Regulatory effects of Arachidonate 5-lipoxygenase on hepatic MTP activity and VLDL-TG and ApoB secretion in obese mice

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

Department of Biochemistry and Molecular Genetics, Hospital Clínic-University of Barcelona, Barcelona 08036

Corresponding Author: 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 down-regulated genes involved in hepatic fatty acid uptake (i.e. L-FABP and FAT/CD36) and normalized PPARalpha and acyl-CoA oxidase expression, whereas the expression of lipogenic genes (i.e. 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.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

R. Horrillo, A. Gonzalez-Periz, M. Martinez-Clemente, M. Lopez-Parra, N. Ferre, E. Titos, E. Moran-Salvador, R. Deulofeu, V. Arroyo, and J. Claria
5-Lipoxygenase Activating Protein Signals Adipose Tissue Inflammation and Lipid Dysfunction in Experimental Obesity
J. Immunol., April 1, 2010; 184(7): 3978 - 3987.
[Abstract] [Full Text] [PDF]

A. Gonzalez-Periz, R. Horrillo, N. Ferre, K. Gronert, B. Dong, E. Moran-Salvador, E. Titos, M. Martinez-Clemente, M. Lopez-Parra, V. Arroyo, et al.
Obesity-induced insulin resistance and hepatic steatosis are alleviated by {omega}-3 fatty acids: a role for resolvins and protectins
FASEB J, June 1, 2009; 23(6): 1946 - 1957.
[Abstract] [Full Text] [PDF]