De novo Expression of Hepatic UCP3 Is Time-Dependently Related with Metabolic Function in Fenofibrate-Treated High Fat Diet Rats

고지방 섭취한 쥐에서 페노파이브레이트 복용에 의한 간 UCP3 발현 기간과 대사변화 관계

  • Park, Mi-Kyoung (Department of Internal Medicine, Medical Science Research Cente, Dong-A University College of Medicine) ;
  • Kang, Ah-Young (Department of Internal Medicine, Medical Science Research Center, Dong-A University College of Medicine) ;
  • Seo, Eun-Hui (Department of Pharmacology, Medical Science Research Center, Dong-A University College of Medicine) ;
  • Joe, Yeon-Soo (Department of Pharmacology, Medical Science Research Center, Dong-A University College of Medicine) ;
  • Kang, Soo-Jeong (Department of Pharmacology, Medical Science Research Center, Dong-A University College of Medicine) ;
  • Hong, Sook-Hee (Department of Pathology, Medical Science Research Center, Dong-A University College of Medicine) ;
  • Kim, Duk-Kyu (Department of Internal Medicine, Medical Science Research Center, Dong-A University College of Medicine) ;
  • Lee, Hye-Jeong (Department of Pharmacology, Medical Science Research Center, Dong-A University College of Medicine)
  • 박미경 (동아대학교 의과대학 내과학교실, 동아대학교 의과학연구원) ;
  • 강아영 (동아대학교 의과대학 내과학교실, 동아대학교 의과학연구원) ;
  • 서은희 (동아대학교 의과대학 약리학교실, 동아대학교 의과학연구원) ;
  • 조연수 (동아대학교 의과대학 약리학교실, 동아대학교 의과학연구원) ;
  • 강수정 (동아대학교 의과대학 약리학교실, 동아대학교 의과학연구원) ;
  • 홍숙희 (동아대학교 의과대학 병리학교실, 동아대학교 의과학연구원) ;
  • 김덕규 (동아대학교 의과대학 내과학교실, 동아대학교 의과학연구원) ;
  • 이혜정 (동아대학교 의과대학 약리학교실, 동아대학교 의과학연구원)
  • Published : 2009.01.30


Uncoupling protein 3 (UCP3) is a mitochondrial protein that is expressed predominantly in skeletal muscle. It may play a role in altering metabolic function. However, its major physiological roles are not fully understood. Recently de novo expression of UCP3 in rat liver by fenofibrate was reported. We also reported previously that fenofibrate-induced de novo expression of UCP3 contributes to reduction of adipose tissue in obese rats. In the present study, we investigated that ienofibrate-induced expression of UCP3 in rat liver is related with metabolic function such as body weight and hepatic lipid content by time-dependent manner in high-fat diet rats. Eight-week-old male Sprague-Dawley rats were randomly divided into two groups; the high fat diet group (HF, n=16) and fenofibrate-treated high fat diet group (HFF, n=16). The mRNA expression of hepatic UCP3 was detected as early as 1 week of fenofibrate treatment by quantitative real-time PCR and the amount of mRNA was increased time-dependently. The mean body weight of the HFF group was significantly less com. pared with the HF group after 6 weeks of fenofibrate treatment, even though there was no difference of food intake between the two groups. Rectal temperature was increased during 4 to 6 weeks of fenofibrate treatment and body weight was decreased after 6 weeks of treatment. These results were corresponded with the increased amount of the expression of UCP3 mRNA and protein. We suggest that de novo expression of hepatic UCP3 is increased time-dependently with fenofibrate treatment and that the amount of expression is correlated with metabolic function.


  1. Acin, A., M. Rodriguez, H. Rique, E. Canet, J. A. Boutin and J. P. Galizzi. 1999. Cloning and characterization of the 5' flanking region of the human uncoupling protein 3 (UCP3) gene. Biochem. Biophys. Res. Commun. 258, 278-283
  2. Auboeuf, D., J. Rieusset, L. Fajas, P. Vallier, V. Frering, J. P. Riou, B. Staels, J. Auwerx, M. Laville and H. Vidal. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. 1997. Diabetes 46, 1319-1327
  3. Braissant, O., F. Foufelle, C. Scotto, M. Dauca and W. Wahli. 1996. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137, 354-366
  4. Clapham, J. C., J. R. Arch, H. Chapman, A. Haynes, C. Lister, G. B. Moore, V. Piercy, S. A. Carter, I. Lehner, S. A. Smith, L. J. Beeley, R. J. Godden, N. Herrity and A. Abuin. 2000. Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 406, 415-418
  5. Desvergne, B. and W. Wahli. Peroxisome proliferator- activated receptors: nuclear control of metabolism. 1999. Endocr. Rev. 20, 649-688
  6. Enerback, S., A. Jacobsson, E. M. Simpson, C. Guerra, H. Yamashita, M. E. Harper and L. P. Kozak. 1997. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90-94
  7. Guerre-Millo, M., P. Gervois, E. Raspe, L. Madsen, P. Poulain, B. Derudas , J. M. Herbert , D. A. Winegar, T. M. Willson, J. C. Fruchart, R. K. Berge, B. Staels. 2000 Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J. Biol. Chem. 275, 16638-16642
  8. Himms-Hagen, J. Brown adipose tissue thermogenesis and obesity. 1989. Prog. Lipid Res. 28, 67-115
  9. Himms-Hagan, J. and M. E. Harper. 2001. Physiological role of UCP3 may be export of fatty acids from mitochondria when fatty acid oxidation predominates: an hypothesis. Exp. Biol. Med. 226, 78-84
  10. Ishigaki, Y., H. Katagiri, T. Yamada, T. Ogihara, J. Imai, K. Uno, Y. Hasegawa, J. Gao, H. Ishihara, T. Shimosegawa, H. Sakoda, T. Asano and Y. Oka. 2005 Dissipating excess energy stored in the liver is a potential treatment strategy for diabetes associated with obesity. Diabetes 54, 322-332
  11. Issemann, I. and S. Green. 1990. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347, 645-650
  12. Lanni, A., F. Mancini, L. Sabatino, E. Silvestri, R. Franco, G. De Rosa, F. Goglia and V. Colantuoni. 2002. De novo expression of uncoupling protein 3 is associated to enhanced mitochondrial thioesterase-1 expression and fatty acid metabolism in liver of fenofibrate-treated rats. FEBS Lett. 525, 7-12
  13. Lee, H. J., S. S. Choi, M. K. Park, Y. J. An, S. Y. Seo, M. C. Kim, S. H. Hong, T. H. Hwang, D. Y. Kang, A. J. Garber and D. K. Kim. 2002. Fenofibrate lowers abdominal and skeletal adiposity and improves insulin sensitivity in OLETF rats. Biochem. Biophys. Res. Comm. 296, 293-299
  14. Linton, M. F. and S. Fazio. 2000. Re-emergence of fibrates in the management of dyslipidemia and cardiovascular risk. Curr. Atheroscler. Rep. 2, 29-35
  15. Mancini, F. P., A. Lanni, L. Sabatino, M. Moreno, A. Giannino, F. Contaldo, V. Colantuoni and F. Goglia. 2001. Fenofibrate prevents and reduces body weight gain and adiposity in diet-induced obese rats. FEBS Lett. 491, 154-158
  16. Mao, W., X. X. Yu, A. Zhong, W. Li, J. Brush, S. W. Sherwood, S. H. Adams and G. Pan. 1999, UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Lett. 443, 326-330
  17. Moore, G. B., J. Himms-Hagen, M. E. Harper and J. C. Clapham. 2001. Overexpression of UCP-3 in skeletal muscle of mice results in increased expression of mitochondrial thioesterase mRNA. Biochem. Biophys. Res. Commun. 283, 785-790
  18. Park, M. K., H. J. Lee, S. H. Hong, S. S. Choi, Y. H. Yoo, K. I. Lee and D. K. Kim. 2007. The increase in hepatic uncoupling by fenofibrate contributes to a decrease in adipose tissue in obese rats. J. Korean Med. Sci. 22, 235-241
  19. Ricquier, D. and F. Boouillaud. 2000. Mitochondrial uncoupling proteins: from mitochondria to the regulation of energy balance. J. Physiol. 529, 3-10
  20. Silva, J. E. and R. Rabelo. 1997. Regulation of the uncoupling protein gene expression. Eur. J. Endocrinol. 136, 251-264
  21. Ye, J. M., P. J. Doyle, M. A. Iglesias, D. G. Watson, G. J. Coone and E. W. Kraegen. 2001. Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes 50, 411-417
  22. Yoon, M., S. Jeong, C. J. Nicol, H. Lee, M. Han, J. J. Kim, Y. J. Seo, C. Ryu, G.T. Oh. 2002. Fenofibrate regulates obesity and lipid metabolism with sexual dimorphism. Exp. Mol. Med. 34, 481-488
  23. Yu, X. X., W. Mao, A. Zhong, P. Schow, J. Brush, S. W. Sherwood, S. H. Adams and G. Pan. 2000. Characterization of novel UCP5/BMCP1 isoforms and differential regulation of UCP4 and UCP5 expression through dietary or temperature manipulation. FASEB J. 14,1611-1618