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Selective inhibition of liver X receptor α-mediated lipogenesis in primary hepatocytes by licochalcone A.

Oh GS, Lee GG, Yoon J, Oh WK, Kim SW - Chin Med (2015)

Bottom Line: The effects of 238 natural chemicals on autonomous transactivity of LXRα were determined by the Gal4-TK-luciferase reporter system.As a consequence, LicA reduced the LXRα agonist-stimulated transcription of several lipogenic genes.LicA is a selective inhibitor of LXRα, repressing lipogenic LXRα target genes but not RCT-related LXRα target genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736 Korea ; Bio-medical Institute of Technology, University of Ulsan College of Medicine, Seoul, 138-736 Korea.

ABSTRACT

Background: Sterol regulatory element binding protein-1c (SREBP-1c) is a regulator of the lipogenic pathway and is transcriptionally activated by liver X receptor α (LXRα). This study aims to investigate phytochemicals inhibiting the autonomous transactivity of LXRα with potentials as SREBP-1c inhibitors. Licochalcone A (LicA) is a flavonoid isolated from licorice root of Glycyrrhiza plant.

Methods: The effects of 238 natural chemicals on autonomous transactivity of LXRα were determined by the Gal4-TK-luciferase reporter system. The inclusion criteria for chemical selection was significant (P < 0.05) inhibition of autonomous transactivity of LXRα from three independent experiments. Transcript levels of mouse primary hepatocytes were measured by conventional or quantitative RT-PCR. Luciferase assay was used to assess synthetic or natural promoter activities of LXRα target genes. The effect of LicA on lipogenic activity was evaluated by measuring cellular triglycerides in mouse primary hepatocytes. The recruitment of RNA polymerase II to the LXR response element (LXRE) region was examined by chromatin immunoprecipitation.

Results: Among 238 natural compounds, LicA considerably inhibited the autonomous transactivity of LXRα and decreased the LXRα-dependent expression of SREBP-1c. LicA inhibited not only LXRα-dependent activation of the synthetic LXRE promoter but also that of the natural SREBP-1c promoter. As a consequence, LicA reduced the LXRα agonist-stimulated transcription of several lipogenic genes. Furthermore, LXRα-dependent hepatic lipid accumulation was repressed by LicA in mouse primary hepatocytes. Interestingly, the LXRα-dependent activation of ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1), other LXR target genes involved in reverse cholesterol transport (RCT), was not inhibited by LicA. LicA hindered the recruitment of RNA polymerase II to the LXRE of the SREBP-1c gene, but not of the ABCA1 gene.

Conclusions: LicA is a selective inhibitor of LXRα, repressing lipogenic LXRα target genes but not RCT-related LXRα target genes.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of selective inhibition of lipogenic pathway by LicA. Combination therapy of LicA and T0901317 could improve atherosclerosis without lipogenic adverse effects.
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Fig6: Schematic diagram of selective inhibition of lipogenic pathway by LicA. Combination therapy of LicA and T0901317 could improve atherosclerosis without lipogenic adverse effects.

Mentions: The inhibition of LXRα-mediated transcription by LicA was selective for lipogenic process (Figure 6). It is well known that LXRα regulates both lipogenic genes and RCT-related genes by direct binding to their LXREs [18,39,40]. Nevertheless, LicA selectively inhibited the transcription of the lipogenic SREBP-1c gene, but did not repress the LXRα-stimulated transcription of RCT-related genes including ABCA1 and ABCG1. The recruitments of RNA polymerase II to the LXREs were differentially regulated by LicA between SREBP-1c and ABCA1 promoters.Figure 6


Selective inhibition of liver X receptor α-mediated lipogenesis in primary hepatocytes by licochalcone A.

Oh GS, Lee GG, Yoon J, Oh WK, Kim SW - Chin Med (2015)

Schematic diagram of selective inhibition of lipogenic pathway by LicA. Combination therapy of LicA and T0901317 could improve atherosclerosis without lipogenic adverse effects.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4416341&req=5

Fig6: Schematic diagram of selective inhibition of lipogenic pathway by LicA. Combination therapy of LicA and T0901317 could improve atherosclerosis without lipogenic adverse effects.
Mentions: The inhibition of LXRα-mediated transcription by LicA was selective for lipogenic process (Figure 6). It is well known that LXRα regulates both lipogenic genes and RCT-related genes by direct binding to their LXREs [18,39,40]. Nevertheless, LicA selectively inhibited the transcription of the lipogenic SREBP-1c gene, but did not repress the LXRα-stimulated transcription of RCT-related genes including ABCA1 and ABCG1. The recruitments of RNA polymerase II to the LXREs were differentially regulated by LicA between SREBP-1c and ABCA1 promoters.Figure 6

Bottom Line: The effects of 238 natural chemicals on autonomous transactivity of LXRα were determined by the Gal4-TK-luciferase reporter system.As a consequence, LicA reduced the LXRα agonist-stimulated transcription of several lipogenic genes.LicA is a selective inhibitor of LXRα, repressing lipogenic LXRα target genes but not RCT-related LXRα target genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736 Korea ; Bio-medical Institute of Technology, University of Ulsan College of Medicine, Seoul, 138-736 Korea.

ABSTRACT

Background: Sterol regulatory element binding protein-1c (SREBP-1c) is a regulator of the lipogenic pathway and is transcriptionally activated by liver X receptor α (LXRα). This study aims to investigate phytochemicals inhibiting the autonomous transactivity of LXRα with potentials as SREBP-1c inhibitors. Licochalcone A (LicA) is a flavonoid isolated from licorice root of Glycyrrhiza plant.

Methods: The effects of 238 natural chemicals on autonomous transactivity of LXRα were determined by the Gal4-TK-luciferase reporter system. The inclusion criteria for chemical selection was significant (P < 0.05) inhibition of autonomous transactivity of LXRα from three independent experiments. Transcript levels of mouse primary hepatocytes were measured by conventional or quantitative RT-PCR. Luciferase assay was used to assess synthetic or natural promoter activities of LXRα target genes. The effect of LicA on lipogenic activity was evaluated by measuring cellular triglycerides in mouse primary hepatocytes. The recruitment of RNA polymerase II to the LXR response element (LXRE) region was examined by chromatin immunoprecipitation.

Results: Among 238 natural compounds, LicA considerably inhibited the autonomous transactivity of LXRα and decreased the LXRα-dependent expression of SREBP-1c. LicA inhibited not only LXRα-dependent activation of the synthetic LXRE promoter but also that of the natural SREBP-1c promoter. As a consequence, LicA reduced the LXRα agonist-stimulated transcription of several lipogenic genes. Furthermore, LXRα-dependent hepatic lipid accumulation was repressed by LicA in mouse primary hepatocytes. Interestingly, the LXRα-dependent activation of ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1), other LXR target genes involved in reverse cholesterol transport (RCT), was not inhibited by LicA. LicA hindered the recruitment of RNA polymerase II to the LXRE of the SREBP-1c gene, but not of the ABCA1 gene.

Conclusions: LicA is a selective inhibitor of LXRα, repressing lipogenic LXRα target genes but not RCT-related LXRα target genes.

No MeSH data available.


Related in: MedlinePlus