Chronic exposure to an insulin-containing lipogenic stimulus results in ectopic cytoplasmic lipid accumulation and altered pro-inflammatory function in mast cells

Greineisen, William Ernest
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[Honolulu] : [University of Hawaii at Manoa], [May 2013]
This thesis presents evidence that mast cells (MC) chronically exposed to insulin respond by developing steatotic levels of cytosolic lipid bodies, suggesting that immunocytes, like hepatocytes and myocytes, are sites of lipid sequestration in response to dysregulated insulin levels. This ectopic lipid accumulation influences mast cell functionality, biasing mast cell phenotype towards the production of bioactive lipid mediators (LTC4) and away from the release of histamine and other secretory granule components. In the current study we present an analysis of the whole cell and lipid body lipidome in control, and insulin-exposed mast cells. Our data show a significant upregulation in lipid-associated pro-inflammatory precursor molecules in response to chronic insulin exposure. We also show that the lipid body population in these cells are heterogeneous to a previously unsuspected degree. Moreover, due to the intimate relationship between the endoplasmic reticulum (ER) and lipid body production, we tested the hypothesis that the ER may be altered in response to chronic insulin exposure. Indeed, our data show that (in a manner analogous to observations in hepatocytes from obese models) the ER is reprogrammed towards a lipogenic phenotype, is morphologically distended, is compromised as a calcium store and exhibits certain indicators of a unfolded protein response (UPR)/ER stress response in response to chronic insulin. Taken together, these data show that chronic insulin exposure in a model mast cell system drives lipidomic remodeling in a manner that alters lipid body formation and mast cell proinflammatory function.
Ph.D. University of Hawaii at Manoa 2013.
Includes bibliographical references.
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