Yin Yang 1 protein negatively regulates high-density lipoprotein receptor gene transcription by disrupting binding of sterol regulatory element binding protein to the sterol regulatory element

Because the high-density lipoprotein receptor (HDL-R) is a key element in c holesterol homeostasis and a potential therapeutic target for hypercholeste rolemic drugs, an understanding of HDL-R regulation is essential. The stero l regulatory element (SRE) binding protein-1a (SREBP-1a) was shown to posit ively regulate HDL-R gene expression through two SREs. SREBP-1a requires th e presence of a coactivator like simian-virus-40-protein-1 (Sp1) to promote maximum activation of the HDL-R promoter. Negative regulatory factors are also known to play a role in cholesterol homeostasis, and the ubiquitous Yi n Yang-1 zinc finger transcription factor (YY1) has been shown to repress s everal sterol-responsive gene promoters. A search of the rat HDL-R promoter revealed two putative Wi binding sites (distal, -1329 to -1321; proximal, -1211 to -1203). Upon removal of both Wi binding sites, Wi was unable to re press HDL-R activation under basal (unstimulated) promoter conditions. Howe ver, Wi was still an efficient transcriptional repressor for SREBP-1a-induc ed activation. YY1 was able to attenuate the transcriptional synergy caused by the combined actions of SREBP-1a and Spl. Two-hybrid studies confirmed that Wi bound with high affinity to SREBP-1a, and mobility shift assays dem onstrated that YY1 could disrupt SREBP-1a binding to both SREs. The molecul ar consequence of YY1 intervention seems to override any positive interacti ons between Sp-1 and SREBP-1a and results in the disruption of SREBP-1a bin ding to the SREs in the HDL-R promoter.