Protection from hepatic lipid accumulation and inflammation by genetic ablation of 5-lipoxygenase.
Five-lipoxygenase (5-LO) has been postulated as a pathogenic factor in liver injury. Indeed, Alox5, the gene coding for 5-LO, is heavily over-expressed in experimental liver disease, in which 5-LO inhibition consistently ameliorates hepatic steatosis, inflammation and fibrosis. Herein, we report the findings in mice with targeted deletion of Alox5 as a proof of concept of the role of 5-LO in liver injury. Our findings demonstrate that ablation of Alox5 in mice confers protection against carbon tetrachloride-induced liver injury since hepatic necroinflammation, inflammatory infiltrate, hepatocyte ballooning and serum ALT levels were significantly reduced in Alox5-deficient mice. These mice also showed a lower degree of hepatic steatosis, which affected micro- and macrosteatosis to a similar extent. Moreover, microarray analysis revealed a differential profile of hepatic gene expression in Alox5-deficient mice, with a total of 117 genes differentially expressed in these animals. Functional grouping of these genes revealed that 28 (approximately 24% of total changes) were related to the category of lipid metabolism, including the lipogenic factors Lpin1, C/EBP, Fasn, Acly and Elovl6. Moreover, Ingenuity Pathway Analysis revealed lipid metabolism as the molecular/cellular function most affected by the loss of Alox5. These findings confirm at a genetic level that Alox5 plays a pathogenic role in the response of the liver to injury.
Department of Biochemistry and Molecular Genetics, Hospital Clínic, IDIBAPS, CIBEK, University of Barcelona, Barcelona 08036, Spain. esther.titos@ciberehd.org
Esther
E
Titos
Natàlia
N
Ferré
Juan José
JJ
Lozano
Raquel
R
Horrillo
Marta
M
López-Parra
Vicente
V
Arroyo
Joan
J
Clària
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency* / Q000235:genetics*; D001835:Body Weight / Q000235:genetics; D050260:Carbohydrate Metabolism / Q000235:genetics; D017353:Gene Deletion; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D009929:Organ Size / Q000235:genetics
D001094:Arachidonate 5-Lipoxygenase