Low-density lipoprotein upregulate SR-BI through Sp1 Ser702 phosphorylation in hepatic cells.
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.
Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Tiantan Xili, Beijing 100050, China.
Fan
F
Yang
Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Tiantan Xili, Beijing 100050, China.
Yu
Y
Du
Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Tiantan Xili, Beijing 100050, China.
Jin
J
Zhang
Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Tiantan Xili, Beijing 100050, China.
Zhibo
Z
Jiang
Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Tiantan Xili, Beijing 100050, China. Electronic address: capricornkey@163.com.
Li
L
Wang
Key Laboratory of Biotechnology of Antibiotics of Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Tiantan Xili, Beijing 100050, China. Electronic address: binhong69@hotmail.com.
Bin
B
Hong
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D008076:Cholesterol, HDL / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D056945:Hep G2 Cells; D022781:Hepatocytes; D056284:Histone Deacetylase 1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051122:Scavenger Receptors, Class B / Q000235:genetics* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D056284:Histone Deacetylase 1; D008077:Lipoproteins, LDL; D051122:Scavenger Receptors, Class B; D016329:Sp1 Transcription Factor; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C495124:SCARB1 protein, human; C108209:SP1 protein, human; C110550:HDAC1 protein, human
Atherosclerosis; Histone acetyltransferase/deacetylase; Low density lipoprotein (LDL); Scavenger receptor class B type I (SR-BI); Specific protein 1 (Sp1); Transcriptional regulation