Hepatitis C Virus Alters Macrophage Cholesterol Metabolism Through Interaction with Scavenger Receptors

Lipid accumulation and inflammation act together to induce, sustain, and further development of chronic liver disease. Hepatitis C virus (HCV) infection induces metabolic and immune changes in liver macrophages, promoting lipid accumulation and inflammation that synergize and culminate in the develo...

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Veröffentlicht in:Viral immunology 2022-04, Vol.35 (3), p.223-235
Hauptverfasser: Jennelle, Lucas T, Magoro, Tshifhiwa, Angelucci, Angelina R, Dandekar, Aditya, Hahn, Young S
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container_end_page 235
container_issue 3
container_start_page 223
container_title Viral immunology
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creator Jennelle, Lucas T
Magoro, Tshifhiwa
Angelucci, Angelina R
Dandekar, Aditya
Hahn, Young S
description Lipid accumulation and inflammation act together to induce, sustain, and further development of chronic liver disease. Hepatitis C virus (HCV) infection induces metabolic and immune changes in liver macrophages, promoting lipid accumulation and inflammation that synergize and culminate in the development of steatohepatitis and fibrogenesis. Chronic HCV patients have increased liver macrophages with disruptions in cholesterol metabolism and alterations in inflammatory mediators. While HCV-induced changes in inflammatory mediators are well documented, how HCV triggers metabolic change in macrophages is unknown. In this report, we examined the mechanism of macrophage sensing of HCV to cause metabolic impairment and subsequent immune dysfunction. We demonstrate that HCV protein and RNA kinetics in macrophages are distinct from hepatocytes. In macrophages, HCV RNAs and protein accumulate rapidly after exposure but internalized RNAs quickly decline to a low-level set point. Notably, exposure of macrophages to HCV resulted in increased lipids and cholesterol and activation of cholesterol-sensing, immunomodulatory liver X receptors (LXRs). Furthermore, we provide evidence that HCV RNA accumulation in macrophages occurs through scavenging receptors. These results suggest that HCV released from infected hepatocytes stimulates accumulation of lipids and activation of LXR in macrophages contributing to metabolic changes involved in HCV-induced chronic liver disease. Our results provide novel insight into mechanisms through which impaired lipid metabolism in macrophages associated with HCV infection promotes development of liver steatohepatitis and fibrosis.
doi_str_mv 10.1089/vim.2021.0101
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subjects Cell activation
Cholesterol
Cholesterol - metabolism
Chronic infection
Fatty Liver
Fibrosis
Hepacivirus
Hepatitis C
Hepatitis C, Chronic
Hepatocytes
Humans
Immunomodulation
Inflammation
Inflammation - metabolism
Inflammation Mediators - metabolism
Lipid Metabolism
Lipids
Liver diseases
Liver X receptors
Macrophages
Metabolic disorders
Metabolism
Original
Original Articles
Receptors, Scavenger - metabolism
RNA - metabolism
Scavenger receptors
Synergism
title Hepatitis C Virus Alters Macrophage Cholesterol Metabolism Through Interaction with Scavenger Receptors
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