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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is one major cause of chronic liver disease in the world and characterized by excessive triglyceride accumulation in the liver clinically and pathologically (Adams et al, 2005; Samuel et al, 2010; Samuel and Shulman, 2012)
The results showed that the expression levels of nine miRNAs located in the miR-379/miR-544 genomic cluster were significantly upregulated in db/db mice compared to WT mice (Figure 1A and Supplementary Table 1)
The expression levels of IGF1R, DLK1, and AKT phosphorylation (Ser 473) in KO-high-fat diet (HFD) mouse livers were significantly higher than those in WT-HFD mouse livers (Figures 4F,G). These findings strongly indicate that the activation of IGF1/IGF1R and PI3K/AKT signaling pathway contributed to the altered glucose and lipid homeostasis in the miR-379/miR-544 cluster KO mice fed on HFD
Summary
Non-alcoholic fatty liver disease (NAFLD) is one major cause of chronic liver disease in the world and characterized by excessive triglyceride accumulation in the liver clinically and pathologically (Adams et al, 2005; Samuel et al, 2010; Samuel and Shulman, 2012). Previous microarray screening showed that the miR-379, miR-411, miR-299, and miR-543 were upregulated in the liver of hyperglucocorticoidemia and obesity (db/db mouse model) as well as human liver in a GC/GR-dependent manner (de Guia et al, 2015) These upregulated miRNAs are all located in the miR-379/miR-544 genomic cluster with high conservation in mammalian species (Glazov et al, 2008), which resides on the human and mouse chromosomes 14 and 12, respectively. Another group reported that the level of serum miR-379 was significantly up-regulated in NAFLD patients compared to normal controls (Okamoto et al, 2020). Previous studies have suggested that deficiency of the miR-379/miR-544 cluster led to CLPG-like muscular hypertrophy (Gao et al, 2015), but no studies have linked this miRNA cluster to hepatic lipid accumulation and metabolic dysfunction
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