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Title 

Cytosolic NADP+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism

Authors 

H J KohS M LeeB G SohnS H LeeZ Y RyooKyu Tae ChangJ W ParkD C ParkB J SongR L VeechH SongT L Huh

Publisher 

American Society for Biochemistry and Molecular Biology

Issue Date 

2004

Citation 

Journal of Biological Chemistry, vol. 279, no. 38, pp. 39968-39974

Keywords 

chemical reactionsDNAlipidsconfactorsenzymatic reactionsmitochondriaacetyl coenzyme Acomplementary DNAfatisocitrate dehydrogenase

Abstract 

NADPH is an essential cofactor for many enzymatic reactions including glutathione metabolism and fat and cholesterol biosynthesis. We have reported recently an important role for mitochondrial NADP+-dependent isocitrate dehydrogenase in cellular defense against oxidative damage by providing NADPH needed for the regeneration of reduced glutathione. However, the role of cytosolic NADP+-dependent isocitrate dehydrogenase (IDPc) is still unclear. We report here for the first time that IDPc plays a critical role in fat and cholesterol biosynthesis. During differentiation of 3T3-L1 adipocytes, both IDPc enzyme activity and its protein content were increased in parallel in a time-dependent manner. Increased expression of IDPc by stable transfection of IDPc cDNA positively correlated with adipogenesis of 3T3-L1 cells, whereas decreased IDPc expression by an antisense IDPc vector retarded adipogenesis. Furthermore, transgenic mice with overexpressed IDPc exhibited fatty liver, hyperlipidemia, and obesity. In the epididymal fat pads of the transgenic mice, the expressions of adipocyte-specific genes including peroxisome proliferator-activated receptor γ were markedly elevated. The hepatic and epididymal fat pad contents of acetyl-CoA and malonyl-CoA in the transgenic mice were significantly lower, whereas the total triglyceride and cholesterol contents were markedly higher in the liver and serum of transgenic mice compared with those measured in wild type mice, suggesting that the consumption rate of those lipogenic precursors needed for fat biosynthesis must be increased by elevated IDPc activity. Taken together, our findings strongly indicate that IDPc would be a major NADPH producer required for fat and cholesterol synthesis.

ISSN 

0021-9258

Link 

http://dx.doi.org/10.1074/jbc.M402260200

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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