Lack of miR-379/miR-544 Cluster Resists High-Fat Diet-Induced Obesity and Prevents Hepatic Triglyceride Accumulation in Mice

Abstract

Non-alcoholic fatty liver disease (NAFLD) affects obesity-associated metabolic syndrome, which exhibits hepatic steatosis, insulin insensitivity and glucose intolerance. Emerging evidence suggests that microRNAs (miRNAs) are essential for the metabolic homeostasis of liver tissues. Many hepatic miRNAs located in the miR-379/miR-544 cluster were significantly increased in leptin-receptor-deficient type 2 mice (db/db), a mouse model of diabetes. However, the function of the miR-379/miR-544 cluster in the process of hepatic steatosis remains unclear. Here, we report that the novel function of miR-379/miR-544 cluster in regulating obesity-mediated metabolic dysfunction. Genetical mutation of miR-379/miR-544 cluster in mice displayed resistance to high-fat diet (HFD)-induced obesity with moderate hepatic steatosis and hypertriglyceridemia. In vitro studies revealed that silencing of miR-379 in human hepatocellular carcinoma (HepG2) cells ameliorated palmitic acid-induced elevation of cellular triglycerides, and overexpression of miR-379 had the opposite effect. Moreover, Igf1r (Insulin-like growth factor 1 receptor) and Dlk1 (Delta-like homolog 1) were directly targeted by miR-379 and miR-329, respectively, and elevated in the livers of the miR-379/miR-544 cluster knockout mice fed on HFD. Further transcriptome analyses revealed that the hepatic gene expressions are dysregulated in miR-379/miR-544 knockout mice fed with HFD. Collectively, our findings identify the miR-379/miR-544 cluster as integral components of a regulatory circuit that functions under conditions of metabolic stress to control hepatic steatosis. Thus, this miRNA cluster provides potential targets for pharmacologic intervention in obesity and NAFLD.

Huaju Xiaoji Formula Regulates ERS-lncMGC/miRNA to Enhance the Renal Function of Hypertensive Diabetic Mice with Nephropathy

“…The deletion of the miR379 cluster attenuates hepatic steatosis and metabolic dysfunction of leptin-receptordeficient type 2 mice induced by a high-fat diet, and the insulin-like growth factor 1 receptor is directly targeted by miR379 [59]. In a study, ERS upregulated the megacluster miR379 along with lncMGC in the kidneys of diabetic mice and induced hypertrophy and fibrosis in mice.…”

Targeted microRNA Profiling Reveals That Exendin-4 Modulates the Expression of Several microRNAs To Reduce Steatosis in HepG2 Cells

“…Also, hepatic miR-379-5p deficiency reduces serum very low-density lipoprotein-associated triglyceride (VLDL-TG) levels by promoting hepatic lipid reuptake and TG accumulation [60]. Recently, Cao and coworkers showed that the lack of miR-379/miR-544 cluster resists high-fat diet-induced obesity and prevents hepatic triglyceride accumulation in mice [61]. Dong et al lately reported that miR-379-5p inhibits STAT1 expression and regulates cholesterol metabolism through the STAT1/HMGCS1 axis in db/db mice, suggesting miR-379-5p might be applied to improve lipotoxicity and relieve diet induced-liver damage [62].…”

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

“…Different data in animals and humans show a relationship of certain miRNAs with hepatic metabolic homeostasis and leptin signaling. Many hepatic miRNAs located in the miR-379/miR-544 cluster were augmented in leptin-receptor-deficient type 2 mice and genetic mutation of this cluster in mice showed resistance to high-fat-diet-induced obesity with lower hypertriglyceridemia and steatosis [ 259 ]. Several compounds in modern diets are risk factors for the development of NAFLD and hepatocellular carcinoma, where various miRNAs are involved, with miR-650 being the most potent for the development of these diseases.…”