Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic Steatohepatitis
Lipid metabolic dysregulation and liver inflammation have been reported to be associated with nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain unclear. Hepatitis B virus x protein (HBx) is a risk factor for NASH. Based on metabolomic and transcriptomic screens and public dat...
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MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/19/11660 |
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| author | You Lan Bo Qian Hai-Yan Huang Pan Wang Ting Li Qi Yuan Han-Yu Zhang Yu-Chun Lin Zhong-Ning Lin |
| author_facet | You Lan Bo Qian Hai-Yan Huang Pan Wang Ting Li Qi Yuan Han-Yu Zhang Yu-Chun Lin Zhong-Ning Lin |
| author_sort | You Lan |
| collection | DOAJ |
| description | Lipid metabolic dysregulation and liver inflammation have been reported to be associated with nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain unclear. Hepatitis B virus x protein (HBx) is a risk factor for NASH. Based on metabolomic and transcriptomic screens and public database analysis, we found that HBx-expressing hepatocyte-derived prostaglandin E2 (PGE2) induced macrophage polarization imbalance via prostaglandin E2 receptor 4 (EP4) through in vitro, ex vivo, and in vivo models. Here, we revealed that the M1-type polarization of macrophages induced by endoplasmic reticulum oxidoreductase-1-like protein α (ERO1α)-dependent endoplasmic reticulum stress was associated with the HBx-related hepatic NASH phenotype. Mechanistically, HBx promoted Niemann–Pick type C1 (NPC1)/oxysterol-binding protein-related protein 5 (ORP5)-mediated cholesterol transport from the lysosome to the endoplasmic reticulum via mammalian target of rapamycin (mTOR) activation. This study provides a novel basis for screening potential biomarkers in the macrophage mTOR–cholesterol homeostasis–polarization regulatory signaling pathway and evaluating targeted interventions for HBx-associated NASH. |
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| id | doaj.art-e287dfdc1b3142a5afa320a844962694 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:38:42Z |
| publishDate | 2022-10-01 |
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| spelling | doaj.art-e287dfdc1b3142a5afa320a8449626942023-11-23T20:37:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123191166010.3390/ijms231911660Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic SteatohepatitisYou Lan0Bo Qian1Hai-Yan Huang2Pan Wang3Ting Li4Qi Yuan5Han-Yu Zhang6Yu-Chun Lin7Zhong-Ning Lin8State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, ChinaState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, ChinaState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, ChinaState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, ChinaState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, ChinaState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, ChinaState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, ChinaState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, ChinaState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, ChinaLipid metabolic dysregulation and liver inflammation have been reported to be associated with nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain unclear. Hepatitis B virus x protein (HBx) is a risk factor for NASH. Based on metabolomic and transcriptomic screens and public database analysis, we found that HBx-expressing hepatocyte-derived prostaglandin E2 (PGE2) induced macrophage polarization imbalance via prostaglandin E2 receptor 4 (EP4) through in vitro, ex vivo, and in vivo models. Here, we revealed that the M1-type polarization of macrophages induced by endoplasmic reticulum oxidoreductase-1-like protein α (ERO1α)-dependent endoplasmic reticulum stress was associated with the HBx-related hepatic NASH phenotype. Mechanistically, HBx promoted Niemann–Pick type C1 (NPC1)/oxysterol-binding protein-related protein 5 (ORP5)-mediated cholesterol transport from the lysosome to the endoplasmic reticulum via mammalian target of rapamycin (mTOR) activation. This study provides a novel basis for screening potential biomarkers in the macrophage mTOR–cholesterol homeostasis–polarization regulatory signaling pathway and evaluating targeted interventions for HBx-associated NASH.https://www.mdpi.com/1422-0067/23/19/11660hepatitis B virus x proteinprostaglandin E2lysosomal mTOR-NPC1 signal axischolesterol transportendoplasmic reticulum stressmacrophage M1-type polarization |
| spellingShingle | You Lan Bo Qian Hai-Yan Huang Pan Wang Ting Li Qi Yuan Han-Yu Zhang Yu-Chun Lin Zhong-Ning Lin Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic Steatohepatitis International Journal of Molecular Sciences hepatitis B virus x protein prostaglandin E2 lysosomal mTOR-NPC1 signal axis cholesterol transport endoplasmic reticulum stress macrophage M1-type polarization |
| title | Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic Steatohepatitis |
| title_full | Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic Steatohepatitis |
| title_fullStr | Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic Steatohepatitis |
| title_full_unstemmed | Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic Steatohepatitis |
| title_short | Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic Steatohepatitis |
| title_sort | hepatocyte derived prostaglandin e2 modulated macrophage m1 type polarization via mtor npc1 axis regulated cholesterol transport from lysosomes to the endoplasmic reticulum in hepatitis b virus x protein related nonalcoholic steatohepatitis |
| topic | hepatitis B virus x protein prostaglandin E2 lysosomal mTOR-NPC1 signal axis cholesterol transport endoplasmic reticulum stress macrophage M1-type polarization |
| url | https://www.mdpi.com/1422-0067/23/19/11660 |
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