DIFFERENTIAL REGULATION BY A PEROXISOME PROLIFERATOR OF THE DIFFERENTMULTIFUNCTIONAL PROTEINS IN GUINEA-PIG - CDNA CLONING OF THE GUINEA-PIG D-SPECIFIC MULTIFUNCTIONAL PROTEIN-2

After our previous report on the cloning of two cDNA species in guinea pig, both encoding the same hepatic 79 kDa multifunctional protein 1 (MFP-1) [Caira, Cherkaoui-Malki, Hoefler and Latruffe (1996) FEES Lett . 378, 57-60], here we report the cloning of a cDNA encoding a second multifunctional peroxi somal protein (MFP-2) in guinea-pig liver. This 2356 nt cDNA encodes a protein of 735 residues (79.7 kDa) whose seque nce shows 83 % identity with rat MFP-2 [Dieuaide-Noubhani, Novikov, Ba umgart, Vanhooren, Fransen, Goethals, Vandekerckhove, Van Veldhoven an d Mannaerts (1996) Eur. J. Biochem. 240, 660-666]. In parallel, we stu died the effect of ciprofibrate, a hypolipaemic agent also known as pe roxisome proliferator in rodent, on the expression of MFP-1 and MFP-2 (2.6 kb) in rats and guinea pigs. By Northern blotting analysis we dem onstrated that three MFP-1-related mRNA species are expressed in the g uinea-pig liver. The expression of two of them (3.5 and 2.6 kb) is sli ghtly increased by ciprofibrate, whereas the 3.0 kb MFP-1 mRNA is, unl ike the rat one, strongly down-regulated in guinea pigs treated with c iprofibrate. In a similar way, the hepatic expression of the guinea-pi g 2.6 kb MFP-2 mRNA is also downregulated in guinea pigs treated with ciprofibrate. These results demonstrate (1) that in contrast with the unique 3.0 kb MFP-1 rat mRNA, at least three hepatic MFP-1-related mRN A species are co-expressed in guinea pig; and (2) that, opposed to the accepted idea of non-responsiveness of the guineapig to ciprofibrate, this drug affects MFP-1 and MFP-2 gene expression in this species. Al so, the mRNA species for acyl-CoA oxidase and thiolase, two other enzy mes of the peroxisomal beta-oxidation pathway that are induced several fold in responsive species are down-regulated in guinea pig. This pape r is the first, to our knowledge, reporting the down-regulation of the expression of genes encoding enzymes involved in the peroxisomal beta -oxidation of fatty acids (MFP-1) and bile acid synthesis (MFP-2) in m ammals.