Selective inhibition of liver X receptor α-mediated lipogenesis in primary hepatocytes by licochalcone A.
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.
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.
Gyun-Sik
GS
Oh
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.
Gang Gu
GG
Lee
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.
Jin
J
Yoon
Korea Bioactive Natural Material Bank, College of Pharmacy, Seoul National University, Seoul, 151-742 Korea.
Won Keun
WK
Oh
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.
Seung-Whan
SW
Kim