Neutral sphingomyelinase-2 and glucocorticoid receptor

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Abstract from Prime Award Some of the leading causes of death among the elderly are a number of chronic conditions associated with persistent low-grade inflammation in which IL-1β has a central role. One of the paths by which low-grade inflammation contributes to aging-associated diseases is by interfering with the ability of the host to maintain homeostasis. The experiments from the previous funding period provided evidence for a novel pathway by which inflammation may deteriorate a major regulatory mechanism. Specifically, we found that IL-1β increases the levels of glucocorticoid receptor, an effect especially potent in aged animals, leading to an augmented response to glucocorticoids. This proposal investigates the mechanisms and impact of IL-1β control of glucocorticoid -dependent functions in the elderly. The proposed studies will do that in the context of fatty liver, a condition of paramount health importance for public health, which is frequent in the elderly and, in some cases, may progress to non-alcoholic fatty liver disease. In aim 1, a series of in vitro studies will identify the mechanisms for IL-1β-induced increases in GR levels and delineate some of the functional consequences in hepatocytes. A candidate approach paralleled by an unbiased genome wide analyses using ChipSeq and mRNA arrays will determine the degree of IL-1β impact on GR-dependent transcriptional regulation of gene expression in the liver. Specific aim 2 is dedicated to investigating the impact IL-1β has on GR responses in vivo using a diet-induced mouse model of steatosis and metabolic syndrome. The magnitude of IL-1β response in hepatocytes will be modulated in vivo or in vitro by targeting a key component of its signaling cascade, nSMase2. The consequences on lipogenesis, gluconeogenesis and insulin sensitivity will be main readouts. Glucocorticoid hypersensitivity underlies many aging-associated disease. The chronic used of glucocorticoids for the treatment of inflammation is associated with significant side effects, particularly in the elderly. Therefore, by uncovering the mechanisms that regulate glucocorticoid response in the liver during aging, the proposed studies have the potential to discover both basic mechanisms of aging, as well as novel approaches to manage unwanted side effects of chronic use of glucocorticoids.