Identification of ALOX5 as a gene regulating adiposity and pancreatic function

Abstract

Aims/hypothesis We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 −/− ) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function. Methods Alox5 −/− and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments. Results Beginning at 12 weeks of age, Alox5 −/− mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p< 0.05). Although Alox5 −/− mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed Diabetologia (2008) that Alox5 −/− mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm 2 islet (p < 0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 −/− islets were significantly lower than in WT islets (p <0.05) and accompanied by a three-to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05). Conclusions/interpretation These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease.

Polyunsaturated Fatty Acids and Cardiovascular Disease: Implications for Nutrigenetics

“…Subsequent reports have also suggested the involvement of 5-LO in atherosclerosis-related phenotypes as well [29,30] , but this has not been consistently observed across all studies [31] . More recently, 5-LO has been implicated in metabolic traits, such as adiposity, bone density, and pancreatic dysfunction [32,33] . Biochemical evidence in human coronary and carotid plaques also provides evidence that the 5-LO pathway promotes proatherogenic processes.…”

ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

“…Their expression is increased in adipose tissue of obese patients and animals with insulin resistance (11,12,23,24). Nevertheless, mice deficient for ALOX5 present an increase in body weight and body fat content and are more prone to fat accumulation when fed an HFD (13,25,26). In addition, other reports on the effects of the genetic disruption of Alox5 on glucose homeostasis are contradictory (13,25,26).…”

“…Nevertheless, mice deficient for ALOX5 present an increase in body weight and body fat content and are more prone to fat accumulation when fed an HFD (13,25,26). In addition, other reports on the effects of the genetic disruption of Alox5 on glucose homeostasis are contradictory (13,25,26). Thus, the role of ALOX5/ALOX5AP in the development of obesity and insulin resistance remains to be clearly established.…”

5-Lipoxygenase Activating Protein Signals Adipose Tissue Inflammation and Lipid Dysfunction in Experimental Obesity

“…In fact, FLAP is overexpressed in the adipose tissue of patients and experimental animals *Department of Biochemistry and Molecular Genetics and ‡ Liver Unit, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute, Esther Koplowitz Biomedical Research Center; and with obesity and insulin resistance (8,9). In addition, 5-LO products have pleiotropic actions on adipose fat accumulation and pancreatic function in mice (10,11). Moreover, we recently identified a novel steatogenic role for 5-LO in the liver of obese ob/ob mice, through mechanisms involving the regulation of hepatic microsomal TG transfer protein activity and very low density lipoprotein-TG and apolipoprotein B secretion (12).…”