Roles Of mir‑21 in The development of Non‑alcoholic fatty liver disease and hepatocellular carcinoma

Non alcoholic fatty liver disease (NAFLD) is a liver metabolic disorder that can progress to non alcoholic steatohepatitis, cirrhosis, and ultimately hepatocellular carcinoma (HCC). The miRNA miR 21 is upregulated in steatotic livers and is considered to exert powerful oncogenic functions. The mechanisms by which miR 21 promotes in vivo hepatic metabolic disorders and hepatocarcinogenesis are however still unclear. We therefore aimed at better delineating the in vivo roles of miR 21 in NAFLD and HCC pathogenesis. We demonstrated that mir-21 alters the expression of critical metabolic regulators of the liver to promote metabolic disorders induced by excessive energy intake in mouse, such as glucose intolerance, increased adiposity, hepatic insulin resistance and steatosis. We however also showed unexpected mir-21 tumor suppressive functions against chemically- and genetically-induced HCC, likely through a hepatic anti-inflammatory action. mir 21 silencing could thus constitute a therapeutic strategy for the treatment of metabolic pathologies, but might be detrimental when used against HCC

MicroRNAs in fatty liver disease

Overweight and obesity, insulin resistance and diabetes, chronic alcoholism, as well as infection by specific genotypes of hepatitis C viruses are all associated with an excessive and chronic ectopic accumulation of fat in the liver (steatosis). If the underlining causes of steatosis development are not resolved, progression toward more severe liver diseases such as inflammation, fibrosis, and cirrhosis can then occur with time. These hepatic metabolic and histological disorders are commonly referred to as fatty liver disease (FLD) and result from multiple deregulated molecular mechanisms controlling hepatic homeostasis. Among these mechanisms, deregulation of a whole network of small noncoding RNAs called microRNAs (miRNAs), which regulate gene expression at a posttranscriptional level, critically contributes to the development and progression of FLD. Specific miRNAs secreted in body fluids are also emerging as useful biomarkers of FLD and therapeutic targeting of miRNAs is currently being evaluated. The authors discuss recent findings highlighting the role and complexity of miRNA regulatory networks, which critically contribute to the development of FLD. As well, the potential therapeutic perspectives for FLD that our understanding of hepatic miRNA biology offers is considered

Arylsulfatases and neuraminidases modulate engagement of CCR5 by chemokines by removing key electrostatic interactions

The chemokine receptor CCR5 is known to exist in cell surface subpopulations that differ in their capacity to engage ligands. One proposed explanation for this phenomenon is the presence of CCR5 species with different levels of post-translational modifications (PTMs). Tyrosine sulfation and O-glycan sialylation are PTMs that add negative charges to the extracellular domain of CCR5 and make strong contributions to chemokine binding but it is not known whether cellular mechanisms to control their levels exist. In this study we used a combination of sulfation-sensitive and sulfation-insensitive CCR5 ligands to show that the rate of turnover of CCR5 tyrosine sulfation is more rapid than the rate of turnover of the receptor itself. This suggests that the steady state level of CCR5 sulfation is maintained through the combination of tyrosine protein sulfotransferase (TPST), the trans-Golgi network (TGN)-resident ‘source enzyme, and a ‘sink’ activity that removes tyrosine sulfation from CCR5. By measuring the effects on ligand binding of knockdown and overexpression experiments, we provided evidence that non-lysosomal cellular arylsulfatases, particularly ARSG, ARSI and ARSJ, are CCR5 sulfation ‘sink’ enzymes. We also used targeted knockdown and sialylation-sensitive and insensitive chemokines to identify the sialidase NEU3 as a candidate ‘sink’ enzyme for CCR5 O-glycan sialylation. This study provides the first experimental evidence of activity of sulfatase and sialidase ‘sink’ enzymes on CCR5, providing a potential mechanism for cells to control steady-state levels of these PTMs and thereby exert dynamic control over receptor-ligand interactions at the cell surface and during receptor desensitization

The mouse interleukin (Il)33 gene is expressed in a cell type- and stimulus-dependent manner from two alternative promoters

GenBank entries for mouse Il33 reveal the existence of two transcripts, Il33a and Il33b, with different 5`UTRs but coding for the same protein. We investigated expression of these transcripts in different mouse organs and cell types in basal and inflammatory conditions. Il33a and Il33b mRNAs start with different noncoding first exons, transcribed from different promoter regions, which both contain a consensus TATA-like sequence. Constitutive Il33a mRNA expression was detected in mouse stomach, lung, spleen, and brain, whereas basal Il33b mRNA expression was observed only in the stomach. Expression of both transcripts increased after systemic LPS administration. In vitro, we observed high constitutive expression of Il33 transcripts in MEFs. Constitutive Il33a mRNA expression was observed also in BMDCs, where it was preferentially increased in response to poly(I:C), whereas LPS increased levels of Il33a and Il33b mRNA. In contrast, BMMs and Raw 264.7 cells did not express Il33 mRNA constitutively, and LPS stimulation selectively induced expression of Il33b mRNA in these cells. Our data indicate that the Il33 gene is expressed from two alternative promoters in the mouse and that the relative expression of Il33a and Il33b transcripts is cell type- and stimulus-dependent

Activation of the oncogenic miR-21-5p promotes HCV replication and steatosis induced by the viral core 3a protein

miR-21-5p is a potent oncogenic microRNA targeting many key tumour suppressors including phosphatase and tensin homolog (PTEN). We recently identified PTEN as a key factor modulated by hepatitis C virus (HCV) to promote virion egress. In hepatocytes, expression of HCV-3a core protein was sufficient to downregulate PTEN and to trigger lipid droplet accumulation. Here, we investigated whether HCV controls PTEN expression through miR-21-5p-dependent mechanisms to trigger steatosis in hepatocytes and to promote HCV life cycle

Stress-activated miR-21/miR-21* in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption

miR-21 is an oncomir highly upregulated in hepatocellular carcinoma and in early stages of liver diseases characterised by the presence of steatosis. Whether upregulation of miR-21 contributes to hepatic metabolic disorders and their progression towards cancer is unknown. This study aims at investigating the role of miR-21/miR-21* in early stages of metabolic liver disorders associated with diet-induced obesity (DIO)

Exercise improves outcomes of surgery on fatty liver in mice: a novel effect mediated by the ampk pathway

To investigate whether exercise improves outcomes of surgery on fatty liver, and whether pharmacological approaches can substitute exercising programs