Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor.

By P. Costet, Yi Luo, Nan Wang, A. Tall. Journal of Biological Chemistry, 2000

1,034 citations recorded by the source corpus.

Tangier disease, a condition characterized by low levels of high density lipoprotein and cholesterol accumulation in macrophages, is caused by mutations in the ATP-binding cassette transporter ABC1. In cultured macrophages, ABC1 mRNA was induced in an additive fashion by 22(R)-hydroxycholesterol and 9-cis-retinoic acid (9CRA), suggesting induction by nuclear hormone receptors of the liver X receptor (LXR) and retinoid X receptor (RXR) family. We cloned the 5'-end of the human ABC1 transcript from cholesterol-loaded THP1 macrophages. When transfected into RAW macrophages, the upstream promoter was induced 7-fold by 22(R)-hydroxycholesterol, 8-fold by 9CRA, and 37-fold by 9CRA and 22(R)-hydroxycholesterol. Furthermore, promoter activity was increased in a sterol-responsive fashion when cotransfected with LXRalpha/RXR or LXRbeta/RXR. Further experiments identified a direct repeat spaced by four nucleotides (from -70 to -55 base pairs) as a binding site for LXRalpha/RXR or LXRbeta/RXR. Mutations in this element abolished the sterol-mediated activation of the promoter. The results show sterol-dependent transactivation of the ABC1 promoter by LXR/RXR and suggest that small molecule agonists of LXR could be useful drugs to reverse foam cell formation and atherogenesis.

Subfields: Molecular Biology, Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/5c440abe5e9fc2e8c546301f97893999e49c2fa5

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In Molecular Biology

1. P. Tontonoz
2. Christopher K. Glass
3. D. Mangelsdorf
4. J. Goldstein
5. Michael S. Brown
6. Michael G. Rosenfeld
7. J. Repa
8. I. Shimomura

In Oncology

1. P. Tontonoz
2. J. Goldstein
3. D. Mangelsdorf
4. Michael S. Brown
5. P. Edwards
6. J. Repa
7. Christopher K. Glass
8. J. Y. Chiang

In Surgery

1. P. Tontonoz
2. J. Goldstein
3. Michael S. Brown
4. D. Mangelsdorf
5. Christopher K. Glass
6. P. Edwards
7. J. Repa
8. I. Shimomura

Citations in the corpus

• Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ (2000, background): “Recently, the ATPbinding cassette transporters, ABC1 and ABC8, which are implicated in the flux of cellular free cholesterol, have been found to be under the transcriptional regulation of the RXR/LXR heterodimer (Costet et al. 2000; Repa et al. 2000; Venkateswaran et al. 2000).”
• Atherosclerosis The Road Ahead (2001, background): “In addition, the ABC-A1 gene is several aspects of fatty acid metabolism, including beta regulated in the intestine and in macrophages by LXRs oxidation and uptake of fatty acids from triglyceride- (Costet et al., 2000; Repa et al., 2000b).”
• Role of LXRs in control of lipogenesis. (2000, background): “…transcription of the major genes of fatty acid synthesis including acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl CoA desaturase-1 (SCD-1), glycerol-3-phosphate acyltransferase, and others (Bennett et al. 1995; Lopez et al. 1996; Ericsson et al. 1997; Shimomura et al. 1998).”
• Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. (2007, background): “…efflux from peripheral cells and cholesterol excretion by the liver by positively regulating the expression of genes involved in cholesterol efflux (Costet et al., 2000; Repa et al., 2000) and genes involved in bile acid biosynthesis and transport (Chiang et al., 2001; Lewis and Rader, 2005).”
• Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. (2004, neutral): “The APR is Abbreviations: ABC, ATP binding cassette; ACC, acetyl CoA carboxylase; ACS, acyl-CoA synthetase; AIDS, acquired immune deficiency syndrome; AP2, adipocyte P2; apoE, apolipoprotein E; APR, acute-phase response; BSEP, bile salt export pump; CAD, coronary artery disease; CAR, constitutive an”
• ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. (2005, background): “Both the ABCG1 and ABCA1 genes are expressed in numerous tissues and are highly activated by the nuclear receptor LXR (Costet et al., 2000; Kennedy et al., 2001; Lorkowski et al., 2001; Schwartz et al., 2000; Venkateswaran et al., 2000).”