Atlas of miRNome variations in different dyslipidemic conditions: a study in C57Bl/6, Ldlr-KO, and Pcsk9-KO mice.

In this study, mice with different genotypes and fed diets with different lipid content were enrolled, aiming to set up an atlas of miRNA expression levels in different organs with a relevant role in lipid/lipoprotein metabolism. Specifically, three genotypes were investigated: C57Bl/6 mice as controls, together with mice knock-out (KO) for LDLr (low-density lipoprotein receptor) and for PCSK9 (proprotein convertase subtilisin/kexin type 9). LDLr and PCSK9 are both involved in LDL turnover, the former mediating LDL clearance [PMID: 19299327], the latter causing the degradation of the LDLr protein [PMID: 17080197]. As a result, LDLrKO mice, because of their impaired LDL catabolism, are hypercholesterolemic and prone to atherosclerosis development, particularly when fed high-fat, cholesterol-containing diets [PMID: 8349823; PMID: 8182121]. On the contrary, PCSK9KO mice, characterized by an accelerated LDL catabolism, are hypocholesterolemic and atherosclerosis resistant [PMID: 15805190]. miRNA expression was investigated in liver, intestine, aorta, white adipose tissue and brain of mice on both standard and Western diet. short RNA sequencing of 7 organs, in 3 different genetic backgrounds, under 2 different diets本研究纳入了不同基因型且饲喂不同脂质含量饲料的小鼠，旨在构建与脂质/脂蛋白代谢密切相关的不同器官的microRNA（miRNA）表达图谱。具体而言，本研究共考察3种基因型小鼠：以C57Bl/6小鼠作为对照，同时包括低密度脂蛋白受体（low-density lipoprotein receptor, LDLr）敲除（knock-out, KO）小鼠与前蛋白转化酶枯草溶菌素/kexin 9型（proprotein convertase subtilisin/kexin type 9, PCSK9）敲除小鼠。LDLr与PCSK9均参与低密度脂蛋白（low-density lipoprotein, LDL）的代谢周转：前者介导LDL的清除[PMID: 19299327]，后者可导致LDLr蛋白降解[PMID: 17080197]。由于LDLr敲除小鼠的LDL分解代谢受损，因此会出现高胆固醇血症，且易发生动脉粥样硬化，尤其在饲喂高脂含胆固醇饲料时[PMID: 8349823; PMID: 8182121]。与之相反，PCSK9敲除小鼠的LDL分解代谢加速，表现为低胆固醇血症且动脉粥样硬化抵抗[PMID: 15805190]。本研究对饲喂标准饲料与西式饲料的小鼠的肝脏、肠道、主动脉、白色脂肪组织以及脑组织中的miRNA表达水平进行了检测，并对3种不同遗传背景、2种不同饲喂条件下的7个器官开展了小RNA测序。