Role of the electrophilic lipid peroxidation product 4-hydroxynonenal in the development and maintenance of obesity in mice.

Abstract

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.

• Authors: Sharda P Singh, Maciej Niemczyk, Deepti Saini, Yogesh C Awasthi, Ludwika Zimniak, Piotr Zimniak
• Journal: Biochemistry (Biochemistry) Vol. 47 Issue 12 Pg. 3900-11 (Mar 25 2008) ISSN: 0006-2960 [Print] United States
• PMID: 18311940 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Aldehydes
• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• Blood Glucose
• CD68 protein, mouse
• Reactive Oxygen Species
• Citric Acid
• Malonyl Coenzyme A
• GSTA4-4 protein, mouse
• Glutathione Transferase
• Aconitate Hydratase
• Acacb protein, mouse
• Acetyl-CoA Carboxylase
• 4-hydroxy-2-nonenal

Topics

• Acetyl-CoA Carboxylase (metabolism)
• Aconitate Hydratase (metabolism)
• Aging (physiology)
• Aldehydes (metabolism, pharmacology)
• Animals
• Antigens, CD (metabolism)
• Antigens, Differentiation, Myelomonocytic (metabolism)
• Blood Glucose (metabolism)
• Citric Acid (metabolism)
• Female
• Glucose Tolerance Test
• Glutathione Transferase (deficiency, physiology)
• Insulin Resistance (physiology)
• Lipid Peroxidation (physiology)
• Male
• Malonyl Coenzyme A (metabolism)
• Mice
• Mice, Inbred C57BL
• Obesity (chemically induced)
• Reactive Oxygen Species (metabolism)