Treatment-Induced Viral Cure of Hepatitis C Virus-Infected Patients Involves a Dynamic Interplay among three Important Molecular Players in Lipid Homeostasis: Circulating microRNA (miR)-24, miR-223, and Proprotein Convertase Subtilisin/Kexin Type 9

• Published in: EBioMedicine 2017-09, Vol.23 (C), p.68-78
• Main Authors: Hyrina, Anastasia, Olmstead, Andrea D., Steven, Paul, Krajden, Mel, Tam, Edward, Jean, François
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Antiviral therapy; Biomarkers; Cell Line; Cells, Cultured; Circulating MicroRNA; Enzyme-Linked Immunosorbent Assay; Female; Genotype; Hepacivirus - genetics; Hepatitis C - drug therapy; Hepatitis C - genetics; Hepatitis C - metabolism; Hepatitis C - virology; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - genetics; Hepatitis C, Chronic - metabolism; Hepatitis C, Chronic - virology; Homeostasis; Humans; Lipid Metabolism; Male; MicroRNAs - genetics; miR-122; miR-223; miR-24; Models, Molecular; Molecular Conformation; Mutation; Proprotein Convertase 9 - chemistry; Proprotein Convertase 9 - genetics; Proprotein Convertase 9 - metabolism; Proprotein convertase subtilisin/kexin type 9; Protein Binding; Receptors, LDL - chemistry; Receptors, LDL - metabolism; Research Design; Research Paper; Viral Load
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2017.08.020

In patients with chronic hepatitis C virus (HCV) infection, viral hijacking of the host-cell biosynthetic pathways is associated with altered lipid metabolism, which contributes to disease progression and may influence antiviral response. We investigated the molecular interplay among four key regulators of lipid homeostasis [microRNA (miR)-122, miR-24, miR-223, and proprotein convertase subtilisin/kexin type 9 (PCSK9)] in HCV-infected patients (n=72) who achieved a treatment-based viral cure after interferon-based therapy with first-generation direct-acting antivirals. Real-time PCR was used to quantify microRNA plasma levels, and ELISA assays were used to determine plasma concentrations of PCSK9. We report that levels of miR-24 and miR-223 significantly increased in patients achieving sustained virologic response (SVR), whereas the levels of miR-122, a liver-specific cofactor for HCV infection, decreased in these patients. PCSK9 concentrations were significantly increased in SVRs, suggesting that PCSK9 may help impede viral infection. The modulatory effect of PCSK9 on HCV infection was also demonstrated in the context of HCV-infected Huh-7.5.1 cells employing recombinant human PCSK9 mutants. Together, these results provide insights into a novel coordinated interplay among three important molecular players in lipid homeostasis — circulating miR-24, miR-223 and PCSK9 — whose regulation is affected by HCV infection and treatment-based viral cure. •Our study implicates an effect of CHC infection on lipid homeostasis via modulation of circulating regulatory markers.•Differential levels of circulating regulators of lipid metabolism (miR-24, miR-223, PCSK9) are associated with SVRs.•Wild type, loss-of-function and gain-of-function mutants showed PCSK9 could inhibit HCV replication in human hepatoma cells. The hepatitis C virus (HCV)-related disease burden continues to increase as the infected population develops more serious liver diseases. Interestingly, cholesterol and lipid metabolism are dysregulated in HCV-infected patients, suggesting that lipid regulatory molecules could play a role in the development and progression of HCV-associated liver diseases. The relationships among four molecules that regulate lipid metabolism were examined in plasma samples from patients undergoing treatment for chronic HCV infection. This research identified correlations among these molecules and treatment success suggesting that differential levels of circulating regulators of