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Low-density lipoprotein upregulate SR-BI through Sp1 Ser702 phosphorylation in hepatic cells Molecular and cell biology of lipids

Yang, Fan, Du, Yu, Zhang, Jin, Jiang, Zhibo, Wang, Li, Hong, Bin
Biochimica et biophysica acta 2016 v.1861 no.9 pp. 1066-1075
acetylation, blood lipids, cardiovascular diseases, genes, hepatocytes, high density lipoprotein cholesterol, histone acetyltransferase, histone deacetylase, histones, lipid content, low density lipoprotein, mass spectrometry, phosphorylation, precipitin tests, promoter regions, risk, site-directed mutagenesis, transcription factors
Scavenger receptor class B type I (SR-BI) is one of the key proteins in the process of reverse cholesterol transport (RCT), and its major function is to uptake high density lipoprotein (HDL) cholesterol from plasma into liver cells. The regulation of SR-BI expression is important for controlling serum lipid content and reducing the risks of cardiovascular diseases. Here we found that SR-BI expression was significantly increased by LDL in vivo and in vitro, and the transcription factor specific protein 1 (Sp1) plays a critical role in this process. Results from co-immunoprecipitation experiments indicate that the activation of SR-BI was associated with Sp1-recruited protein complexes in the promoter region of SR-BI, where histone acetyltransferase p300 was recruited and histone deacetylase HDAC1 was dismissed. As a result, histone acetylation increased, leading to activation of SR-BI transcription. With further investigation, we found that LDL phosphorylated Sp1 through ERK1/2 pathway, which affected Sp1 protein complexes formation in SR-BI promoter. Using mass spectrometry and site directed mutagenesis, a new Sp1 phosphorylation site Ser702 was defined to be associated with Sp1-HDAC1 interaction and may be important in SR-BI activation, shedding light on the knowledge of delicate mechanism of hepatic HDL receptor SR-BI gene modulation by LDL.