Peroxisome Proliferator-activated Receptor α-Isoform Deficiency Leads to Progressive Dyslipidemia with Sexually Dimorphic Obesity and Steatosis

• Published in: The Journal of biological chemistry Vol. 273; no. 45; pp. 29577 - 29585
• Main Authors: Costet, Philippe, Legendre, Christiane, Moré, Jean, Edgar, Alan, Galtier, Pierre, Pineau, Thierry
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.11.1998; American Society for Biochemistry and Molecular Biology
• Subjects: ADIPOSE TISSUES; ANIMAL TRANSGENIQUE; ANIMALES TRANSGENICOS; Animals; ARN MENSAJERO; ARN MESSAGER; Biochemistry; Biochemistry, Molecular Biology; BIOLOGICAL DIFFERENCES; BLOOD LIPIDS; CALORIC INTAKE; CELLS; CELLULE; CELULAS; CHOLESTEROL; COLESTEROL; DIFERENCIAS BIOLOGICAS; DIFFERENCE BIOLOGIQUE; ENERGY VALUE; FACTEUR DE TRANSCRIPTION; FACTORES DE TRANSCRIPCION; FATTY LIVER; Fatty Liver - complications; Fatty Liver - pathology; Female; FEMALES; FEMELLE; FOIE; FOSFOLIPIDOS; HEMBRA; HEMOLIPIDOS; HIGADO; HIGADO GRASO; Hyperlipidemias - complications; Hyperlipidemias - genetics; Life Sciences; LIPID METABOLISM; LIPIDE SANGUIN; LIPOPROTEINAS; LIPOPROTEINE; LIPOPROTEINS; LIVER; LOW DENSITY LIPOPROTEIN; MACHO; MALE; MALES; MESSENGER RNA; METABOLIC DISORDERS; METABOLISME DES LIPIDES; METABOLISMO DE LIPIDOS; MICE; Mice, Inbred C57BL; Mice, Knockout; MUTANT; MUTANTES; MUTANTS; Obesity - complications; OVERWEIGHT; PHOSPHATIDE; PHOSPHOLIPIDS; RATON; Receptors, Cytoplasmic and Nuclear - genetics; SEX; Sex Characteristics; SEXE; SEXO; SOBREPESO; SOURIS; STEATOSE HEPATIQUE; SURPOIDS; TEJIDO ADIPOSO; TISSU ADIPEUX; TRANSCRIPTION FACTORS; Transcription Factors - genetics; TRANSGENIC ANIMALS; TRASTORNOS METABOLICOS; TRIGLICERIDOS; TRIGLYCERIDE; TRIGLYCERIDES; TROUBLE DU METABOLISME; VALEUR ENERGETIQUE; VALOR ENERGETICO; VERY LOW DENSITY LIPOPROTEIN; HISTOLOGIE; PHARMACOLOGIE; SANTE; ADIPOGENESE
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.45.29577

The α-isoform of the peroxisome proliferator-activated receptor (PPARα) is a nuclear transcription factor activated by structurally diverse chemicals referred to as peroxisome proliferators. Activators can be endogenous molecules (fatty acids/steroids) or xenobiotics (fibrate lipid-lowering drugs). Upon pharmacological activation, PPARα modulates target genes encoding lipid metabolism enzymes, lipid transporters, or apolipoproteins, suggesting a role in lipid homeostasis. Transgenic mice deficient in PPARα were shown to lack hepatic peroxisomal proliferation and have an impaired expression and induction of several hepatic target genes. Young adult males show hypercholesterolemia but normal triglycerides. Using a long term experimental set up, we identified these mice as a model of monogenic, spontaneous, late onset obesity with stable caloric intake and a marked sexual dimorphism. Serum triglycerides, elevated in aged animals, are higher in females that develop a more pronounced obesity than males. The latter show a marked and original centrilobular-restricted steatosis and a delayed occurrence of obesity. Fat cells from their liver express substantial levels of PPARγ2 transcripts when compared with lean cells. These studies demonstrate, in rodents, the involvement of PPARα nuclear receptor in lipid homeostasis, with a sexually dimorphic control of circulating lipids, fat storage, and obesity. Characterization of this pathological link may help to delineate new molecular targets for therapeutic intervention and could lead to new insights into the etiology and heritability of mammalian obesity.