Mechanism of minimally modified LDL-mediated induction of serum amyloid A gene in monocyte/macrophage cells

Minimally modified low-density lipoprotein (MM-LDL) is regarded as a major risk factor for the development of atherosclerosis, In this report, we show that this lipoprotein complex can induce expression of an inflammatory pro tein, serum amyloid A (SAA), in monocyte/macrophage cells, a key cell type implicated in the pathogenesis of atherosclerosis, By promoter function ana lysis and site-directed mutagenesis, we have located promoter regions respo nsive to MM-LDL action, Using electrophoretic mobility shift, antibody abla tion/supershift, and Western blot assays, we showed that induction of SAA b y MM-LDL is mediated via activation of SAS binding factor (SAF) and C/EBP t ranscription factors. We further show that tamoxifen, a downregulator of CD 36, one of the major scavenger receptors which binds MM-LDL, can inhibit MM -LDL-mediated SAA induction in THP-1 cells, This finding suggests that CD36 participates in the manifestation of the inflammatory effects of MM-LDL, O ur experiments provide the first evidence for transcription factor activati on by MM-LDL.