A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression[S]

• Published in: Journal of lipid research Vol. 55; no. 7; pp. 1397 - 1407
• Main Authors: Singh, Amar Bahadur, Kan, Chin Fung Kelvin, Shende, Vikram, Dong, Bin, Liu, Jingwen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2014; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: 3' Untranslated Regions; adenylate-uridylate-rich element-binding proteins; Animals; Cholesterol, Dietary - pharmacology; Gene Expression Regulation - drug effects; heterogeneous nuclear ribonucleoprotein D; Heterogeneous-Nuclear Ribonucleoprotein D - genetics; Heterogeneous-Nuclear Ribonucleoprotein D - metabolism; hypercholesterolemia; Liver - metabolism; low density lipoprotein; Male; messenger ribonucleic acid stability; Mice; Mice, Transgenic; posttranscriptional regulation; Receptors, LDL - biosynthesis; Receptors, LDL - genetics; RNA Stability - drug effects; posttranscriptional regulation; adenylate-uridylate-rich element-binding proteins; low density lipoprotein; heterogeneous nuclear ribonucleoprotein D; messenger ribonucleic acid stability; hypercholesterolemia
• DOI: 10.1194/jlr.M049429
• ISSN: 0022-2275

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.