Abstract
Aim:
Sterol-regulatory element binding proteins (SREBPs) are major transcription factors that regulate liver lipid biosynthesis. In this article we reported a novel synthetic compound 2-(3-benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (ZJ001) that inhibited the SREBP-1c pathway, and effectively reduced hepatic lipid accumulation in diet-induced obesity (DIO) mice.
Methods:
A luciferase reporter driven by an SRE-containing promoter transfected into HepG2 cells was used to discover the compound. Two approaches were used to evaluate the lipid-lowering effects of ZJ001: (1) diet-induced obesity (DIO) mice that were treated with ZJ001 (15 mg·kg−1·d−1, po) for 7 weeks; and (2) HepG2 cells and primary hepatocytes used as in vitro models.
Results:
ZJ001 (10, 20 μmol/L) dose-dependently inhibited the activity of SRE-containing promoter. ZJ001 administration ameliorated lipid metabolism and improved glucose tolerance in DIO mice, accompanied by significantly reduced mRNA levels of SREBP-1C and SREBP-2, and their downstream genes. In HepG2 cells and insulin-treated hepatocytes, ZJ001 (10–40 μmol/L) dose-dependently inhibited lipid synthesis, and reduced mRNA levels of SREBP-1C and SREBP-2, and their downstream genes. Furthermore, ZJ001 dose-dependently increased the phosphorylation of AMPK and regulatory-associated protein of mTOR (Raptor), and suppressed the phosphorylation of mTOR in insulin-treated hepatocytes. Moreover, ZJ001 increased the ADP/ATP ratio in insulin-treated hepatocytes.
Conclusion:
ZJ001 exerts multiple beneficial effects in diet-induced obesity mice. Its lipid-lowering effects may result from the suppression of mTORC1, which regulates SREBP-1c transcription. The results suggest that the SREBP-1c pathway may be a potential therapeutic target for the treatment of lipid metabolic disorders.
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Acknowledgements
This work was supported by a grant from National Program on Key Basic Research Project (973 Program; 2012CB524906), National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (2012ZX09301001-004), and the National Natural Science Foundation of China (81125023, 81270942, and 81001463).
We thank Tian-cheng DONG for his assistance in the animal experiments.
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Supplementary information
Supplementary Information, Table S1
Nucleotide sequences of gene-specific primers used for quantitative real-time PCR related to the experimental procedures (DOC 64 kb)
Supplementary Information, Figure S1
Distribution of ZJ001 in tissues. (DOC 68 kb)
Supplementary Information, Figure S2
ZJ001 had no effect on adipogenesis and respiration in 3T3-L1 adipocytes. (DOC 679 kb)
Supplementary Information, Figure S3
ZJ001 treatment had no effect on the phosphorylation of pre-SREBP-1c. (DOC 70 kb)
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Zhang, J., Zhang, Ln., Chen, Dm. et al. 2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice. Acta Pharmacol Sin 36, 483–496 (2015). https://doi.org/10.1038/aps.2014.149
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DOI: https://doi.org/10.1038/aps.2014.149
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