PMID- 32132633
OWN - NLM
STAT- MEDLINE
DCOM- 20201109
LR  - 20210304
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 10
IP  - 1
DP  - 2020 Mar 4
TI  - Very-long-chain fatty acid metabolic capacity of 17-beta-hydroxysteroid 
      dehydrogenase type 12 (HSD17B12) promotes replication of hepatitis C virus and 
      related flaviviruses.
PG  - 4040
LID - 10.1038/s41598-020-61051-w [doi]
LID - 4040
AB  - Flaviviridae infections represent a major global health burden. By deciphering 
      mechanistic aspects of hepatitis C virus (HCV)-host interactions, one could 
      discover common strategy for inhibiting the replication of related flaviviruses. 
      By elucidating the HCV interactome, we identified the 17-beta-hydroxysteroid 
      dehydrogenase type 12 (HSD17B12) as a human hub of the very-long-chain fatty acid 
      (VLCFA) synthesis pathway and core interactor. Here we show that HSD17B12 
      knockdown (KD) impairs HCV replication and reduces virion production. 
      Mechanistically, depletion of HSD17B12 induces alterations in VLCFA-containing 
      lipid species and a drastic reduction of lipid droplets (LDs) that play a 
      critical role in virus assembly. Oleic acid supplementation rescues viral RNA 
      replication and production of infectious particles in HSD17B12 depleted cells, 
      supporting a specific role of VLCFA in HCV life cycle. Furthermore, the 
      small-molecule HSD17B12 inhibitor, INH-12, significantly reduces replication and 
      infectious particle production of HCV as well as dengue virus and Zika virus 
      revealing a conserved requirement across Flaviviridae virus family. Overall, the 
      data provide a strong rationale for the advanced evaluation of HSD17B12 
      inhibition as a promising broad-spectrum antiviral strategy for the treatment of 
      Flaviviridae infections.
FAU - Mohamed, Bassim
AU  - Mohamed B
AD  - Centre de Recherche du CHUM (CRCHUM) et Faculte de Medecine, Universite de 
      Montreal, Montreal, Canada.
AD  - Pharmacology Department, Medical Research Division, National Research Centre, 
      Cairo, Egypt.
FAU - Mazeaud, Clement
AU  - Mazeaud C
AD  - Institut National de la Recherche Scientifique, Centre Armand-Frappier Sante 
      Biotechnologie, Universite du Quebec, Laval, Canada.
FAU - Baril, Martin
AU  - Baril M
AD  - Centre de Recherche du CHUM (CRCHUM) et Faculte de Medecine, Universite de 
      Montreal, Montreal, Canada.
FAU - Poirier, Donald
AU  - Poirier D
AD  - Centre de recherche du CHU de Quebec et Faculte de medecine, Universite Laval, 
      Quebec, Canada.
FAU - Sow, Aissatou Aicha
AU  - Sow AA
AD  - Institut National de la Recherche Scientifique, Centre Armand-Frappier Sante 
      Biotechnologie, Universite du Quebec, Laval, Canada.
FAU - Chatel-Chaix, Laurent
AU  - Chatel-Chaix L
AD  - Institut National de la Recherche Scientifique, Centre Armand-Frappier Sante 
      Biotechnologie, Universite du Quebec, Laval, Canada.
FAU - Titorenko, Vladimir
AU  - Titorenko V
AUID- ORCID: 0000-0001-5819-7545
AD  - Concordia University, Montreal, Canada.
FAU - Lamarre, Daniel
AU  - Lamarre D
AD  - Centre de Recherche du CHUM (CRCHUM) et Faculte de Medecine, Universite de 
      Montreal, Montreal, Canada. daniel.lamarre@umontreal.ca.
AD  - Department of Pathology, Case Western Reserve University, 2103 Cornell Road, 
      Cleveland, Ohio, 44106, USA. daniel.lamarre@umontreal.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200304
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 2UMI9U37CP (Oleic Acid)
RN  - EC 1.1.- (17-Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.- (17beta-hydroxysteroid dehydrogenase type 3)
SB  - IM
MH  - 17-Hydroxysteroid Dehydrogenases/genetics/*metabolism
MH  - Animals
MH  - Chlorocebus aethiops
MH  - HeLa Cells
MH  - Hep G2 Cells
MH  - Hepacivirus/*physiology
MH  - Hepatitis C/*enzymology/genetics
MH  - Humans
MH  - Oleic Acid/*pharmacology
MH  - Vero Cells
MH  - Virus Replication/*drug effects/genetics
PMC - PMC7055353
COIS- The authors declare no competing interests.
EDAT- 2020/03/07 06:00
MHDA- 2020/11/11 06:00
PMCR- 2020/03/04
CRDT- 2020/03/06 06:00
PHST- 2019/06/12 00:00 [received]
PHST- 2020/02/10 00:00 [accepted]
PHST- 2020/03/06 06:00 [entrez]
PHST- 2020/03/07 06:00 [pubmed]
PHST- 2020/11/11 06:00 [medline]
PHST- 2020/03/04 00:00 [pmc-release]
AID - 10.1038/s41598-020-61051-w [pii]
AID - 61051 [pii]
AID - 10.1038/s41598-020-61051-w [doi]
PST - epublish
SO  - Sci Rep. 2020 Mar 4;10(1):4040. doi: 10.1038/s41598-020-61051-w.