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Inhibition of SREBP transcriptional activity by a boron-containing compound improves lipid homeostasis in diet-induced obesity.

Zhao X - Diabetes (2014)

Bottom Line: Recently, we have synthesized several boron-containing small molecules.Among these novel compounds, BF175 can specifically block the binding of MED15-KIX to SREBP1a-TAD in vitro, resulting in an inhibition of the SREBP transcriptional activity and a decrease of SREBP target gene expression in cultured hepatocytes.These results suggest that blocking the interaction between SREBP-TADs and the Mediator complex by small molecules may represent a novel approach for treating diseases with aberrant lipid homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NYDepartment of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NYDepartment of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.

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A: Chemical structures of BF175 and BF62. B: Effects of the indicated doses of BF175 or BF62 on the binding of MED15-KIX to purified Flag-tagged SREBP-1a by GST pull-down assays. C: Effects of BF175 (50 µmol/L) on the binding of SREBP1a-TAD to overexpressed Flag-tagged MED15 in HEK293 cell lysates by GST pull-down assays. D: Effects of 50 µmol/L BF175 or BF62 on the activity of SREBP1a-TAD in HepG2 cells by dual-luciferase assays. Data represent the mean ± SD (n = 3). *P < 0.05; #P < 0.01 vs. control (DMSO).
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Figure 1: A: Chemical structures of BF175 and BF62. B: Effects of the indicated doses of BF175 or BF62 on the binding of MED15-KIX to purified Flag-tagged SREBP-1a by GST pull-down assays. C: Effects of BF175 (50 µmol/L) on the binding of SREBP1a-TAD to overexpressed Flag-tagged MED15 in HEK293 cell lysates by GST pull-down assays. D: Effects of 50 µmol/L BF175 or BF62 on the activity of SREBP1a-TAD in HepG2 cells by dual-luciferase assays. Data represent the mean ± SD (n = 3). *P < 0.05; #P < 0.01 vs. control (DMSO).

Mentions: Using a novel synthetic strategy, we recently synthesized several boron-containing compounds (16). When tested in cultured hepatocytes, some of the compounds displayed an inhibitory effect on the biosynthesis of palmitate and cholesterol through inhibiting lipogenic gene expression, although some compounds were either inactive or toxic at higher doses to cultured cells (16). Based on those results, we chose one compound, named BF175 (Fig. 1A), for further analysis, as it was less toxic to hepatocytes in tissue culture (data not shown).


Inhibition of SREBP transcriptional activity by a boron-containing compound improves lipid homeostasis in diet-induced obesity.

Zhao X - Diabetes (2014)

A: Chemical structures of BF175 and BF62. B: Effects of the indicated doses of BF175 or BF62 on the binding of MED15-KIX to purified Flag-tagged SREBP-1a by GST pull-down assays. C: Effects of BF175 (50 µmol/L) on the binding of SREBP1a-TAD to overexpressed Flag-tagged MED15 in HEK293 cell lysates by GST pull-down assays. D: Effects of 50 µmol/L BF175 or BF62 on the activity of SREBP1a-TAD in HepG2 cells by dual-luciferase assays. Data represent the mean ± SD (n = 3). *P < 0.05; #P < 0.01 vs. control (DMSO).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4066337&req=5

Figure 1: A: Chemical structures of BF175 and BF62. B: Effects of the indicated doses of BF175 or BF62 on the binding of MED15-KIX to purified Flag-tagged SREBP-1a by GST pull-down assays. C: Effects of BF175 (50 µmol/L) on the binding of SREBP1a-TAD to overexpressed Flag-tagged MED15 in HEK293 cell lysates by GST pull-down assays. D: Effects of 50 µmol/L BF175 or BF62 on the activity of SREBP1a-TAD in HepG2 cells by dual-luciferase assays. Data represent the mean ± SD (n = 3). *P < 0.05; #P < 0.01 vs. control (DMSO).
Mentions: Using a novel synthetic strategy, we recently synthesized several boron-containing compounds (16). When tested in cultured hepatocytes, some of the compounds displayed an inhibitory effect on the biosynthesis of palmitate and cholesterol through inhibiting lipogenic gene expression, although some compounds were either inactive or toxic at higher doses to cultured cells (16). Based on those results, we chose one compound, named BF175 (Fig. 1A), for further analysis, as it was less toxic to hepatocytes in tissue culture (data not shown).

Bottom Line: Recently, we have synthesized several boron-containing small molecules.Among these novel compounds, BF175 can specifically block the binding of MED15-KIX to SREBP1a-TAD in vitro, resulting in an inhibition of the SREBP transcriptional activity and a decrease of SREBP target gene expression in cultured hepatocytes.These results suggest that blocking the interaction between SREBP-TADs and the Mediator complex by small molecules may represent a novel approach for treating diseases with aberrant lipid homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NYDepartment of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NYDepartment of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.

Show MeSH
Related in: MedlinePlus