The role of 12-lipoxygenase in pancreatic -cells (Review).
Leukocyte type 12-lipoxygenase (12-LO) catalyzes the conversion of arachidonic acid (AA; C20:4) to 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and linoleic acid (LA; C18:2) to 13-hydroperoxyoctadecadienoic acid (13-HPODE). Previous studies have demonstrated that 12-LO, but not 5- or 15-lipoxygenase (5-LO, 15-LO respectively), is specifically expressed in pancreatic -cells and is involved in regulating glucose-stimulated insulin secretion. Lipoxygenase products also have been linked with inflammatory pathways in endothelial cells, kidney mesangial cells, inflammatory bowel disease, and corneal epithelial cells. Therefore, 12-LO may play a role in cytokine mediated inflammation in pancreatic beta-cells (i.e. beta -cell dysfunction and cytotoxicity). Cytokines such as IL-1 stimulate both de novo 12-LO protein synthesis and enzyme activity in pancreatic beta-cells. The products generated by 12-LO may ultimately be involved in cellular events that lead to lipid peroxidation. Hydroperoxide and free radical production in beta-cells can activate intracellular signaling pathways that lead to cell death or may directly damage mitochondrial and plasma membranes. Increased 12-LO expression has also been found in islets from prediabetic Zucker fatty rats, a model that demonstrates insulin secretory defects similar to human type 2 diabetes. In this review, we present an overview of the 12-LO pathway in regulating glucose-stimulated insulin secretion in beta-cells as well as more recent data which supports the hypothesis that the 12-LO pathway participates in cytokine mediated beta-cell dysfunction and cytotoxicity.
Bleich
D
D
Division of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center, Duarte, CA 91010, USA.
Chen
S
S
Gu
J L
JL
Nadler
J L
JL
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000502:physiology*; D016207:Cytokines / Q000633:toxicity; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats
D016207:Cytokines; D007328:Insulin; D001092:Arachidonate 12-Lipoxygenase; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat