PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA-ISOFORM DEFICIENCY LEADS TO PROGRESSIVE DYSLIPIDEMIA WITH SEXUALLY DIMORPHIC OBESITY AND STEATOSIS

The alpha-isoform of the peroxisome proliferator-activated receptor (P PAR alpha) 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 (fi brate lipid-lowering drugs). Upon pharmacological activation, PPAR alp ha modulates target genes encoding lipid metabolism enzymes, lipid tra nsporters, or apolipoproteins, suggesting a role in lipid homeostasis. Transgenic mice deficient in PPAR alpha were shown to lack hepatic pe roxisomal proliferation and have an impaired expression and induction of several hepatic target genes. Young adult males show hypercholester olemia 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 dimorphis m. Serum triglycerides, elevated in aged animals, are higher in female s 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 PPAR gamma 2 transcripts when compared with lean cells. Thes e studies demonstrate, in rodents, the involvement of PPAR alpha nucle ar receptor in lipid homeostasis, with a sexually dimorphic control of circulating lipids, fat storage, and obesity. Characterization of thi s pathological link may help to delineate new molecular targets for th erapeutic intervention and could lead to new insights into the etiolog y and heritability of mammalian obesity.