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Toxicologic Pathology
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Decreased Longevity and Enhancement of Age-Dependent Lesions in Mice Lacking the Nuclear Receptor Peroxisome Proliferator-Activated Receptor {alpha} (PPAR{alpha})

Paul Howroyd

Experimental Pathology Laboratories, Inc., PO Box 12766, Research Triangle Park, North Carolina 27709, USA, CT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA

Cyndi Swanson

CT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA

Corrie Dunn

CT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA

Russell C. Cattley

CT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA

J. Christopher Corton

CT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA, ccorton{at}msn.com, Toxico Genomics, Chapel Hill, North Carolina 27514, USA

The nuclear receptor peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) is activated by peroxisome proliferators (PP), a large class of structurally diverse xenobiotic chemicals, hypolipidemic drugs, and endogenous lipids. PPAR{alpha} alters the transcriptional programs of genes whose functions include lipid metabolism, inflammation, cell fate, and stress responses in liver, heart, kidney, and skin. Many of these genes are also under control of PPAR{alpha} in the absence of exogenous peroxisome proliferator exposure. Mice that lack PPAR {alpha} (PPAR{alpha}-null mice) exhibit a number of defects in lipid metabolism and accumulate lipids in the liver. Here, we compared the age-dependent lesions in the liver, kidney, and heart in PPAR{alpha}-null mice with those observed in wild-type SV129 mice, in the absence of exogenous chemical exposure. Groups of mice were sacrificed, at 6, 12, 18, 21, or 24 months of age, or allowed to age until moribund or found dead. PPAR{alpha}-null mice had decreased longevity, due to a variety of causes. Statistically significant differences in the occurrence of a number of lesions between strains was observed. Hepatocellular carcinomas and multiple hepatocellular adenomas occurred in PPAR{alpha}-null mice but not wild type mice. Various nonneoplastic spontaneous aging lesions occurred at higher incidence, shorter latency, or increased severity in PPAR{alpha}-null mice compared with wild-type mice. In the liver, these included vacuolated hepatocytes and sinusoidal cells and mixed cell inflammation. The kidneys of PPAR{alpha}-null mice exhibited higher incidences and severities of cortical mineralization. Minimal myocardial mineralization occurred at a higher incidence in PPAR{alpha}-null mice. Our results imply that PPAR{alpha} delays the development of some spontaneous lesions associated with aging in the liver, kidney, and heart of SV129 mice.

Key Words: Peroxisome proliferator-activated receptor {alpha} • peroxisome proliferator • heart • kidney • liver • aging.

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Toxicologic Pathology, Vol. 32, No. 5, 591-599 (2004)
DOI: 10.1080/01926230490515283
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