Role of the electrophilic lipid peroxidation product 4-hydroxynonenal in the development and maintenance of obesity in mice.
The lipid peroxidation product 4-hydroxynonenal (4-HNE) is a signaling mediator with wide-ranging biological effects. In this paper, we report that disruption of mGsta4, a gene encoding the 4-HNE-conjugating enzyme mGSTA4-4, causes increased 4-HNE tissue levels and is accompanied by age-dependent development of obesity which precedes the onset of insulin resistance in 129/sv mice. In contrast, mGsta4 null animals in the C57BL/6 genetic background have normal 4-HNE levels and remain lean, indicating a role of 4-HNE in triggering or maintaining obesity. In mGsta4 null 129/sv mice, the expression of the acetyl-CoA carboxylase (ACC) transcript is enhanced several-fold with a concomitant increase in the tissue level of malonyl-CoA. Also, mitochondrial aconitase is partially inhibited, and tissue citrate levels are increased. Accumulation of citrate could lead to allosteric activation of ACC, further augmenting malonyl-CoA levels. Aconitase may be inhibited by 4-HNE or by peroxynitrite generated by macrophages which are enriched in white adipose tissue of middle-aged mGsta4 null 129/sv mice and, upon lipopolysaccharide stimulation, produce more reactive oxygen species and nitric oxide than macrophages from wild-type mice. Excessive malonyl-CoA synthesized by the more abundant and/or allosterically activated ACC in mGsta4 null mice leads to fat accumulation by the well-known mechanisms of promoting fatty acid synthesis and inhibiting fatty acid beta-oxidation. Our findings complement the recent report that obesity causes both a loss of mGSTA4-4 and an increase in the level of 4-HNE [Grimsrud, P. A., et al. (2007) Mol. Cell. Proteomics 6, 624-637]. The two reciprocal processes are likely to establish a positive feedback loop that would promote and perpetuate the obese state.
Singh
Sharda P
SP
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Niemczyk
Maciej
M
Saini
Deepti
D
Awasthi
Yogesh C
YC
Zimniak
Ludwika
L
Zimniak
Piotr
P
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000154:Aconitate Hydratase / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000447:Aldehydes / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D019343:Citric Acid / Q000378:metabolism; D005260:Female; D005951:Glucose Tolerance Test; D005982:Glutathione Transferase / Q000172:deficiency / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology; D015227:Lipid Peroxidation / Q000502:physiology*; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000139:chemically induced*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000097382:CD68 Molecule
D000103:Acetyl-CoA Carboxylase; D000154:Aconitate Hydratase; D000447:Aldehydes; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001786:Blood Glucose; D019343:Citric Acid; D005982:Glutathione Transferase; D008316:Malonyl Coenzyme A; D017382:Reactive Oxygen Species; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C529117:GSTA4-4 protein, mouse; C498191:Acacb protein, mouse; C027576:4-hydroxy-2-nonenal