Lysophosphatidylcholine acyltransferase 1 is downregulated by hepatitis C virus: impact on production of lipo-viro-particles

Frauke Beilstein (1, 2) , Matthieu Lemasson (3) , Véronique Pène (3) , Dominique Rainteau (4) , Sylvie Demignot (1, 2) , Arielle R Rosenberg (5, 3)

1 CRC - Centre de Recherche des Cordeliers
2 EPHE - École Pratique des Hautes Études
3 EA 4474 - Virologie de l'hépatite C
4 LBM-E4 - Microorganismes, Molécules Bioactives et Physiopathologie Intestinale
5 Service de Virologie [CHU Cochin]

Objective: HCV is intimately linked with the liver lipid metabolism, devoted to the efflux of triacylglycerols stored in lipid droplets (LDs) in the form of triacylglycerol-rich very-low-density lipoproteins (VLDLs): (i) the most infectious HCV particles are those of lowest density due to association with triacylglycerol-rich lipoproteins and (ii) HCV-infected patients frequently develop hepatic steatosis (increased triacylglycerol storage). The recent identification of lysophosphatidylcholine acyltransferase 1 (LPCAT1) as an LD phospholipid-remodelling enzyme prompted us to investigate its role in liver lipid metabolism and HCV infectious cycle. Design Huh-7.5.1 cells and primary human hepatocytes (PHHs) were infected with JFH1-HCV. LPCAT1 depletion was achieved by RNA interference. Cells were monitored for LPCAT1 expression, lipid metabolism and HCV production and infectivity. The density of viral particles was assessed by isopycnic ultracentrifugation. Results: Upon HCV infection, both Huh-7.5.1 cells and PHH had decreased levels of LPCAT1 transcript and protein, consistent with transcriptional downregulation. LPCAT1 depletion in either naive or infected Huh-7.5.1 cells resulted in altered lipid metabolism characterised by LD remodelling, increased triacylglycerol storage and increased secretion of VLDL. In infected Huh-7.5.1 cells or PHH, LPCAT1 depletion increased production of the viral particles of lowest density and highest infectivity. Conclusions: We have identified LPCAT1 as a modulator of liver lipid metabolism downregulated by HCV, which appears as a viral strategy to increase the triacylglycerol content and hence infectivity of viral particles. Targeting this metabolic pathway may represent an attractive therapeutic approach to reduce both the viral titre and hepatic steatosis.

Domaines: Virologie; Maladies infectieuses

Frauke Beilstein, Matthieu Lemasson, Véronique Pène, Dominique Rainteau, Sylvie Demignot, et al.. Lysophosphatidylcholine acyltransferase 1 is downregulated by hepatitis C virus: impact on production of lipo-viro-particles. Gut, 2016, 66, pp.2160-2169. ⟨10.1136/gutjnl-2016-311508⟩. ⟨hal-01366451⟩