coordinately regulated alternative splicing of genes involved in cholesterol biosynthesis and uptake协调调控选择性剪接的基因参与胆固醇生物合成和吸收.pdfVIP

Coordinately Regulated Alternative Splicing of Genes Involved in Cholesterol Biosynthesis and Uptake 1 . 1. 1 2 2 Marisa Wong Medina * , Feng Gao , Devesh Naidoo , Lawrence L. Rudel , Ryan E. Temel , Allison L. 2 2 1 McDaniel , Stephanie M. Marshall , Ronald M. Krauss * 1 Department of Atherosclerosis Research, Children’s Hospital Oakland Research Institute, Oakland, California, United States of America, 2 Department of Pathology – Lipid Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States of America Abstract Genes involved in cholesterol biosynthesis and uptake are transcriptionally regulated in response to cellular sterol content in a coordinated manner. A number of these genes, including 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and LDL receptor (LDLR), undergo alternative splicing, resulting in reductions of enzyme or protein activity. Here we demonstrate that cellular sterol depletion suppresses, and sterol loading induces, alternative splicing of multiple genes involved in the maintenance of cholesterol homeostasis including HMGCR and LDLR, the key regulators of cellular cholesterol biosynthesis and uptake, respectively. These changes were observed in both in vitro studies of the HepG2 human hepatoma derived cell line, as well as in vivo studies of St. Kitts vervets, also known as African green monkeys, a commonly used primate model for investigating cholesterol metabolism. These effects are mediated in part by sterol regulation of polypyrimidine tract binding protein 1 (PTBP1), since knock-down