In vivo role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the regulation of intracellular redox state and accumulation of abdominal adipose tissue.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoprotein that utilizes NAD(P)H as an electron donor, catalyzing the two-electron reduction and detoxification of quinones and their derivatives. NQO1-/- mice deficient in NQO1 activity and protein were generated in our laboratory (Rajendirane, V., Joseph, P., Lee, Y. H., Kimura, S., Klein-Szanto, A. J. P., Gonzalez, F. J., and Jaiswal, A. K. (1998) J. Biol. Chem. 273, 7382-7389). Mice lacking a functional NQO1 gene (NQO1-/-) were born normal and reproduced adeptly as the wild-type NQO1+/+ mice. In the present report, we show that NQO1-/- mice exhibit significantly lower levels of abdominal adipose tissue as compared with the wild-type mice. The NQO1-/- mice showed lower blood levels of glucose, no change in insulin, and higher levels of triglycerides, beta-hydroxy butyrate, pyruvate, lactate, and glucagon as compared with wild-type mice. Insulin tolerance test demonstrated that the NQO1-/- mice are insulin resistant. The NQO1-/- mice livers also showed significantly higher levels of triglycerides, lactate, pyruvate, and glucose. The liver glycogen reserve was found decreased in NQO1-/- mice as compared with wild-type mice. The livers and kidneys from NQO1-/- mice also showed significantly lower levels of pyridine nucleotides but an increase in the reduced/oxidized NAD(P)H:NAD(P) ratio. These results suggested that loss of NQO1 activity alters the intracellular redox status by increasing the concentration of NAD(P)H. This leads to a reduction in pyridine nucleotide synthesis and reduced glucose and fatty acid metabolism. The alterations in metabolism due to redox changes result in a significant reduction in the amount of abdominal adipose tissue.
Gaikwad
A
A
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA.
Long
D J
DJ
Stringer
J L
JL
Jaiswal
A K
AK
D000005:Abdomen; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D038181:FMN Reductase; D005260:Female; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D014280:Triglycerides; D009243:NAD; D009249:NADP; D038181:FMN Reductase; D009247:NADH, NADPH Oxidoreductases