title: A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression.
abstract: It is well-established that over-accumulation of dietary cholesterol in the liver inhibits sterol-regulatory element binding protein (SREBP)-mediated LDL receptor (LDLR) gene transcription leading to a reduced hepatic LDLR mRNA level in hypercholesterolemic animals. However, it is unknown whether elevated cholesterol levels can elicit a cellular response to increase LDLR mRNA turnover to further repress LDLR expression in liver tissue. In the current study, we examined the effect of a high cholesterol diet on the hepatic expression of LDLR mRNA binding proteins in three different animal models and in cultured hepatic cells. Our results demonstrate that high cholesterol feeding specifically elevates the hepatic expression of LDLR mRNA decay promoting factor heterogeneous nuclear ribonucleoprotein (HNRNP)D without affecting expressions of other LDLR mRNA binding proteins in vivo and in vitro. Employing the approach of adenovirus-mediated gene knockdown, we further show that depletion of HNRNPD in the liver results in a marked reduction of serum LDL-cholesterol and a substantial increase in liver LDLR expression in hyperlipidemic mice. Additional studies of gene knockdown in albumin-luciferase-untranslated region (UTR) transgenic mice provide strong evidence supporting the essential role of 3'UTR in HNRNPD-mediated LDLR mRNA degradation in liver tissue. Altogether, this work identifies a novel posttranscriptional regulatory mechanism by which dietary cholesterol inhibits liver LDLR expression via inducing HNRNPD to accelerate LDLR mRNA degradation.
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304 Department of Medicine, Stanford University, Stanford, CA 94305.
authors.forename: Amar Bahadur
authors.initials: AB
authors.lastname: Singh
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Chin Fung Kelvin
authors.initials: CF
authors.lastname: Kan
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304 Department of Medicine, Stanford University, Stanford, CA 94305.
authors.forename: Vikram
authors.initials: V
authors.lastname: Shende
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Bin
authors.initials: B
authors.lastname: Dong
authors.affiliation: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020871:RNA Stability / Q000187:drug effects*; D011973:Receptors, LDL / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D002791:Cholesterol, Dietary; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D011973:Receptors, LDL
keywords: adenylate-uridylate-rich element-binding proteins; heterogeneous nuclear ribonucleoprotein D; hypercholesterolemia; low density lipoprotein; messenger ribonucleic acid stability; posttranscriptional regulation