MicroRNA‐10a Impairs Liver Metabolism in Hepatitis C Virus‐Related Cirrhosis Through Deregulation of the Circadian Clock Gene Brain and Muscle Aryl Hydrocarbon Receptor Nuclear Translocator‐Like 1

The circadian rhythm of the liver plays an important role in maintaining its metabolic homeostasis. We performed comprehensive expression analysis of microRNAs (miRNAs) using TaqMan polymerase chain reaction of liver biopsy tissues to identify the miRNAs that are significantly up‐regulated in advanced chronic hepatitis C (CHC). We found miR‐10a regulated various liver metabolism genes and was markedly up‐regulated by hepatitis C virus infection and poor nutritional conditions. The expression of miR‐10a was rhythmic and down‐regulated the expression of the circadian rhythm gene brain and muscle aryl hydrocarbon receptor nuclear translocator‐like 1 (Bmal1) by directly suppressing the expression of RA receptor‐related orphan receptor alpha (RORA). Overexpression of miR‐10a in hepatocytes blunted circadian rhythm of Bmal1 and inhibited the expression of lipid synthesis genes (sterol regulatory element binding protein [SREBP]1, fatty acid synthase [FASN], and SREBP2), gluconeogenesis (peroxisome proliferator‐activated receptor gamma coactivator 1 alpha [PGC1α]), protein synthesis (mammalian target of rapamycin [mTOR] and ribosomal protein S6 kinase [S6K]) and bile acid synthesis (liver receptor homolog 1 [LRH1]). The expression of Bmal1 was significantly correlated with the expression of mitochondrial biogenesis‐related genes and reduced Bmal1 was associated with increased serum alanine aminotransferase levels and progression of liver fibrosis in CHC. Thus, impaired circadian rhythm expression of Bmal1 by miR‐10a disturbs metabolic adaptations, leading to liver damage, and is closely associated with the exacerbation of abnormal liver metabolism in patients with advanced CHC. In patients with hepatitis C‐related liver cirrhosis, liver tissue miR‐10a levels were significantly associated with hepatic reserve, fibrosis markers, esophageal varix complications, and hepatitis C‐related hepatocellular carcinoma recurrence. Conclusion: MiRNA‐10a is involved in abnormal liver metabolism in cirrhotic liver through down‐regulation of the expression of the circadian rhythm gene Bmal1. Therefore, miR‐10a is a possible useful biomarker for estimating the prognosis of liver cirrhosis.