MicroRNA-541-3p alters lipoproteins to reduce atherosclerosis by degrading Znf101 and Casz1 transcription factors

Abstract

High apoB-containing low-density lipoproteins (LDL) and low apoA1-containing high-density lipoproteins (HDL) are associated with atherosclerosis. In search of a molecular regulator that could simultaneously and reciprocally control both LDL and HDL levels, we screened a microRNA (miR) library using human hepatoma Huh-7 cells. We identified miR-541-3p that both decreases apoB and increases apoA1 expression by inducing mRNA degradation of two different transcription factors, Znf101 and Casz1. Znf101 enhances apoB expression while Casz1 represses apoA1 expression. The hepatic knockdown of orthologous Zfp961 and Casz1 genes in mice altered plasma lipoproteins and reduced atherosclerosis without causing hepatic lipid accumulation, most likely by lowering hepatic triglyceride production, increasing HDL cholesterol efflux capacity, and reducing lipogenesis. Notably, human genetic variants in the MIR541, ZNF101, and CASZ1 loci are significantly associated with plasma lipids and lipoprotein levels. This study identifies miR-541-3p and Znf101/Casz1 as potential therapeutic agent and targets, respectively, to reduce plasma lipoproteins and atherosclerosis without causing liver steatosis. O_FIG O_LINKSMALLFIG WIDTH=153 HEIGHT=200 SRC="FIGDIR/small/565110v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@741dd1org.highwire.dtl.DTLVardef@151ad9aorg.highwire.dtl.DTLVardef@15c96a9org.highwire.dtl.DTLVardef@1a73b2d_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract. A schematic diagram depicting the role of miR-541-3p in the control of plasma lipoproteins and atherosclerosis.Our data show that miR-541-3p downregulates ZNF101 and CASZ1 by enhancing post-transcriptional degradation of mRNAs after interacting with their 3'-UTRs. Furthermore, our data indicate that ZNF101 is an enhancer of APOB, and CASZ1 is a repressor of APOA1. Hepatic knockdown (KD) of Zfp961, an orthologue of ZNF101, reduces plasma apoB-containing lipoproteins, whereas KD of Casz1 increases high density lipoproteins in mice. Furthermore, we show that hepatic KDs of these transcription factors reduces atherosclerosis in mice induced by the expression of mutant PCSK9. C_FIG