PLX283538

GSE139830: RNA sequencing analysis of liver after overexpressing of hepatic miR-378

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

An improved mechanistic understanding of the thyroid hormone (TH) action on bile acid (BA) synthetic pathway, the major route for cholesterol elimination, will facilitate the identification of novel therapeutic targets for hypercholesterolemia. Here, we show that hepatic miR-378 is positively regulated by TH. Transient overexpression of miR-378 in the liver of mice reduces the serum cholesterol levels, which is accompanied with an upregulation of key enzymes involved in the intrahepatic conversion of cholesterol to BAs. Importantly, transgenic mice with liver-specific and moderate overexpression of miR-378 also display a decrease in serum cholesterol levels accompanied with an enhanced BA synthesis and are resistant to diet-induced hypercholesterolemia. In contrast, mice lacking miR-378 exhibit an elevation of serum cholesterol levels accompanied with an impaired BA synthesis. Mechanistic studies reveal that hepatic miR-378 regulates BA synthesis and cholesterol homeostasis through its direct target gene MAFG, which is a transcriptional repressor of BA synthetic genes. We also show that miR-378 serves as an essential component in either incoherent or coherent feed-forward loop to confer robust and precise controls on BA synthesis in response to TH signalling. Together, we identify a previously undescribed miR-378-mediated mechanism underlying the cholesterol-lowering effect of TH. Our findings not only add a new dimension to our understanding the regulation of BA synthesis by TH, but also provide new therapeutic regimens to manage serum cholesterol levels. SOURCE: chao sun (sunchao@sibs.ac.cn) - CAS Key Laboratory of Nutrition, Metabolism and Food Safety Shanghai Institutes for Biological Sciences, University of Chinese Academy ofSciences