In vivo role of NAD(P)H : quinone oxidoreductase 1 (NQO1) in the regulation of intracellular redox state and accumulation of abdominal adipose tissues

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoprotein that utilizes NAD (P)II as an electron donor, catalyzing the two-electron reduction and detox ification of quinones and their derivatives. NQO1-/- mice deficient in NQO1 activity and protein were generated in our laboratory (Rajendirane, V,, Jo seph, P., Lee, Y, H., Kimura, S., Klein-Szanto, A. J. P., Gonzalez, F, J., and Jaiswal, A. R. (1998) J. Biol. Chem. 273, 7382-7389). Mice lacking a fu nctional NQO1 gene (NQO1-/-) were born normal and reproduced adeptly as the wild-type NQO1+/+ mice. In the present report, we show that NQO1-/- mice e xhibit significantly lower levels of abdominal adipose tissue as compared w ith the wild-type mice. The NQO1-/- mice showed lower blood levels of gluco se, no change in insulin, and higher levels of triglycerides, P-hydroxy but yrate, pyruvate, lactate, and glucagon as compared with wild-type mice. Ins ulin tolerance test demonstrated that the NQO1-/- mice are insulin resistan t. The NQO1-/- mice livers also showed significantly higher levels of trigl ycerides, lactate, pyruvate, and glucose. The liver glycogen reserve was fo und decreased in NQO1-/- mice as compared with mild-type mice, The livers a nd kidneys from NQO1-/- mice also showed significantly lower levels of pyri dine nucleotides but an increase in the reduced/oxidized NAD(P)H: NAD(P) ra tio. These results suggested that loss of NQO1 activity alters the intracel lular redox status by increasing the concentration of NAD(P)H. This leads t o a reduction in pyridine nucleotide synthesis and reduced glucose and fatt y acid metabolism. The alterations in metabolism due to redox changes resul t in a significant reduction in the amount of abdominal adipose tissue.