Circulating MicroRNAs in Patients with Chronic Hepatitis C and Non-Alcoholic Fatty Liver Disease

Abstract

MicroRNAs miR-122, miR-34a, miR-16 and miR-21 are commonly deregulated in liver fibrosis and hepatocellular carcinoma. This study examined whether circulating levels of these miRNAs correlate with hepatic histological disease severity in patients with chronic hepatitis C infection (CHC) or non-alcoholic fatty-liver disease (NAFLD) and can potentially serve as circulating markers for disease stage assessment. We first used an in vitro model of hepatitis C virus (HCV) infection to measure the extracellular levels of these four miRNAs. Whereas miR-21 extracellular levels were unchanged, extracellular levels of miR-122, miR-34a and to a lesser extent miR-16, steadily increased during the course of HCV infection, independently of viral replication and production. Similarly, in CHC patients, serum levels of miR-122, miR-34a and miR-16 were significantly higher than in control individuals, while miR-21 levels were unchanged. There was no correlation between the serum levels of any of these microRNAs and HCV viral loads. In contrast, miR-122 and miR-34a levels positively correlated with disease severity. Identical results were obtained in an independent cohort of CHC patients. We extended the study to patients with NAFLD. As observed in CHC patients, serum levels of miR-122, miR-34a and miR-16 were significantly higher in NAFLD patients than in controls, while miR-21 levels were unchanged. Again, miR-122 and miR-34a levels positively correlated with disease severity from simple steatosis to steatohepatitis. In both CHC and NAFLD patient groups, serum levels of miR-122 and miR-34a correlated with liver enzymes levels, fibrosis stage and inflammation activity. miR-122 levels also correlated with serum lipids in NAFLD patients. Conclusion: Serum levels of miR-34a and miR-122 may represent novel, noninvasive biomarkers of diagnosis and histological disease severity in patients with CHC or NAFLD.

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…As a consequence the colonization and dissemination of HCC are also favored. Serum levels of this miRNA (Cermelli et al, 2011) are elevated in patients with chronic hepatitis C infection than in control individuals and these are related to the degree of fibrosis. Recently, Xu et al (2015) found that miR-34a induces cellular senescence through the negative modulation of telomere pathway in human HCC by targeting c-Myc and FoxM1 involved in the activation of telomerase reverse transcriptase (hTERT) transcription.…”

MicroRNAs in Liver Disease: Bench to Bedside

“…40,44,45 Serum/plasma levels of miR-122 correlate with hepatic necro-inflammation, liver damage, cell death and increased aminotransferase levels in acute and chronic liver diseases. 44,[46][47][48][49] Interestingly, hepatic and circulating miR-122 levels do not correlate in NAFLD 14,39,[50][51][52][53][54][55] or viral hepatitis 41,47,49,56 although both have been statistically associated with various measures of disease severity in these studies. Together these studies show that miR-122 may play a role in most liver diseases.…”

“…14 Together these studies suggest that differentially expressed miRs in humans and animal models of NASH regulate genes with diverse functions involved in the pathogenesis of NAFLD, including metabolism of lipid and glucose, regulation of the unfolded protein response, endoplasmic reticulum stress, oxidative stress, cellular differentiation, inflammation and apoptosis. 14,36 Notably, miR-34a has been shown to be up-regulated in both human serum 50,51 and liver in humans and animal models of NAFLD. 14,55,121,122 Two recent studies suggest two differing mechanisms for the involvement of miR-34a in NASH pathogenesis through down-regulation of SIRT-1; a) leading to AMP kinase dephosphorylation and subsequent decreased phosphorylation of HMGCoA, ultimately leading to cholesterol accumulation 121 ; b) increased acetylation of p53 causing activation of apoptosis.…”

879 the Effects of Hepatitis C Virus Core Protein on the Expression of Mir-122 in Vitro

“…no positive correlation was observed between miR-122 level and HCV [22,23]. It may be due to not strong correlation between miR-122 level and HCV RNA level or the different cell line.…”