Regulatory effects of arachidonate 5-lipoxygenase on hepatic microsomal TG transfer protein activity and VLDL-triglyceride and apoB secretion in obese mice.
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 (PPARalpha) 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.
López-Parra
Marta
M
Department of Biochemistry and Molecular Genetics, Centro de Investigación Biomédica Esther Koplowitz (CIBEK), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona 08036, Spain.
Titos
Esther
E
Horrillo
Raquel
R
Ferré
Natàlia
N
González-Périz
Ana
A
Martínez-Clemente
Marcos
M
Planagumà
Anna
A
Masferrer
Jaime
J
Arroyo
Vicente
V
Clària
Joan
J
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D014280:Triglycerides / Q000378:metabolism*
D001055:Apolipoproteins B; D002352:Carrier Proteins; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C030106:very low density lipoprotein triglyceride; D001094:Arachidonate 5-Lipoxygenase