Although more than 95% of dietary lipids are absorbed from the small intestine via the intestinal lymphatics, transported via the mesenteric collecting lymphatics through the lymphatic network en route to the blood, the role of lymph transport in the regulation of lipid metabolism is poorly understood. We have recently shown that high fructose diet-induced metabolic syndrome (MetSyn) rats exhibit impaired mesenteric lymphatic function. Dietary endotoxin readily associates with chylomicrons and are primarily absorbed through the mesenteric lymphatics along with many other gut peptides and hormones, suggesting that the primary trafficking of dietary endotoxins, such as, lipopolysaccharide (LPS) is via lymphatics. Hence, important questions remain unanswered: 1) what are the roles of lymphatic function in and responsiveness to dietary endotoxin and 2) how does that affect the progression of MetSyn. Our preliminary data show that immune cells, eosinophils and neutrophils are present on or adjacent to the lymphatic wall, and that the number of these immune cells on the lymphatic wall is decreased in LPS-induced inflamed mesenteric tissue. These data provide the basis for our central hypothesis: That dietary endotoxins alters the local cues (major cytokines of eosinophil and neutrophil: IL-4, IL-5, IL-8 and IL-13) in the mesenteric milieu that impairs lymphatic function and chylomicron transport, which leads to dyslipidemia and mesenteric adipose accumulation, both key pathologic determinants of the development of MetSyn. We will use the high-fructose and high-fat diet-induced MetSyn rat models and a LPS-induced inflammation model to determine the roles of the lymphatic system in the pathophysiology of MetSyn.
Specific Aims are: 1) To demonstrate the linkages between dietary endotoxins, pro-inflammatory cytokines and lymphatic function during the development of MetSyn;2) To determine the functional consequences and molecular mechanisms of reduced lymph transport in the development of MetSyn;and 3) To test the roles of micro RNAs (miRs) that interconnect the regulation of IL-8, IL-4, IL-5 and IL-13 in modulating lymphatic function during the development of MetSyn. We will use whole-mount mesenteric preparations for immunohistochemical studies, in situ preparations for lymph flow and lymphatic contractility, isolated/cannulated vessels for contractile characteristics of lymphatics, wire-myograph studies for length- tension and force-calcium measurements. These experiments will specifically address how dietary endotoxins effect the M1 and M2 macrophage polarization on lymphatics and the mechanisms by which the eosinophil and neutrophil interleukins, IL-4, IL-5, IL-8 and IL-13, and miR-19a, 93, 200c and 203 in lymphatic muscle cells regulate the lymphatic structure and function. Thus, this proposal will identify important targets bridging the mesentery milieu and lymphatic function, which could potentially provide diagnostic tools and/or therapies to improve lymph transport, and thus improve health in chronic inflammatory conditions such as MetSyn.

Public Health Relevance

Metabolic syndrome is defined by the cluster of three or more of the following physiologic and metabolic abnormalities: central obesity, elevated fasting glucose levels, dyslipidemia, hypertension, and intimal atherogenesis, which lead to increased risk for the development of type 2 diabetes, fatty liver disease and cardiovascular diseases. The lymphatic system plays critical roles in maintaining body fluid, macromolecular homeostasis, lipid absorption and transport, and immune system function. In this study we will identify the mechanisms by which metabolic syndrome conditions affect the lymph transport and lymphatic pumping activity, and how the dysfunction of lymphatics contribute to the progression of disease. Thus, this proposal will identify important targets bridging the mesentery milieu and lymphatic function, which could potentially provide diagnostic tools and/or therapies to improve lymph transport, and thus improve health in chronic inflammatory conditions such as metabolic syndrome and others.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK099221-01
Application #
8562940
Study Section
Special Emphasis Panel (ZRG1-DKUS-D (57))
Program Officer
Carrington, Jill L
Project Start
2013-09-01
Project End
2016-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$292,000
Indirect Cost
$92,000
Name
Texas A&M University
Department
Physiology
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
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Zawieja, Scott D; Wang, Wei; Chakraborty, Sanjukta et al. (2016) Macrophage alterations within the mesenteric lymphatic tissue are associated with impairment of lymphatic pump in metabolic syndrome. Microcirculation 23:558-570
Cromer, Walter; Wang, Wei; Zawieja, Scott D et al. (2015) Colonic Insult Impairs Lymph Flow, Increases Cellular Content of the Lymph, Alters Local Lymphatic Microenvironment, and Leads to Sustained Inflammation in the Rat Ileum. Inflamm Bowel Dis 21:1553-63
Chakraborty, Sanjukta; Zawieja, David C; Davis, Michael J et al. (2015) MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation. Am J Physiol Cell Physiol 309:C680-92
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Chakraborty, Sanjukta; Zawieja, Scott D; Wang, Wei et al. (2015) Lipopolysaccharide modulates neutrophil recruitment and macrophage polarization on lymphatic vessels and impairs lymphatic function in rat mesentery. Am J Physiol Heart Circ Physiol 309:H2042-57
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Zawieja, Scott D; Wang, Wei; Wu, Xin et al. (2012) Impairments in the intrinsic contractility of mesenteric collecting lymphatics in a rat model of metabolic syndrome. Am J Physiol Heart Circ Physiol 302:H643-53