Disruption of TR4 orphan nuclear receptor reduces the expression of liver apolipoprotein E/C-I/C-II gene cluster.
Apolipoprotein E (apoE) is synthesized in many tissues, and the liver is the primary site from which apoE redistributes cholesterol and other lipids to peripheral tissues. Here we demonstrate that the TR4 orphan nuclear receptor (TR4) can induce apoE expression in HepG2 cells. This TR4-mediated regulation of apoE gene expression was further confirmed in vivo using TR4 knockout mice. Both serum apoE protein and liver apoE mRNA levels were significantly reduced in TR4 knockout mice. Gel shift and luciferase reporter gene assays further demonstrated that TR4 can induce apoE gene expression via a TR4 response element located in the hepatic control region that is 15 kb downstream of the apoE gene. Furthermore our in vivo data from TR4 knockout mice prove that TR4 can also regulate apolipoprotein C-I and C-II gene expression via the TR4 response element within the hepatic control region. Together our data show that loss of TR4 down-regulates expression of the apoE/C-I/C-II gene cluster in liver cells, demonstrating important roles of TR4 in the modulation of lipoprotein metabolism.
Kim
Eungseok
E
George Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
Xie
Shaozhen
S
Yeh
Shauh-Der
SD
Lee
Yi-Fen
YF
Collins
Loretta L
LL
Hu
Yueh-Chiang
YC
Shyr
Chih-Rong
CR
Mu
Xiao-Min
XM
Liu
Ning-Chun
NC
Chen
Yen-Ta
YT
Wang
Peng-Hui
PH
Chang
Chawnshang
C
D000818:Animals; D053302:Apolipoprotein C-I; D053304:Apolipoprotein C-II; D001053:Apolipoproteins / Q000096:biosynthesis* / Q000235:genetics; D001056:Apolipoproteins C / Q000096:biosynthesis / Q000235:genetics; D001057:Apolipoproteins E / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family; D012333:RNA, Messenger / Q000032:analysis; D011987:Receptors, Steroid / Q000172:deficiency / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000172:deficiency / Q000502:physiology*; D020218:Response Elements; D014162:Transfection
D053302:Apolipoprotein C-I; D053304:Apolipoprotein C-II; D001053:Apolipoproteins; D001056:Apolipoproteins C; D001057:Apolipoproteins E; C490515:NR2C2 protein, human; C490514:Nr2c2 protein, mouse; D012333:RNA, Messenger; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone