Temporal proteome and lipidome profiles reveal hepatitis C virus-associated reprogramming of hepatocellular metabolism and bioenergetics.
Proteomic and lipidomic profiling was performed over a time course of acute hepatitis C virus (HCV) infection in cultured Huh-7.5 cells to gain new insights into the intracellular processes influenced by this virus. Our proteomic data suggest that HCV induces early perturbations in glycolysis, the pentose phosphate pathway, and the citric acid cycle, which favor host biosynthetic activities supporting viral replication and propagation. This is followed by a compensatory shift in metabolism aimed at maintaining energy homeostasis and cell viability during elevated viral replication and increasing cellular stress. Complementary lipidomic analyses identified numerous temporal perturbations in select lipid species (e.g. phospholipids and sphingomyelins) predicted to play important roles in viral replication and downstream assembly and secretion events. The elevation of lipotoxic ceramide species suggests a potential link between HCV-associated biochemical alterations and the direct cytopathic effect observed in this in vitro system. Using innovative computational modeling approaches, we further identified mitochondrial fatty acid oxidation enzymes, which are comparably regulated during in vitro infection and in patients with histological evidence of fibrosis, as possible targets through which HCV regulates temporal alterations in cellular metabolic homeostasis.
Diamond
Deborah L
DL
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA. ddiamond@u.washington.edu
Syder
Andrew J
AJ
Jacobs
Jon M
JM
Sorensen
Christina M
CM
Walters
Kathie-Anne
KA
Proll
Sean C
SC
McDermott
Jason E
JE
Gritsenko
Marina A
MA
Zhang
Qibin
Q
Zhao
Rui
R
Metz
Thomas O
TO
Camp
David G
DG
Waters
Katrina M
KM
Smith
Richard D
RD
Rice
Charles M
CM
Katze
Michael G
MG
D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D004734:Energy Metabolism / Q000502:physiology; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D008055:Lipids / Q000032:analysis*; D008099:Liver / Q000378:metabolism* / Q000821:virology*; D013058:Mass Spectrometry; D011506:Proteins / Q000032:analysis* / Q000378:metabolism; D020543:Proteome; D014779:Virus Replication
D008055:Lipids; D011506:Proteins; D020543:Proteome