Year of Publication

2010

Degree Name

Doctor of Philosophy (PhD)

Document Type

Dissertation

College

Medicine

Department

Nutritional Sciences

First Advisor

Dr. Nancy R. Webb,

Abstract

The secretory phospholipase A2 (sPLA2) family is a group of enzymes that catalyze the hydrolysis of glycerophospholipids at the sn-2 position, generating free fatty acids and lysophospholipids. The sPLA2 family has been implicated in various physiological and pathological activities. Eleven sPLA2’s have been identified in mammals, and the function of each isoform likely reflects its tissue distribution and substrate specificity. Studies in vitro indicate that Group X (GX) sPLA2 potently releases arachidonic acid (AA) and lysophosphatidylcholine from mammalian cell membranes. Interestingly, some of the biological effects mediated by GX sPLA2 in vitro are independent of its catalytic activity. Despite a wealth of in vitro data, the in vivo function of GX sPLA2 still remains to be elucidated.

In order to define the function of GX sPLA2 in vivo, our laboratory recently generated C57BL/6 mice with targeted deletion of GX sPLA2 (GX-/- mice). When fed a normal rodent diet, GX-/- mice gained significantly more weight and had increased adiposity compared to GX+/+ mice, which was not attributable to alterations in food consumption or energy expenditure. When treated with adipogenic stimuli ex vivo, stromal vascular cells isolated from adipose tissue of GX-/- mice accumulated significantly more (20%) triglyceride compared to cells from GX+/+ mice. Conversely, overexpression of GX sPLA2, but not catalytically inactive GX sPLA2, resulted in a significant 50% reduction in triglyceride accumulation in OP9 adipocytes. The induction of adipogenic genes, including PPAR-γ, SREBP-1c, SCD-1 and FAS was also significantly blunted by 50-80% in OP9 cells overexpressing GX sPLA2. Activation of the liver X receptor (LXR), a nuclear receptor known to upregulate adipogenic gene expression, was suppressed in 3T3-L1 and OP9 cells when GX sPLA2 was overexpressed. Thus, hydrolytic products generated by GX sPLA2 negatively regulate adipogenesis, possibly by suppressing LXR activation.

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Nutrition Commons

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