Glycolipid metabolic disease (GLMD) is an umbrella term for a series of chronic diseases associated with glucose and lipid metabolism disorders including type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), obesity, hypertension, dyslipidemia and atherosclerosis. GLMD has become a worldwide problem threatening human health due to its high prevalence. As a major metabolic control hub, the liver is responsible for maintaining energy and nutrient homeostasis upon alterations of physiological conditions, which determines its vital role in GLMD. However, the regulatory mechanism of glycolipid metabolism in the liver has not been fully clarified.
On August 17, 2020, the research team of Prof. REN Jin from the Center for Drug Safety Evaluation and Research (CDSER) of the Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences and the team of Prof. XIE Qing, chief physician from the Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University published jointly an online article entitled “miR-552-3p modulates transcriptional activities of FXR and LXR to ameliorate hepatic glycolipid metabolism disorder” in Journal of hepatology.
Through the analysis of RNA-seq, mass spectrometry and bioinformatics, they discovered firstly the new biological function of miR-552-3p in regulating the downstream genes of liver X receptor (LXR) and farnesol X receptor (FXR) in the nucleus, and further verified its improvement effect on liver glycolipid metabolism in several animal models. LXR and FXR belong to NR1 family, which serve important roles in the regulation of hepatic glucose and lipid homeostasis.
Using a variety of molecular biological techniques, such as FRET, ChIP, pull down and EMSA, they found 2 particular AGGTCA-like sequences, the cis-element of NR1 subfamily, in miR-552-3p can bind with the antisense strand of LXR response element (LXRE, DR4) and both sense and antisense strands of FXR response element (FXRE, IR1) to affect their transcriptional activities and downstream genes expression related to glycolipid metabolism. Furthermore, this mechanism is verified in the primary human hepatocytes. Finally, the clinical relevance of miR-552-3p and some pathological features of liver including lipid accumulation and liver injury in NAFLD patients was also found.
This study proposes for the first time that miR-552-3p can improve liver glycolipid metabolism, confirms the new mechanism for miRNA to regulate gene expression through interacting with nuclear receptor and its cis-acting elements, and supplies the possibility for miR-552-3p to become a biomarker in noninvasive diagnosis of NAFLD and miR-552-3p-based therapy in GLMD. These discoveries put forward a novel mechanism of miRNAs regulating gene expression, give a new evidence for miRNAs participating in glucose and lipid metabolism, and provide a probable direction for the development of drugs against GLMD.
The research team of CDSER has been dedicated to the non-coding RNA-related research including their biological function, molecular mechanism and application in the occurrence and development of diseases for many years. This study is another outstanding research achievement judged by international peers after the articles were published in Oncogene and Cell Death & Differentiation . At the same time, this work is a continuation of the previous work that was ever published in Biochimica et Biophysica Acta (BBA) gene regulatory mechanisms in 2016, in which they discovered firstly that the miR-552-3p can be located in both nucleus and cytoplasm, and play a regulatory role in gene transcription and translation.
The first authors of this article are Dr. FAN Lei from SIMM and LAI Rongtao from Ruijin Hospital. The corresponding authors are Prof. REN Jin and Prof. CHEN Jing from SIMM, and Prof. XIE Qing from Ruijin Hospital. This work was supported by the Personalized Medicines—Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences, and the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” of China.