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

It is well-established that over-accumulation of dietary cholesterol in the liver inhibits sterol-regulatory ele- ment binding protein (SREBP)-mediated LDL receptor (LDLR) gene transcription leading to a reduced hepatic LDLR mRNA level in hypercholesterolemic animals. How- ever, 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 pro- teins in three different animal models and in cultured he- patic cells. Our results demonstrate that high cholesterol feeding specifi cally elevates the hepatic expression of LDLR mRNA decay promoting factor heterogeneous nuclear ri- bonucleoprotein (HNRNP)D without affecting expressions of other LDLR mRNA binding proteins in vivo and in vitro. Employing the approach of adenovirus-mediated gene knock- down, 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 hy- perlipidemic 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 identifi es a novel post- transcriptional regulatory mechanism by which dietary cho- lesterol inhibits liver LDLR expression via inducing HNRNPD to accelerate LDLR mRNA degradation. —Singh, A. B., C. F. K. Kan, V. Shende, B. Dong, and J. Liu. A novel posttranscriptional mechanism for dietary cholesterol-me- diated suppression of liver LDL receptor expression. J. Lipid Res. 2014. 55: 1397 - 1407 .