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Journal of Lipid Research, Vol. 49, 2513-2523, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Regulatory effects of arachidonate 5-lipoxygenase on hepatic microsomal TG transfer protein activity and VLDL-triglyceride and apoB secretion in obese mice

Marta López-Parra^*, Esther Titos^*, Raquel Horrillo^*, Natàlia Ferré^*, Ana González-Périz^*, Marcos Martínez-Clemente^*, Anna Planagumà^*, Jaime Masferrer, Vicente Arroyo and Joan Clària^1,*

^* Department of Biochemistry and Molecular Genetics, Centro de Investigación Biomédica Esther Koplowitz (CIBEK) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona 08036, Spain
Liver Unit, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz (CIBEK) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona 08036, Spain
Pfizer, St. Louis, MO 63017

Published, JLR Papers in Press, July 21, 2008.

Supported by a grant from the Ministerio de Educación y Ciencia (MEC) (SAF 06/03191). Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD) is funded by the Instituto de Salud Carlos III. M. López-Parra has a contract with Instituto de Salud Carlos III, E. Titos is a recipient of a CIBEREHD contract, and N. Ferré is under a MEC Juan de la Cierva contract. A. González-Périz (BES-2004-5054) and M. Martínez-Clemente (BES-2007-16147) are supported by MEC fellowships. R. Horrillo is supported by Generalitat de Catalunya-European Social Funds (2006FI-00091).

¹ To whom correspondence should be addressed. e-mail: jclaria{at}clinic.ub.es

As 5-lipoxygenase (5-LO) is an emerging target in obesity and insulin resistance, we have investigated whether this arachidonate pathway is also implicated in the progression of obesity-related fatty liver disease. Our results show that 5-LO activity and 5-LO-derived product levels are significantly elevated in the liver of obese ob/ob mice with respect to wild-type controls. Treatment of ob/ob mice with a selective 5-LO inhibitor exerted a remarkable protection from hepatic steatosis as revealed by decreased oil red-O staining and reduced hepatic triglyceride (TG) concentrations. In addition, 5-LO inhibition in ob/ob mice downregulated genes involved in hepatic fatty acid uptake (i.e., L-FABP and FAT/CD36) and normalized peroxisome proliferator-activated receptor alpha (PPAR) and acyl-CoA oxidase expression, whereas the expression of lipogenic genes [i.e., fatty acid synthase (FASN) and SREBP-1c] remained unaltered. Furthermore, 5-LO inhibition restored hepatic microsomal TG transfer protein (MTP) activity in parallel with a stimulation of hepatic VLDL-TG and apoB secretion in ob/ob mice. Consistent with these findings, 5-LO products directly inhibited MTP activity and triggered cytosolic TG accumulation in CC-1 cells, a murine hepatocyte cell line. Taken together, these findings identify a novel steatogenic role for 5-LO in the liver through mechanisms involving the regulation of hepatic MTP activity and VLDL-TG and apoB secretion.

Supplementary key words arachidonate 5-LO • VLDL-TG • hepatic steatosis

Abbreviations: 5-LO, 5-lipoxygenase; ACO, acyl-CoA oxidase; DPBS, Dulbecco's Phosphate Buffered Saline; EMEM, Eagle's minimal essential medium; FBS, fetal bovine serum; FASN, fatty acid synthase; FAT/CD36, fatty acid translocase; L-FABP, liver fatty acid-binding protein; LTB₄, leukotriene B₄; LTD₄, leukotriene D₄; MTP, microsomal TG transfer protein; NEAA, nonessential amino acids; OCT, optimal cutting temperature; PPAR, peroxisome proliferator-activated receptor alpha; SREBP-1c, sterol response element-binding protein-1c; TG, triglyceride

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