title: The PPAR alpha-humanized mouse: a model to investigate species differences in liver toxicity mediated by PPAR alpha.
abstract: To determine the impact of the species difference between rodents and humans in response to peroxisome proliferators (PPs) mediated by peroxisome proliferator-activated receptor (PPAR)alpha, PPAR alpha-humanized transgenic mice were generated using a P1 phage artificial chromosome (PAC) genomic clone bred onto a ppar alpha-null mouse background, designated hPPAR alpha PAC. In hPPAR alpha PAC mice, the human PPAR alpha gene is expressed in tissues with high fatty acid catabolism and induced upon fasting, similar to mouse PPAR alpha in wild-type (Wt) mice. Upon treatment with the PP fenofibrate, hPPAR alpha PAC mice exhibited responses similar to Wt mice, including peroxisome proliferation, lowering of serum triglycerides, and induction of PPAR alpha target genes encoding enzymes involved in fatty acid metabolism in liver, kidney, and heart, suggesting that human PPAR alpha (hPPAR alpha) functions in the same manner as mouse PPAR alpha in regulating fatty acid metabolism and lowering serum triglycerides. However, in contrast to Wt mice, treatment of hPPAR alpha PAC mice with fenofibrate did not cause significant hepatomegaly and hepatocyte proliferation, thus indicating that the mechanisms by which PPAR alpha affects lipid metabolism are distinct from the hepatocyte proliferation response, the latter of which is only induced by mouse PPAR alpha. In addition, a differential regulation of several genes, including the oncogenic let-7C miRNA by PPs, was observed between Wt and hPPAR alpha PAC mice that may contribute to the inherent difference between mouse and human PPAR alpha in activation of hepatocellular proliferation. The hPPAR alpha PAC mouse model provides an in vivo platform to investigate the species difference mediated by PPAR alpha and an ideal model for human risk assessment PPs exposure.
authors: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Qian
authors: Q
authors: Yang
authors: Tomokazu
authors: T
authors: Nagano
authors: Yatrik
authors: Y
authors: Shah
authors: Connie
authors: C
authors: Cheung
authors: Shinji
authors: S
authors: Ito
authors: Frank J
authors: FJ
authors: Gonzalez
mesh_terms: D000818:Animals; D000963:Antimetabolites; D015152:Blotting, Northern; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D022222:Chromosomes, Artificial, Human / Q000235:genetics; D003001:Cloning, Molecular; D011345:Fenofibrate / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism; D008954:Models, Biological; D047493:PPAR alpha / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity
chemical_list: D000963:Antimetabolites; D000960:Hypolipidemic Agents; D008055:Lipids; D047493:PPAR alpha; D012313:RNA; D001973:Bromodeoxyuridine; D011345:Fenofibrate
references: Mol Pharmacol. 2005 Apr;67(4):1257-67
references: 15635043
references: Physiol Genomics. 2003 Sep 29;15(1):9-19
references: 12851464
references: Toxicol Sci. 2005 Nov;88(1):250-64
references: 16081524
references: Carcinogenesis. 1997 Nov;18(11):2029-33
references: 9395198
references: Cancer Res. 1999 Oct 1;59(19):4776-80
references: 10519382
references: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2999-3004
references: 14973191
references: FEBS Lett. 1998 Jul 3;430(3):227-30
references: 9688544
references: Mol Cell Biol. 1995 Jun;15(6):3012-22
references: 7539101
references: Mol Cell Biol. 2007 Jun;27(12):4238-47
references: 17438130
references: Gene Expr. 2001;9(6):291-304
references: 11764000
references: J Cell Biochem Suppl. 2000;34:61-6
references: 10762016
references: Curr Med Chem. 2003 Feb;10(4):267-80
references: 12570700
references: Biochem J. 1982 Apr 1;203(1):161-8
references: 7103935
references: Mol Pharmacol. 2005 Mar;67(3):681-94
references: 15576629
references: Toxicol Pathol. 2005;33(1):181-4
references: 15805070
references: Biochem Biophys Res Commun. 2002 Jan 25;290(3):1114-22
references: 11798191
references: Crit Rev Toxicol. 2003;33(6):655-780
references: 14727734
references: Biochemistry. 1993 Jun 1;32(21):5598-604
references: 7684926
references: J Lipid Res. 1997 Sep;38(9):1851-8
references: 9323594
references: Toxicol Sci. 1999 Jan;47(1):1-8
references: 10048147
references: Cancer Lett. 1999 Aug 23;143(1):87-94
references: 10465342
references: Cancer Res. 2004 Jun 1;64(11):3849-54
references: 15172993
references: J Mol Med (Berl). 2005 Oct;83(10):774-85
references: 15976920
references: Am J Pathol. 2000 Jun;156(6):2149-57
references: 10854235
references: J Biol Chem. 2000 Sep 1;275(35):27117-22
references: 10852923
references: Nature. 1980 Jan 24;283(5745):397-8
references: 6766207
references: Toxicol Lett. 1998 Dec 28;102-103:85-90
references: 10022237
references: Regul Toxicol Pharmacol. 1998 Feb;27(1 Pt 2):47-60
references: 9618323
references: Science. 1975 Nov 21;190(4216):787-9
references: 1198095
references: Toxicol Appl Pharmacol. 2002 Dec 15;185(3):180-96
references: 12498735
references: Atherosclerosis. 1996 Jul;124 Suppl:S29-37
references: 8831913
references: Toxicol Pathol. 2004 Jul-Aug;32 Suppl 2:6-11
references: 15503658
references: Proc Natl Acad Sci U S A. 1976 Jun;73(6):2043-6
references: 180535
references: Carcinogenesis. 2006 May;27(5):1074-80
references: 16377806
references: Annu Rev Med. 2002;53:409-35
references: 11818483
references: Carcinogenesis. 2007 Jun;28(6):1171-7
references: 17331954