Abstract
During replication, hepatitis C virus (HCV) utilizes macromolecules produced by its host cell. This process requires host cellular metabolic reprogramming to favor elevated levels of aerobic glycolysis. Therefore, we evaluated whether pyruvate dehydrogenase kinase (PDK), a mitochondrial enzyme that promotes aerobic glycolysis, can regulate HCV replication. Levels of c-Myc, hypoxia-inducible factor-1α (HIF-1α), PDK1, PDK3, glucokinase, and serine biosynthetic enzymes were compared between HCV-infected and uninfected human liver and Huh-7.5 cells infected with or without HCV. Protein and mRNA expression of c-Myc, HIF-1α, and glycolytic enzymes were significantly higher in HCV-infected human liver and hepatocytes than in uninfected controls. This increase was accompanied by upregulation of serine biosynthetic enzymes, suggesting cellular metabolism was altered toward facilitated nucleotide synthesis essential for HCV replication. JQ1, a c-Myc inhibitor, and dichloroacetate (DCA), a PDK inhibitor, decreased the expression of glycolytic and serine synthetic enzymes in HCV-infected hepatocytes, resulting in suppressed viral replication. Furthermore, when co-administered with IFN-α or ribavirin, DCA further inhibited viral replication. In summary, HCV reprograms host cell metabolism to favor glycolysis and serine biosynthesis; this is mediated, at least in part, by increased PDK activity, which provides a surplus of nucleotide precursors. Therefore, blocking PDK activity might have therapeutic benefits against HCV replication.
Highlights
At least 185 million people around the world are infected by hepatitis C virus (HCV)[1,2]
We found that protein and mRNA expression levels of pyruvate dehydrogenase kinase (PDK) was elevated in HCV-infected hepatocytes
Because de novo synthesized serine and glycine are utilized in nucleotide synthesis, we hypothesized that these metabolic changes create a cellular milieu that favors rapid HCV replication
Summary
At least 185 million people around the world are infected by hepatitis C virus (HCV)[1,2]. Given that modulation of PDK activity can determine the metabolic balance between oxidative phosphorylation and aerobic glycolysis within a cell[15], and that serine is derived from the early glycolytic intermediate 3-phosphoglycerate, we reasoned that inhibiting PDK activity would disturb serine/glycine synthesis, thereby inhibiting HCV replication. It is unclear whether blocking glycolysis by modulating PDK will inhibit HCV replication, as it does for cancer cells. We show that the PDK inhibitor dichloroacetate (DCA) shifts glucose metabolism away from aerobic glycolysis and subsequently inhibits the serine biosynthetic pathway in HCV-infected hepatocytes, thereby blocking HCV replication
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