Alterations in Lipoprotein Metabolism in Peroxisome Proliferator-activated Receptor α-deficient Mice

To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in rodents, we disrupted the ligand-binding domain of the alpha isoform of mouse PPAR (mPPAR alpha) by homologous recombination. Mice homozygous for the mutation lack expression of mPPAR alpha protein and yet are viable and fertile and exhibit no detectable gross phenotypic defects. Remarkably, these animals do not display the peroxisome proliferator pleiotropic response when challenged with the classical peroxisome proliferators, clofibrate and Wy-14,643. Following exposure to these chemicals, hepatomegaly, peroxisome proliferation, and transcriptional-activation of target genes were not observed. These results clearly demonstrate that mPPAR alpha is the major isoform required for mediating the pleiotropic response resulting from the actions of peroxisome proliferators. mPPAR alpha-deficient animals should prove useful to further investigate the role of this receptor in hepatocarcinogenesis, fatty acid metabolism, and cell cycle regulation.

Inflammation is a local immune response to 'foreign' molecules, infection and injury. Leukotriene B4, a potent chemotactic agent that initiates, coordinates, sustains and amplifies the inflammatory response, is shown to be an activating ligand for the transcription factor PPARalpha. Because PPARalpha regulates the oxidative degradation of fatty acids and their derivatives, like this lipid mediator, a feedback mechanism is proposed that controls the duration of an inflammatory response and the clearance of leukotriene B4 in the liver. Thus PPARalpha offers a new route to the development of anti- or pro-inflammatory reagents.

The three peroxisome proliferator-activated receptors (PPARs), PPAR alpha, delta and gamma, form a subfamily of the nuclear hormone receptor gene family. PPAR alpha has been shown to bind and be activated by leukotriene B4 and fibrates, whereas prostaglandin J2 derivatives and the antidiabetic thiazolidinediones, respectively, are natural and synthetic ligands for PPAR gamma. The availability of ligands and activators for PPAR alpha and PPAR gamma allowed an initial assessment of their respective functions. PPAR alpha and PPAR gamma are shown to function as important regulators in lipid and glucose metabolism, adipocyte differentiation, inflammatory response and energy homeostasis. PPAR alpha seems to mediate its pleiotropic effects mainly through the stimulation of oxidation of lipids, whereas PPAR gamma is a key mediator of lipid storage. The next few years will be very exciting as additional studies will refine our current knowledge about PPAR alpha and PPAR gamma and may reveal a ligand and role for the lonesome orphan among the PPARs, PPAR delta.