MicroRNA-541-3p alters lipoproteins to reduce atherosclerosis by degrading Znf101 and Casz1 transcription factors.
Abulaish AnsariPradeep Kumar YadavLiye ZhouBinu PrakashBhargavi GangulaLaraib IjazAmanda ChristianoSameer AhmadAntoine RimbertM Mahmood HussainPublished in: bioRxiv : the preprint server for biology (2023)
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.
Keyphrases
- poor prognosis
- transcription factor
- long non coding rna
- low density lipoprotein
- cardiovascular disease
- endothelial cells
- high density
- genome wide
- cell proliferation
- binding protein
- high fat diet induced
- induced pluripotent stem cells
- induced apoptosis
- long noncoding rna
- pluripotent stem cells
- cell death
- oxidative stress
- dna binding
- cell cycle arrest