IFISE   05411
INSTITUTO DE FISIOLOGIA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
Arylacetamide deacetylase: A novel host factor with important roles in the lipolysis of cellular triacylglycerol stores, VLDL assembly and HCV production.
Autor/es:
NOURBAKHSH, M; DOUGLAS, DN; PU, CH; LEWIS, JT; KAWAHARA, T; LISBOA, LF; WEI, E; ASTHANA, S; QUIROGA, ARIEL DARIO; LAW, LM; CHEN, C; ADDISON, WR; NELSON, RANDY; HOUGHTON, M; LEHNER, RICHARD; KNETEMAN, NM
Revista:
JOURNAL OF HEPATOLOGY
Editorial:
ELSEVIER SCIENCE BV
Referencias:
Lugar: Amsterdam; Año: 2013 p. 1 - 8
ISSN:
0168-8278
Resumen:
Background &
Aims
Very low density
lipoproteins (VLDLs) are triacylglycerol (TG)-rich lipoproteins produced by the
human liver. VLDLs derive the majority of their TG cargo from the lipolysis of
TG stored in hepatocellular lipid droplets (LDs). Important roles for LDs and
the VLDL secretory pathway in the cell culture production of infectious
hepatitis C virus (HCV) have been established. We hypothesized that TG
lipolysis and VLDL production are impaired during HCV infection so that these
cellular processes can be diverted towards HCV production.
Methods
We used an HCV
permissive cell culture system (JFH-1/HuH7.5 cells) to examine the relationship
between TG lipolysis, VLDL assembly, and the HCV lifecycle using standard
biochemical approaches.
Results
Lipolysis of
cellular TG and VLDL production were impaired in HCV infected cells during the
early peak of viral infection. This was partially explained by an apparent
deficiency of a putative TG lipase, arylacetamide deacetylase (AADAC). The
re-introduction of AADAC to infected cells restored cellular TG lipolysis,
indicating a role for HCV-mediated downregulation of AADAC in this process.
Defective lipolysis of cellular TG stores and VLDL production were also
observed in HuH7.5 cells stably expressing a short hairpin RNA targeting AADAC
expression, proving AADAC deficiency contributes to these defective pathways.
Finally, impaired production of HCV was observed with AADAC knockdown cells,
demonstrating a role for AADAC in the HCV lifecycle.
Conclusions
This insight into
the biology of HCV infection and possibly pathogenesis identifies AADAC as a
novel and translationally relevant therapeutic target.