GPM6A expression is suppressed in hepatocellular carcinoma through miRNA-96 production.

GPM6A is a glycoprotein in endothelial cells, and its biological function in the development of hepatocellular carcinoma (HCC) is unknown. Through Affymetrix gene expression microarray and bioinformatic analysis, very low GPM6A expression was found in HCC tissue. The present study aims to explore the function and regulatory mechanism of GPM6A in HCC development and progression. Levels of GPM6A expression in HCC specimens from different disorders and various hepatoma cell lines were determined, and its role on cell proliferation was evaluated in hepatoma cells stably overexpressing GPM6A. Modulation of a specific microRNA (miRNA) on its expression and function was evaluated with miRNA mimetic transfection. Herein, it is reported that much lower GPM6A levels were found in HCC tissues than pericancerous liver tissues and correlated to a poor prognosis. GPM6A overexpression inhibited cell proliferation, suppressed colony formation, migration and invasion in two hepatoma cell types. Available evidence does not support that genetic and epigenetic dysregulation contributes significantly to GPM6A inactivation in HCC. Additional findings demonstrated that miR-96-5p acted directly on the 3'-UTR of the GPM6A gene and significantly decreased its mRNA and protein levels. MiR-96-5p transfection promoted proliferation, migration and invasion of SMMC-7721 and MHCC-97H hepatoma cells; whereas the function of oncogenic microRNA-96 was significantly inhibited in GPM6A-overexpressed hepatoma cells. In conclusion, GPM6A expression in HCC is commonly suppressed regardless its base disease types, and its low expression in HCC tissues is most likely attributed to upregulated miR-96-5p. GPM6A may function as a valuable biomarker for HCC progression and prognosis.

NLRP3 deficiency did not attenuate NASH development under high fat calorie diet plus high fructose and glucose in drinking water.

NOD-like receptor protein 3 (NLRP3) promotes the inflammatory response during progression of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). This study aimed to further delineate the role of NLRP3 in NASH development by abolishing its expression in mice. A high-fat and calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) was used to establish NASH in both wild-type (WT) and NLRP3 knock-out (KO) mice. Hepatocellular injury, hepatic steatosis and fibrosis, as well as inflammatory response and insulin resistance in the liver and epidydimal white adipose tissue (eWAT) were determined. Elevated body weight, liver weight and serum alanine transaminase level, increased hepatic triglyceride accumulation and collagen deposition, and worsened systemic insulin resistance were observed in Nlrp3-/- mice compared to WT mice under HFCD-HF/G feeding. Upregulated hepatic transcription of tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1), and enhanced infiltration of inducible nitric oxide synthase-positive (iNOS+) M1 macrophages were also documented in HFCD-HF/G-fed Nlrp3-/- mice in comparison to HFCD-HF/G-fed WT mice. Moreover, transcription of TNF-α and MCP-1 and infiltration of iNOS+ M1 macrophages were increased in the liver of Nlrp3-/- mice under control diet. NLRP3 deficiency did not attenuate, but instead aggravated NASH development under HFCD-HF/G feeding. The worsened extent of NASH might be attributed to enhanced hepatic MCP-1 expression and M1 macrophage infiltration in Nlrp3-/- mice. Our study points to additional caution when NLRP3 blockade is considered as a therapeutic strategy in the treatment of human NASH.

Hepalatide ameliorated progression of nonalcoholic steatohepatitis in mice.

BACKGROUND: No FDA-approved medications are available for the treatment of nonalcoholic steatohepatitis (NASH). The present study aimed to assess the effects of Hepalatide, a sodium taurocholate cotransporting polypeptide (NTCP) receptor-binding agent, on metabolic and histopathologic changes of a mouse model of NASH caused by high fat/calorie diet plus high fructose/glucose in drinking water (HFCD-HF/G) for 16 weeks. METHODS: Male mice were randomly divided into 4 groups: controls (normal diet), HFCD-HF/G group, HFCD-HF/G plus low or high dose of Hepalatide (20 or 60 mg/kg, LH or HH, s.c. from 9 to 16 weeks). RESULTS: Compared to HFCD-HF/G-fed mice, serum triglyceride and cholesterol levels in mice fed HFCD-HF/G plus LH or HH were decreased. The treatment with Hepalatide decreased serum alanine aminotransferase levels significantly. Liver histology and TUNEL staining showed that Hepalatide remarkably attenuated inflammation, hepatocellular steatosis and apoptosis. Hepalatide treatment decreased fasting blood glucose, serum insulin and HOMA insulin resistance index in the HH group. Moreover, Masson's staining, semi-quantitative score of fibrosis, and hydroxyproline content demonstrated that Hepalatide mitigated fibrotic progression in this murine NASH model. Additionally, most components of liver and few serum bile acids were increased in mice treated with HH. CONCLUSION: Hepalatide effectively alleviated the pathological process, metabolic profile, hepatocellular steatosis and injury, insulin resistance, halted hepatic fibrotic progression in a mouse model of NASH, most likely through the increase of serum bile acids.