Abstract P3001: Disruption of Endothelial BBSome Causes Vascular Dysfunction and Hepatosteatosis

Abstract

Almost every single cell in the human body possesses primary cilium. The primary cilium function as a sensor of blood flow and sheer stress and contribute to both calcium and nitric oxide signaling in the endothelium. The BBS1 protein is an important member of the BBSome complex which mediates protein trafficking to the cilia membrane and other cellular compartments. To investigate the role of the BBSome in endothelial cells, we generated mice lacking the Bbs1 gene specifically in endothelial cells by crossing the Bbs1 fl/fl mice with the endothelial-specific Tie2 cre mice. The Bbs1 fl/fl /Tie2 Cre mice developed normally compared to littermate controls. We assessed vascular function ex vivo using aortic rings and resistance-sized mesenteric arteries. Interestingly, loss of the Bbs1 gene in endothelial cells caused endothelial dysfunction with a more severe effect in female mice as indicated by the impaired acetylcholine (ACh)-induced relaxation (Max relax of mesenteric artery: males: 43.6±7.6% vs 56.4±6.2% in controls, P<0.05; females: 35.8±8.0% vs 75.9±10.0% in controls, P<0.05). Of note, the relaxation responses evoked by sodium nitroprusside in both the aorta and mesenteric artery were not different in male and female Bbs1 fl/fl /Tie2 Cre mice, indicative of endothelial but not smooth muscle dysfunction in the endothelium-specific Bbs1 null mice. Blood pressure tended to be elevated in Bbs1 fl/fl /Tie2 Cre mice particularly females. Strikingly, endothelial Bbs1 gene deletion caused hepatosteatosis as indicated by the significant lipid deposition in the liver of Bbs1 fl/fl /Tie2 Cre mice by oil-red-O staining (females: 7.75±2.34 vs 0.59±0.16 % area in controls, P<0.05; males: 1.67±0.62 vs 0.40±0.09 in controls, P<0.05). Lipid extraction revealed a 2-6-fold increase in triglycerides and cholesterol in the liver of Bbs1 fl/fl /Tie2 Cre mice. Consistent with this, Bbs1 fl/fl /Tie2 Cre mice exhibited 80-90% reduction (P<0.05) in the expression of liver fatty acid transport and binding protein (Fatp2 and Fabp1). Thus, we conclude that the endothelial BBSome is required for the control of vascular endothelial function and hepatic lipid metabolism.