Peroxisome proliferator-activated receptor-α regulates lipid homeostasis, but is not associated with obesity -: Studies with congenic mouse lines

被引:113
作者
Akiyama, TE
Nicol, CJ
Fievet, C
Staels, B
Ward, JM
Auwerx, J
Lee, SST
Gonzalez, FJ
Peters, JM
机构
[1] Penn State Univ, Dept Vet Sci, Ctr Mol Toxicol, University Pk, PA 16802 USA
[2] NCI, Met Lab, NIH, Bethesda, MD 20892 USA
[3] Inst Pasteur, INSERM, Dept Atherosclerose, F-59019 Lille, France
[4] NCI, Vet & Tumour Pathol Sect, Off Lab Anim Resources, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA
[5] Univ Strasbourg 1, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, F-67400 Illkirch Graffenstaden, France
[6] Chinese Univ Hong Kong, Dept Biochem, Shatin, Hong Kong, Peoples R China
关键词
D O I
10.1074/jbc.M107073200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Considerable controversy exists in determining the role of peroxisome proliferator-activated receptor-a (PPAR alpha) in obesity. Two purebred congenic strains of PPAR alpha -null mice were developed to study the role of this receptor in modulating lipid transport and storage. Weight gain and average body weight in wild-type and PPAR alpha -null mice on either an Sv/129 or a C57BL/6N background were not markedly different between genotypes from 3 to 9 months of age. However, gonadal adipose stores were significantly greater in both strains of male and female PPAR alpha -null mice. Hepatic accumulation of lipids was greater in both strains and sexes of PPAR alpha -null mice compared with wild-type controls. Administration of the peroxisome proliferator WY-14643 caused hepatomegaly, alterations in mRNAs encoding proteins that regulate lipid metabolism, and reduced serum triglycerides in a PPAR alpha -dependent mechanism. Constitutive differences in serum cholesterol and triglycerides in PPAR alpha -null mice were found between genetic backgrounds. Results from this work establish that PPAR alpha is a critical modulator of lipid homeostasis in two congenic mouse lines. This study demonstrates that disruption of the murine gene encoding PPAR alpha results in significant alterations in constitutive serum, hepatic, and adipose tissue lipid metabolism. However, an overt, obese phenotype in either of the two congenic strains was not observed. In contrast to earlier published work, this study establishes that PPAR alpha is not associated with obesity in mice.
引用
收藏
页码:39088 / 39093
页数:6
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