Metabolic Effects of Selective Deletion of Group VIA Phospholipase A2 from Macrophages or Pancreatic Islet Beta-Cells.

John Turk,Mary Wohltmann,Xiaoyong Lei,Sasanka Ramanadham,Cheryl Frankfater,Haowei Song

doi:10.3390/biom10101455

John Turk, Mary Wohltmann + Show 4 more

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https://doi.org/10.3390/biom10101455

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Abstract

To examine the role of group VIA phospholipase A2 (iPLA2β) in specific cell lineages in insulin secretion and insulin action, we prepared mice with a selective iPLA2β deficiency in cells of myelomonocytic lineage, including macrophages (MØ-iPLA2β-KO), or in insulin-secreting β-cells (β-Cell-iPLA2β-KO), respectively. MØ-iPLA2β-KO mice exhibited normal glucose tolerance when fed standard chow and better glucose tolerance than floxed-iPLA2β control mice after consuming a high-fat diet (HFD). MØ-iPLA2β-KO mice exhibited normal glucose-stimulated insulin secretion (GSIS) in vivo and from isolated islets ex vivo compared to controls. Male MØ-iPLA2β-KO mice exhibited enhanced insulin responsivity vs. controls after a prolonged HFD. In contrast, β-cell-iPLA2β-KO mice exhibited impaired glucose tolerance when fed standard chow, and glucose tolerance deteriorated further when introduced to a HFD. β-Cell-iPLA2β-KO mice exhibited impaired GSIS in vivo and from isolated islets ex vivo vs. controls. β-Cell-iPLA2β-KO mice also exhibited an enhanced insulin responsivity compared to controls. These findings suggest that MØ iPLA2β participates in HFD-induced deterioration in glucose tolerance and that this mainly reflects an effect on insulin responsivity rather than on insulin secretion. In contrast, β-cell iPLA2β plays a role in GSIS and also appears to confer some protection against deterioration in β-cell functions induced by a HFD.

Highlights

Glycerophospholipids are the most abundant molecular components of biological membrane bilayers and are both critical determinants of membrane structure and the source of signaling molecules produced from their hydrolysis by phospholipase enzymes
Loss of these actions of iPLA2β in β-cells provides a plausible explanation for the impaired glucose tolerance in global iPLA2β-null mice, the reduced insulin secretory response to glucose of islets isolated from global iPLA2β-null mice compared to their wild-type littermates, and the exaggerated deterioration in glucose tolerance for global iPLA2β-null mice fed a high-fat diet (HFD) compared to wild-type controls [23,24]
Because iPLA2β-derived 2-lysophosphatidic acid (LPA) appears to be required for monocyte migration in response to the cytokine Monocyte Chemoattractant-1 (MCP-1) [29,37,38,39], we postulated that iPLA2β-deficiency in cells of the monocyte/macrophage lineage might confer protection against the HFD-induced deterioration of insulin sensitivity because of a failure of iPLA2β-null monocytes to migrate into peripheral tissues and differentiate into macrophages

Summary

Introduction

Glycerophospholipids are the most abundant molecular components of biological membrane bilayers and are both critical determinants of membrane structure and the source of signaling molecules produced from their hydrolysis by phospholipase enzymes. Glycerophospholipids consist of a glycerol backbone with a phosphate ester in the sn-3 position that may form a phosphodiester linkage to a polar head-group, such as choline, ethanolamine, serine, inositol, or glycerol, inter alia. A fatty acid is esterified to the glycerol backbone in the sn-2 position of phospholipids, and in the sn-1 position there is an ester, ether, or vinyl ether linkage to a fatty acid, fatty alcohol, or fatty aldehyde residue, respectively. The PLA2 superfamily consists of at least 16 groups of structurally and functionally diverse enzymes that include secreted (sPLA2), cytosolic (cPLA2), calcium-independent (iPLA2), lipoprotein-associated (Lp-PLA2), and adipose-PLA2 (AdPLA). These enzymes play central roles in cellular lipid metabolism and signaling [1]

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