93 Mixed Lineage Leukemia Histone Methylases Regulate Human HDLR-SRB1 and Blood Cholesterol

Wednesday, November 4, 2009: 3:00 PM
Kohlberg (Camino Real Hotel)
Khairul I. Ansari , Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX
Sahba Kasiri , Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX
Imran Hussain , Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX
Subhrangsu S. Mandal , Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX
Human HDLR-SRB1 (or SRB1) plays critical role in cholesterol uptake by the steroidogenic tissues and hence proper expression of this gene is important to maintain blood cholesterol level. We demonstrated that the splice variant 1 of SRB1 is transcriptionally regulated by estrogen (E2) via involvement of estrogen receptors ER. Depletion of ER abrogates the effects of E2 on SRB1 expression. Similarly, depletion of MLL family of histone methylases suppresses E2 induced expression of SRB1. Our results indicate that ER and MLLs plays critical roles in E2 induced SRB1 expression. ChIP experiments demonstrated that ER and MLLs recruit to the ERE regions of SRB1 promoter in an E2 dependent manner. However, the recruitment of MLLs was dependent on ER and depletion of ER restricts their recruitment to ERE regions of SRB1 promoter. Functional analysis demonstrated that ER and MLLs affect the cholesterol uptake efficiency of steroidogenic JAR cells. Antisense mediated knockdown of MLL, in mouse, down regulated the expression of SRB1 in liver and resulted in blood cholesterol level. These results demonstrated that MLLs, in coordination with ER, play critical roles on steroid hormone induced regulation of SRB1 which in turn plays important role in controlling blood cholesterol in vivo and which is associated with cardiovascular diseases.