A peroxisome proliferator-activated receptor-alpha (PPARα) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARα: implications for species differences in responses to peroxisome proliferators

1998 ◽  
Vol 72 (3) ◽  
pp. 169-177 ◽  
Author(s):  
Jonathan D. Tugwood ◽  
Peter R. Holden ◽  
Neil H. James ◽  
Rebecca A. Prince ◽  
Ruth A. Roberts
Keyword(s):  
Guinea Pig ◽  
Species Differences ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferators ◽  
Pig Liver ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha ◽  
Guinea Pig Liver

scholarly journals Molecular basis of non-responsiveness to peroxisome proliferators: the guinea-pig PPARα is functional and mediates peroxisome proliferator-induced hypolipidaemia

1998 ◽  
Vol 332 (3) ◽  
pp. 689-693 ◽  
Author(s):  
Alex R. BELL ◽  
Richard SAVORY ◽  
Neill J. HORLEY ◽  
Agharul I. CHOUDHURY ◽  
Maurice DICKINS ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Molecular Basis ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferators ◽  
Luciferase Reporter Gene ◽  
Pig Liver ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Response Element ◽  
Guinea Pig Liver

The guinea pig does not undergo peroxisome proliferation in response to peroxisome proliferators, in contrast with other rodents. To understand the molecular basis of this phenotype, the peroxisome proliferator activated receptor α (PPARα) from guinea-pig liver was cloned; it encodes a protein of 467 amino acid residues that is similar to rodent and human PPARα. The guinea-pig PPARα showed a high substitution rate: maximum likelihood analysis was consistent with rodent monophyly, but could not exclude rodent polyphyly (P≈ 0.06). The guinea-pig PPARα cDNA was expressed in 293 cells and mediated the induction of the luciferase reporter gene by the peroxisome proliferator, Wy-14,643, dependent on the presence of a peroxisome proliferator response element. Moreover the PPARα RNA and protein were expressed in guinea-pig liver, although at lower levels than in a species which is responsive to peroxisome proliferators, the mouse. To determine whether the guinea-pig PPARα mediated any physiological effects, guinea pigs were exposed to two selective PPARα agonists, Wy-14,643 and methylclofenapate; both compounds induced hypolipidaemia. Thus the guinea pig is a useful model for human responses to peroxisome proliferators.

scholarly journals Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences

1999 ◽  
Vol 22 (1) ◽  
pp. 1-8 ◽  
Author(s):  
PR Holden ◽  
JD Tugwood
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Species Differences ◽  
Plasma Cholesterol ◽  
Specific Gene ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Apparent Lack ◽  
Receptor Alpha ◽  
Rats And Mice

Peroxisome proliferators (PPs) are chemicals of industrial and pharmaceutical importance that elicit liver carcinogenesis by a non-genotoxic mechanism. One of the intriguing properties of PPs is that the pleiotropic effects of these compounds (including increased DNA synthesis and peroxisome proliferation) are seen in rats and mice only, but not humans. It is important to determine the risks to humans of environmental and therapeutic exposure to these compounds by understanding the mechanisms of non-genotoxic hepatocarcinogenesis in rodents. To understand this apparent lack of human susceptibility, attention has focused on the peroxisome proliferator-activated receptor alpha (PPARalpha), which appears to mediate the effects of PPs in rodents. It is also known to mediate the hypolipidaemic effects that fibrate drugs exert on humans with elevated plasma cholesterol and triglyceride levels. Human PPARalphas share many functional characteristics with the rodent receptors, in that they can be transcriptionally activated by PPs and regulate specific gene expression. However, one key difference is that PPARalpha is less abundant in human than in rodent liver, which has led to the suggestion that species differences result from quantitative differences in gene expression. In this review we describe the effects of PPs and what is known of the molecular mechanisms of action and species differences with respect to rodents and man. Attention will be given to differences in the amounts of PPARalpha between species as well as the 'qualitative' aspects of PPARalpha-mediated gene regulation which might also explain the activation of some genes and not of others in human liver by PPs.

scholarly journals Biliary excretion of some anionic derivatives of diethylstilboestrol and phenolphthalein in the guinea pig

1977 ◽  
Vol 168 (3) ◽  
pp. 373-377 ◽  
Author(s):  
P A Barford ◽  
A H Olavesen ◽  
C G Curtis ◽  
G M Powell
Keyword(s):  
Guinea Pig ◽  
Biliary Excretion ◽  
Comparative Studies ◽  
Enzyme Activities ◽  
Species Differences ◽  
Pig Liver ◽  
Biliary Elimination ◽  
Derivatives Of ◽  
Guinea Pig Liver

The metabolic fates and modes of excretion of diethylstilboestrol mono[35S]sulphate and diethylstilboestrol di[35S]sulphate were studied in the guinea pig. Comparative studies were also made with [G-3H]diethylstilboestrol and phenolphthalein di[35S]sulphate. Diethylstiboesterol di[35S]sulphate was extensively eliminated in the bile unchanged. After administration of diethylstilboestrol mono[35S]sulphate, extensive biliary elimination of radioactivity was also recorded. Radioactive components were identified as diethylstilboestrol disulphate, diethylstilboestrol monosulphate monoglucuronide and unchanged diethylstilboestrol monosulphate. When [G-3H]diethylstilboestrol was administered, 3H-labelled diethylstilboestrol monoglucuronide, diethylstilboestrol monosulphate monoglucuronide and diethylstilboestrol disulphate appeared in the bile. Phenolphthalein di[35S]sulphate was excreted unchanged in bile. These findings are discussed in relation to studies carried out in the rat [Barford, Olavesen, Curtis & Powell (1977) Biochem. J. 164, 423–430] and species differences are related to differences in enzyme activities in rat and guinea-pig liver.

Role of peroxisome proliferator-activated receptor alpha (PPARα) and PPARα-mediated species differences in triclosan-induced liver toxicity

2018 ◽  
Vol 92 (11) ◽  
pp. 3391-3402 ◽  
Author(s):  
Yangshun Tang ◽  
Michelle M. Vanlandingham ◽  
Yuanfeng Wu ◽  
Frederick A. Beland ◽  
Greg R. Olson ◽  
...  
Keyword(s):  
Species Differences ◽  
Liver Toxicity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha

scholarly journals Differential regulation by a peroxisome proliferator of the different multifunctional proteins in guinea pig: cDNA cloning of the guinea pig D-specific multifunctional protein 2

1998 ◽  
Vol 330 (3) ◽  
pp. 1361-1368 ◽  
Author(s):  
Françoise CAIRA ◽  
Marie-Claude CLÉMENCET ◽  
Mustapha CHERKAOUI-MALKI ◽  
Martine DIEUAIDE-NOUBHANI ◽  
Corinne PACOT ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
Acid Synthesis ◽  
Northern Blotting ◽  
Peroxisome Proliferator ◽  
Pig Liver ◽  
Multifunctional Protein ◽  
Mrna Species ◽  
Hepatic Expression ◽  
Guinea Pig Liver

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) FEBS Lett. 378, 57-60], here we report the cloning of a cDNA encoding a second multifunctional peroxisomal protein (MFP-2) in guinea-pig liver. This 2356 nt cDNA encodes a protein of 735 residues (79.7 kDa) whose sequence shows 83% identity with rat MFP-2 [Dieuaide-Noubhani, Novikov, Baumgart, Vanhooren, Fransen, Goethals, Vandekerckhove, Van Veldhoven and Mannaerts (1996) Eur. J. Biochem. 240, 660-666]. In parallel, we studied the effect of ciprofibrate, a hypolipaemic agent also known as peroxisome 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 demonstrated that three MFP-1-related mRNA species are expressed in the guinea-pig liver. The expression of two of them (3.5 and 2.6 kb) is slightly increased by ciprofibrate, whereas the 3.0 kb MFP-1 mRNA is, unlike the rat one, strongly down-regulated in guinea pigs treated with ciprofibrate. In a similar way, the hepatic expression of the guinea-pig 2.6 kb MFP-2 mRNA is also down-regulated 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 mRNA species are co-expressed in guinea pig; and (2) that, opposed to the accepted idea of non-responsiveness of the guinea pig to ciprofibrate, this drug affects MFP-1 and MFP-2 gene expression in this species. Also, the mRNA species for acyl-CoA oxidase and thiolase, two other enzymes of the peroxisomal β-oxidation pathway that are induced severalfold in responsive species are down-regulated in guinea pig. This paper is the first, to our knowledge, reporting the down-regulation of the expression of genes encoding enzymes involved in the peroxisomal β-oxidation of fatty acids (MFP-1) and bile acid synthesis (MFP-2) in mammals.

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