(827.3) Dedicator of cytokinesis 2 (DOCK2) mediates chronic high-fat and high-fructose diet induced lung injury

Poster Board Number: D37

Xia Guo (University of Texas Health Science Center at Tyler), Oluwaseun Adeyanju (University of Texas Health Science Center at Tyler), Christudas Sunil (University of Texas Health Science Center at Tyler), Steven Huang (University of Michigan), Shi-You Chen (University of Missouri), Torry Tucker (University of Texas Health Science Center at Tyler), Steven Idell (University of Texas Health Science Center at Tyler), Guoqing Qian (University of Texas Health Science Center at Tyler)

Obesity is involved in the pathogenesis of multiple lung diseases. However, little is known about the effects of chronic high-fat and high-fructose (HFHF) diet-induced obesity on lung inflammatory/injury. We have reported that dedicator of cytokinesis 2 (DOCK2) is important for high-fat diet (HFD)-induced obesity and adipose tissue inflammation. DOCK2 deficient mice were protected from HFD induced body weight gain, insulin resistance, and increased proinflammatory cytokines in the adipose tissue and peripheral circulation. However, it remains elusive whether DOCK2 plays a role in lung injury associated with chronic HFHF diet-induced obesity. In this study, we showed that chronic HFHF diet (20 weeks) induced lung inflammatory infiltration and collagen expression in the wild-type (WT) C57BL/6 mice. Macrophage marker CD68 and monocyte chemoattractant protein-1 (MCP-1) expression were notably increased in the lungs of WT mice fed a HFHF diet. Further, HFHF diet increased lung DOCK2 expression that co-localized with fibroblast-specific protein 1, suggesting a potential role of DOCK2 in regulating proinflammatory phenotype of lung fibroblasts. Conversely, DOCK2 deficiency attenuated lung inflammation and fibrosis induced by chronic HFHF diet. In primary human lung fibroblast, TNF-α and IL-1β induced DOCK2 expression concurrent with MCP-1, IL-6, and matrix metalloproteinase-2. DOCK2 knockdown also suppressed TNF-α induced increase of these inflammatory mediators. Taken together, these findings suggest a previously unrecognized role of DOCK2 in mediating lung inflammation and fibrosis in chronic HFHF diet caused obesity.

This work was supported by National Institutes of Health (HL141583 to XG); University of Texas Rising Star Award (to XG); University of Texas Health Science Center at Tyler Startup fund (to GQ and XG).