Physiological Roles of Group X-secreted Phospholipase A2 in Reproduction, Gastrointestinal Phospholipid Digestion, and Neuronal Function

Abstract

Although the secreted phospholipase A 2 (sPLA 2 ) family has been generally thought to participate in pathologic events such as inflammation and atherosclerosis, relatively high and constitutive expression of group X sPLA 2 (sPLA 2 -X) in restricted sites such as reproductive organs, the gastrointestinal tract, and peripheral neurons raises a question as to the roles played by this enzyme in the physiology of reproduction, digestion, and the nervous system. Herein we used mice with gene disruption or transgenic overexpression of sPLA 2 -X to clarify the homeostatic functions of this enzyme at these locations. Our results suggest that sPLA 2 -X regulates 1) the fertility of spermatozoa, not oocytes, beyond the step of flagellar motility, 2) gastrointestinal phospholipid digestion, perturbation of which is eventually linked to delayed onset of a lean phenotype with reduced adiposity, decreased plasma leptin, and improved muscle insulin tolerance, and 3) neuritogenesis of dorsal root ganglia and the duration of peripheral pain nociception. Thus, besides its inflammatory action proposed previously, sPLA 2 -X participates in physiologic processes including male fertility, gastrointestinal phospholipid digestion linked to adiposity, and neuronal outgrowth and sensing.

A new era of secreted phospholipase A2

“…1 and 2 ) ( 64,70,74,112,121,132,134,135 ). It is now obvious that individual sPLA 2 s play unique and tissue-specifi c roles by acting on extracellular phospholipids, which include adjacent cell membranes, noncellular lipid components, and foreign phospholipids, such as those in microbes and food.…”

“…In humans, polymorphisms in the PLA2G10 gene are linked to a decreased risk of recurrent cardiovascular events ( 125 ), or not associated with plasma sPLA 2 activity or with coronary heart disease risk ( 126 ). Additionally, in different studies, Pla2g10 Ϫ / Ϫ mice display altered or unaltered macrophage functions ( 127 ) or increased or decreased adiposity ( 121,128 ). Although some of these studies were performed under the assumption that sPLA 2 -X is expressed in macrophages or adipocytes, our own investigations have shown that its expression in these cells is low or almost undetectable.…”

A new era of secreted phospholipase A2

“…Unlike sPLA 2 -V, however, sPLA 2 -X does not infl uence the Th2 response itself, because antigen-sensitized Pla2g10 Ϫ / Ϫ and wild-type mice have similar IgE and IL-4 levels ( 94 ). Pla2g10 Ϫ / Ϫ mice are also protected from myocardial infarction or aneurysm (118)(119)(120), show a reduced infl ammatory pain ( 121 ), have an increased adrenal steroidogenesis ( 122 ), and exhibit alteration in insulin secretion by pancreatic ␤ cells, perhaps as a result of reduced prostaglandin E 2 (PGE 2 ) synthesis ( 123 ). However, several of the phenotypes reported for Pla2g10 Ϫ / Ϫ mice are controversial.…”

“…sPLA 2 -X is released from activated sperm cells during the acrosome reaction. Pla2g10 Ϫ / Ϫ spermatozoa display a poorer acrosome reaction and lower fertility, despite showing normal maturation and motility ( 121,132 ). Thus, sPLA 2 -X, a "reproductive sPLA 2 ," plays a specifi c role in sperm activation, boosting the acrosome reaction probably through production of some lipid products from sperm membranes in a paracrine or autocrine manner.…”

The Roles of the Secreted Phospholipase A2 Gene Family in Immunology

“…2. POTENTIAL ROLES OF sPLA 2 s: LESSONS FROM sPLA 2 TRANSGENIC MICE Some of the biological actions of sPLA 2 s in vivo have been addressed using sPLA 2 -overexpressing TG mice, which have provided informative insights into the potential pathophysiological roles of sPLA 2 s (Ait-Oufella et al, 2013;Cash, Kuhel, Goodin, & Hui, 2011;Curfs et al, 2008;Grass et al, 1996;Ivandic et al, 1999;Laine, Grass, & Nevalainen, 1999;Mulherkar et al, 2003;Ohtsuki et al, 2006;Sato et al, 2011Sato et al, , 2008Sato et al, , 2009Taketomi et al, 2013;Yamamoto et al, 2015Yamamoto et al, , 2011. In this section, we briefly summarize general aspects, rather than describing individual topics in detail, of sPLA 2 -TG mice.…”