A combined model of six serum microRNAs as diagnostic markers for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is associated with high morbidity and mortality, and its poor prognosis is mainly due to the lack of an effective means of early diagnosis. This study aimed to identify a group of serum microRNAs (miRNAs) as potential biomarkers for the diagnosis of HCC. METHODS: We collected 190 HCC cases, 109 benign lesions of the liver, 40 cases of non-HCC tumors, and 130 healthy controls. The 469 participants were divided into training and validation sets. A literature search revealed 12 miRNAs closely associated with HCC. In the training set, significantly differentially expressed miRNAs (DEmiRNAs) were screened using real-time quantitative PCR, and a diagnostic model of HCC was constructed using logistic regression analysis. An independent validation was performed using a validation set. The identified DE miRNAs were subjected to target gene prediction and functional analyses. RESULTS: Compared to the controls, the levels of miR-21, miR-221, miR-801, and miR-1246 significantly decreased in HCC (P < 0.05), while the levels of miR-26a and miR-122 significantly increased (P < 0.05). A diagnostic model based on the six DE miRNAs was successfully constructed, with AUC values of 0.953 for the training set and 0.952 for the verification set. Finally, 100 target genes of the DE miRNAs were predicted and were significantly enriched in the B cell receptor, neurotrophin, ferroptosis, and EGFR tyrosine kinase inhibitor resistance signaling pathways. CONCLUSIONS: The constructed diagnostic model based on six DE miRNA combinations has important clinical value for the early diagnosis of HCC.

Exosomal miR-199a-5p promotes hepatic lipid accumulation by modulating MST1 expression and fatty acid metabolism.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) and its complications has become an expanding health problem worldwide with limited therapeutic approaches. The current study was aiming to identify novel microRNA in the regulation of hepatic lipid metabolism in NAFLD. APPROCHES AND RESULTS: Systematic screening of microRNA expression by high-throughput small RNA sequencing demonstrated that microRNA 199a-5p (miR-199a-5p) was significantly upregulated in high fat diet-induced steatosis mouse model, with the most abundant expression in adipose tissue. MST1 was further identified as the target gene for miR-199a with specific recognition at the 3' untranslated region with dural luciferase reporter assay. Delivery of miR-199a-5p with exosomes into mice aggravated liver lipid accumulation in hepatocytes, accompanied by down-regulation of hepatic MST1 expression and modulation of hepatic lipogenesis and lipolysis, including SREBP-1c, AMPK signaling cascades and the down-stream CPT1α and FASN. Conversely, administration of exosome containing anti-miR-199a-5p resulted in attenuated steotosis in mice fed on high fat diet. Importanly, miR-199a-5p-induced abnormal cellular lipid accumulation could be markedly reversed by overexpression of MST1. CONCLUSION: miR-199a-5p might be an essentail regulator for hepatic lipid metabolism, possibly through its interction with MST1 and the subsequent signaling cascade. Thus, miR-199a-5p may serve as an important therapeutic target in the treatment of NAFLD.

Lycium barbarum polysaccharide attenuates high-fat diet-induced hepatic steatosis by up-regulating SIRT1 expression and deacetylase activity.

In this study, we aimed to investigate the protective effects and underlying mechanism of Lycium barbarum polysaccharide (LBP) on high-fat-induced nonalcoholic fatty liver disease (NAFLD). Recently, sirtuin 1 (SIRT1) has been shown to play an important role in the regulation of hepatocellular lipid metabolism. Here, we demonstrated that LBP up-regulates SIRT1 deacetylase activity and protein expression by enhancing the NAD+/NADH ratio. Subsequently, LBP promoted LKB1 deacetylation and AMPK phosphorylation via SIRT1-dependent signalling. We also found that LBP increases acetyl-CoA carboxylase (ACC) phosphorylation and adipose triglyceride lipase (ATGL) protein expression and decreases fatty acid synthase (FAS) by activating the SIRT1/LKB1/AMPK pathway in vitro and in vivo. However, SIRT1 small interfering RNA (siRNA)-mediated knockdown reversed the LBP-mediated effects on ACC, FAS and ATGL. Moreover, LBP elevated carnitine palmitoyltransferase-1 alpha (CPT-1α) expression by suppressing malonyl-CoA accumulation. Taken together, our data indicate that LBP plays a vital role in the regulation of hepatic lipid metabolism and that pharmacological activation of SIRT1 by LBP may be a strategy for the prevention of NAFLD.