitic Acid (pharmacology)
• Signal Transduction (drug effects)
• Transcytosis (drug effects)