Hepatocyte-restricted constitutive activation of PPAR alpha induces hepatoproliferation but not hepatocarcinogenesis.

Publisher: Irl Press At Oxford University Press Country of Publication: England NLM ID: 8008055 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0143-3334 (Print) Linking ISSN: 01433334 NLM ISO Abbreviation: Carcinogenesis Subsets: MEDLINE

Publication: Oxford : Irl Press At Oxford University Press
Original Publication: [New York, IRL Press]

Cell Proliferation*; Hepatocytes/*cytology ; Hepatocytes/*pathology ; Liver Neoplasms/*genetics ; Liver Neoplasms/*metabolism ; PPAR alpha/*genetics ; PPAR alpha/*metabolism; Animals ; Liver Neoplasms/chemically induced ; Liver Neoplasms/pathology ; Mice ; Mice, Transgenic ; PPAR alpha/physiology ; Peroxisome Proliferators/metabolism ; Peroxisome Proliferators/pharmacology

Peroxisome proliferator-activated receptor alpha (PPARalpha) is responsible for peroxisome proliferator-induced pleiotropic responses, including the development of hepatocellular carcinoma in rodents. However, it remains to be determined whether activation of PPARalpha only in hepatocytes is sufficient to induce hepatocellular carcinomas. To address this issue, transgenic mice were generated that target constitutively activated PPARalpha specifically to hepatocytes. The transgenic mice exhibited various responses that mimic wild-type mice treated with peroxisome proliferators, including significantly decreased serum fatty acids and marked induction of PPARalpha target genes encoding fatty acid oxidation enzymes, suggesting that the transgene functions in the same manner as peroxisome proliferators to regulate fatty acid metabolism. However, the transgenic mice did not develop hepatocellular carcinomas, even though they exhibited peroxisome proliferation and hepatocyte proliferation, indicating that these events are not sufficient to induce liver cancer. In contrast to the transgenic mice, peroxisome proliferators activate proliferation of hepatic non-parenchymal cells (NPCs). Thus, activation of hepatic NPCs and/or associated molecular events is an important step in peroxisome proliferators-induced hepatocarcinogenesis.

Cancer Res. 1988 Dec 1;48(23):6739-44. (PMID: 3180084)
Cancer Res. 2004 Jun 1;64(11):3849-54. (PMID: 15172993)
Carcinogenesis. 1998 Jul;19(7):1217-22. (PMID: 9683180)
Carcinogenesis. 1997 Nov;18(11):2029-33. (PMID: 9395198)
Crit Rev Toxicol. 2003;33(6):655-780. (PMID: 14727734)
Cancer Res. 1996 Jan 1;56(1):1-4. (PMID: 8548746)
Curr Med Chem. 2003 Feb;10(4):267-80. (PMID: 12570700)
J Biol Chem. 1995 Feb 3;270(5):2367-71. (PMID: 7836471)
J Biol Chem. 2004 Oct 22;279(43):44740-8. (PMID: 15292250)
Carcinogenesis. 2000 Dec;21(12):2159-65. (PMID: 11133804)
EXS. 2000;89:141-51. (PMID: 10997287)
Endocrinology. 2006 Oct;147(10):4772-80. (PMID: 16857745)
Toxicol Appl Pharmacol. 1983 Jan;67(1):15-25. (PMID: 6845354)
Mutat Res. 2000 Mar 17;448(2):159-77. (PMID: 10725470)
Cell Mol Life Sci. 2004 Feb;61(4):393-416. (PMID: 14999402)
Chem Res Toxicol. 1997 Oct;10(10):1198-204. (PMID: 9348444)
Biochem J. 1982 Apr 1;203(1):161-8. (PMID: 7103935)
Carcinogenesis. 2000 Apr;21(4):823-6. (PMID: 10753222)
J Biol Chem. 2000 Sep 1;275(35):27117-22. (PMID: 10852923)
Nature. 1980 Jan 24;283(5745):397-8. (PMID: 6766207)
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10933-8. (PMID: 8855286)
Carcinogenesis. 2001 Mar;22(3):519-23. (PMID: 11238195)
Mutat Res. 2000 Mar 17;448(2):193-200. (PMID: 10725472)
Toxicol Pathol. 2004 Jul-Aug;32 Suppl 2:6-11. (PMID: 15503658)
Carcinogenesis. 2005 Jan;26(1):219-27. (PMID: 15447978)
Carcinogenesis. 1998 Nov;19(11):1989-94. (PMID: 9855014)
Proc Natl Acad Sci U S A. 1976 Jun;73(6):2043-6. (PMID: 180535)
Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5547-51. (PMID: 1319065)
Regul Toxicol Pharmacol. 1998 Feb;27(1 Pt 2):47-60. (PMID: 9618323)
J Biol Chem. 1996 Oct 4;271(40):24698-710. (PMID: 8798738)
Annu Rev Med. 2002;53:409-35. (PMID: 11818483)
Science. 1975 Nov 21;190(4216):787-9. (PMID: 1198095)
Carcinogenesis. 1997 Aug;18(8):1453-6. (PMID: 9276615)
Science. 1995 Jun 23;268(5218):1766-9. (PMID: 7792603)
Nature. 1990 Oct 18;347(6294):645-50. (PMID: 2129546)
J Invest Dermatol. 2000 Nov;115(5):788-94. (PMID: 11069615)
J Invest Dermatol. 2006 Feb;126(2):374-85. (PMID: 16374467)

Z01 BC005708-14 United States Intramural NIH HHS

0 (PPAR alpha)
0 (Peroxisome Proliferators)

Date Created: 20070303 Date Completed: 20070807 Latest Revision: 20240414

20240414

PMC1885989

10.1093/carcin/bgm046

17331954