The aryl hydrocarbon receptor-cytochrome P450 1A1 pathway controls lipid accumulation and enhances the permissiveness for hepatitis C virus assembly.

Abstract

Viruses hijack and modify host cell functions to maximize viral proliferation. Hepatitis C virus (HCV) reorganizes host cell metabolism to produce specialized membrane structures and to modify organelles such as double-membrane vesicles and enlarged lipid droplets (LDs), thereby enabling virus replication and assembly. However, the molecular bases of these host-HCV interactions are largely unknown. Here, using a chemical screen, we demonstrate that the benzamide derivative flutamide reduces the host capacity to produce infectious HCV. Flutamide disrupted the formation of enlarged LDs in HCV-infected cells, thereby abolishing HCV assembly. We also report that aryl hydrocarbon receptor (AhR), a known flutamide target, plays a key role in mediating LD accumulation and HCV production. This AhR function in lipid production was also observed in HCV-uninfected Huh-7 cells and primary human hepatocytes, suggesting that AhR signaling regulates lipid accumulation independently of HCV infection. We further observed that a downstream activity, that of cytochrome P450 1A1 (CYP1A1), was the primary regulator of AhR-mediated lipid production. Specifically, blockade of AhR-induced CYP1A1 up-regulation counteracted LD overproduction, and overproduction of CYP1A1, but not of CYP1B1, in AhR-inactivated cells restored lipid accumulation. Of note, HCV infection up-regulated the AhR-CYP1A1 pathway, resulting in the accumulation of enlarged LDs. In conclusion, we demonstrate that the AhR-CYP1A1 pathway has a significant role in lipid accumulation, a hallmark of HCV infection that maximizes progeny virus production. Our chemical-genetic analysis reveals a new strategy and lead compounds to control hepatic lipid accumulation as well as HCV infection.

• Authors: Hirofumi Ohashi, Kazane Nishioka, Syo Nakajima, Sulyi Kim, Ryosuke Suzuki, Hideki Aizaki, Masayoshi Fukasawa, Shinji Kamisuki, Fumio Sugawara, Naoko Ohtani, Masamichi Muramatsu, Takaji Wakita, Koichi Watashi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 51 Pg. 19559-19571 (12 21 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 30381393 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Ohashi et al.

Chemical References

• Receptors, Aryl Hydrocarbon
• Flutamide
• Cytochrome P-450 CYP1A1

Topics

• Cell Line
• Cytochrome P-450 CYP1A1 (metabolism)
• Flutamide (pharmacology)
• Hepacivirus (drug effects, physiology)
• Humans
• Lipid Droplets (drug effects, metabolism)
• Lipid Metabolism (drug effects)
• Protein Binding
• Receptors, Aryl Hydrocarbon (metabolism)
• Virus Assembly (drug effects)