Biology subjects

Hussain, M. M.

Publications and source records attributed to Hussain, M. M..

3 recordsLinked to original sources

bioRxiv2023

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

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

physiology↗

bioRxiv2022

Pla2g12b is Essential for Expansion of Nascent Lipoprotein Particles

SUMMARYTriglyceride-rich lipoproteins (TRLs) are micelle-like particles that enable efficient transport of lipids throughout the bloodstream, but also promote atherosclerotic cardiovascular disease. Despite this central relevance to cardiovascular disease, very little is known about how lipids are loaded onto nascent TRLs prior to secretion. Here we show that Pla2g12b, a gene with no previously described function, concentrates components of the TRL biogenesis machinery along the ER membrane to ensure efficient delivery of lipids to nascent TRLs. We find that the lipid-poor TRLs secreted in PLA2G12B-/- mice and zebrafish support surprisingly normal growth and physiology while conferring profound resistance to atherosclerosis, and demonstrate that these same processes are conserved in human cells. Together these findings shed new light on the poorly understood process of TRL expansion, ascribe function to the previously uncharacterized gene Pla2g12b, and reveal a promising new strategy to remodel serum lipoproteins to prevent cardiovascular disease.

cell biology↗

bioRxiv2019

A missense mutation dissociates triglyceride and phospholipid transfer activities in zebrafish and human microsomal triglyceride transfer protein

Microsomal triglyceride transfer protein (MTP) transfers triglycerides and phospholipids and is essential for the assembly of Apolipoprotein B (ApoB)-containing lipoproteins in the endoplasmic reticulum. We have discovered a zebrafish mutant (mttpc655) expressing a C-terminal missense mutation (G863V) in Mttp, one of the two subunits of MTP, that is defective at transferring triglycerides, but retains phospholipid transfer activity. Mutagenesis of the conserved glycine in the human MTTP protein (G865V) also eliminates triglyceride but not phospholipid transfer activity. The G863V mutation reduces the production and size of ApoB-containing lipoproteins in zebrafish embryos and results in the accumulation of cytoplasmic lipid droplets in the yolk syncytial layer. However, mttpc655 mutants exhibit only mild intestinal lipid malabsorption and normal growth as adults. In contrast, zebrafish mutants bearing the previously identified mttpstl mutation (L475P) are deficient in transferring both triglycerides and phospholipids and exhibit gross intestinal lipid accumulation and defective growth. Thus, the G863V point mutation provides the first evidence that the triglyceride and phospholipid transfer functions of a vertebrate MTP protein can be separated, arguing that selective inhibition of the triglyceride transfer activity of MTP may be a feasible therapeutic approach for dyslipidemia.

physiology↗