Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ

By J. Repa, G. Liang, J. Ou, Y. Bashmakov, J. Lobaccaro, I. Shimomura, B. Shan, Michael S. Brown, J. Goldstein, D. Mangelsdorf. 2000

1,589 citations recorded by the source corpus.

The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that are bound and activated by oxysterols. These receptors serve as sterol sensors to regulate the transcription of gene products that control intracellular cholesterol homeostasis through catabolism and transport. In this report, we describe a novel LXR target, the sterol regulatory element-binding protein-1c gene (SREBP-1c), which encodes a membrane-bound transcription factor of the basic helix-loop-helix-leucine zipper family. SREBP-1c expression was markedly increased in mouse tissues in an LXR-dependent manner by dietary cholesterol and synthetic agonists for both LXR and its heterodimer partner, the retinoid X receptor (RXR). Expression of the related gene products, SREBP-1a and SREBP-2, were not increased. Analysis of the mouse SREBP-1c gene promoter revealed an RXR/LXR DNA-binding site that is essential for this regulation. The transcriptional increase in SREBP-1c mRNA by RXR/LXR was accompanied by a similar increase in the level of the nuclear, active form of the SREBP-1c protein and an increase in fatty acid synthesis. Because this active form of SREBP-1c controls the transcription of genes involved in fatty acid biosynthesis, our results reveal a unique regulatory interplay between cholesterol and fatty acid metabolism.

Subfields: Molecular Biology, Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/df5100b5f24d0aa37fb17a7c4ca3e47a002435a5

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. J. Y. Chiang
2. P. Tontonoz
3. J. Goldstein
4. Liangyou Rui
5. Michael S. Brown
6. A. Calkin
7. Tiangang Li
8. Christopher K. Glass

In Oncology

1. J. Y. Chiang
2. P. Tontonoz
3. Liangyou Rui
4. J. Goldstein
5. Tiangang Li
6. Michael S. Brown
7. A. Calkin
8. D. Mangelsdorf

In Surgery

1. J. Y. Chiang
2. P. Tontonoz
3. J. Goldstein
4. Michael S. Brown
5. Liangyou Rui
6. A. Calkin
7. D. Mangelsdorf
8. Tiangang Li

Citations in the corpus

• SREBP Activity Is Regulated by mTORC1 and Contributes to Akt-Dependent Cell Growth (2008, background): “The observed induction of flSREBP in response to sterol treatment is most likely due to activation of the liver X receptor (LXR) (Repa et al., 2000) (Figure 2F).”
• Enzymes of triacylglycerol synthesis and their regulation. (2004, background): “The SREBP-1c promoter contains an LXR binding site [219], and mice lacking LXRa and b express less SREBP-1c and its target liver genes [220].”
• The human ATP-binding cassette (ABC) transporter superfamily. (2001, positive): “The ABCA1-mediated efflux of cholesterol is regulated by nuclear hormone receptors, such as oxysterol receptors (LXRs) and the bile acid receptor (FXR), as heterodimers with retinoid X receptors (RXRs) (Repa et al. 2000).”
• ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. (2005, background): “An increase in cholesterol levels can also lead to the activation of LXR and SREBP1c and SREBP1ctarget genes in an effort to buffer the effect of toxic free cholesterol within the cell (Peet et al., 1998b; Repa et al., 2000).”
• Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR (2012, background): “LXR stimulates lipogenesis through the induction of sterol-regulatory element-binding protein 1C (SREBP1C), acetyl CoA carboxylase (ACC), steroyl CoA desaturase 1 (SCD1) and fatty acid synthase (FAS) expressio”
• 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).”
• Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. (2015, neutral): “Journal of Hepatology 201 transcriptional activity [95,100].”
• Bile Acid Signaling in Metabolic Disease and Drug Therapy (2014, background): “Insulin is known to induce both SREBP-1c mRNA expression by the liver orphan receptor (LXR) and proteolytic cleavage (Repa et al., 2000; Shao and Espenshade, 2012).”