Induction of phospholipase A2 group 4C by HCV infection regulates lipid droplet formation
Background & Aims: Hepatic steatosis, characterized by lipid accumulation in hepatocytes, is a key diagnostic feature in patients with chronic hepatitis C virus (HCV) infection. This study aimed to clarify the involvement of phospholipid metabolic pathways in the pathogenesis of HCV-induced...
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Elsevier
2025-01-01
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| Series: | JHEP Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555924002295 |
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| author | Masahiko Ito Jie Liu Masayoshi Fukasawa Koji Tsutsumi Yumi Kanegae Mitsutoshi Setou Michinori Kohara Tetsuro Suzuki |
| author_facet | Masahiko Ito Jie Liu Masayoshi Fukasawa Koji Tsutsumi Yumi Kanegae Mitsutoshi Setou Michinori Kohara Tetsuro Suzuki |
| author_sort | Masahiko Ito |
| collection | DOAJ |
| description | Background & Aims: Hepatic steatosis, characterized by lipid accumulation in hepatocytes, is a key diagnostic feature in patients with chronic hepatitis C virus (HCV) infection. This study aimed to clarify the involvement of phospholipid metabolic pathways in the pathogenesis of HCV-induced steatosis. Methods: The expression and distribution of lipid species in the livers of human liver chimeric mice were analyzed using imaging mass spectrometry. Triglyceride accumulation and lipid droplet formation were studied in phospholipase A2 group 4C (PLA2G4C) knockout or overexpressing cells. Results: Imaging mass spectrometry of the infected mouse model revealed increased lysophosphatidylcholine levels and decreased phosphatidylcholine levels in HCV-positive regions of the liver. Among the transcripts associated with phosphatidylcholine biosynthesis, upregulation of PLA2G4C mRNA was most pronounced following HCV infection. Activation of the transcription factor NF-κB and upregulation of c-Myc were important for activation of PLA2G4C transcription by HCV infection and expression of the viral proteins Core-NS2. The amount and size of lipid droplets were reduced in PLA2G4C-knockout cells. Inhibition of NF-κB or c-Myc activity suppressed lipid droplet formation in HCV-infected cells. HCV infection promoted the stabilization of lipid droplets, but this stability was reduced in PLA2G4C-knockout cells. Overexpression of PLA2G4C decreased the levels of phosphatidylcholine species in the lipid droplet fraction and led to lower levels of key factors involved in lipolysis (breakdown of triglycerides into glycerol and free fatty acids), such as ATGL, PLIN1 and ABHD5 on the lipid droplets. Conclusions: HCV infection markedly increases PLA2G4C expression. This may alter the phospholipid composition of the lipid droplet membrane, leading to stabilization and enlargement of the droplets. Impact and implications:: The involvement of phospholipid metabolism pathways in the pathogenesis of hepatitis C virus (HCV)-related liver diseases remains unclear. We found that PLA2G4C expression is upregulated through NF-κB and c-Myc activation upon HCV infection, and this upregulation is associated with a decrease in phosphatidylcholine species. The increased expression of PLA2G4C resulted in changes in the phospholipid composition of lipid droplets, led to the dissociation of lipolysis-related factors from the lipid droplet surface and the accumulation of lipid content within the droplets. These findings suggest that the disruption of the phospholipid metabolism pathway caused by HCV infection may contribute to the development of HCV-associated fatty liver. It would be interesting to determine whether alcohol- and/or metabolic dysfunction-associated steatohepatitis are also associated with increased PLA2 activity, altered phospholipid composition and decreased levels of ATGL and its cofactors in lipid droplet membranes. |
| format | Article |
| id | doaj-art-fdf11cc526dc486cabaf1a0434e8d00a |
| institution | Kabale University |
| issn | 2589-5559 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | JHEP Reports |
| spelling | doaj-art-fdf11cc526dc486cabaf1a0434e8d00a2025-01-10T04:38:04ZengElsevierJHEP Reports2589-55592025-01-0171101225Induction of phospholipase A2 group 4C by HCV infection regulates lipid droplet formationMasahiko Ito0Jie Liu1Masayoshi Fukasawa2Koji Tsutsumi3Yumi Kanegae4Mitsutoshi Setou5Michinori Kohara6Tetsuro Suzuki7Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Hamamatsu, JapanDepartment of Microbiology and Immunology, Hamamatsu University School of Medicine, Hamamatsu, JapanDepartment of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, JapanDepartment of Biosciences, Kitasato University, Sagamihara, JapanCore Research Facilities, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, JapanDepartment of Cellular & Molecular Anatomy, Hamamatsu University School of Medicine, Hamamatsu, JapanDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, JapanDepartment of Microbiology and Immunology, Hamamatsu University School of Medicine, Hamamatsu, Japan; Corresponding author. Address: Department of Microbiology and Immunology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 4313192, Japan; Tel.: (81)-53-4352336.Background & Aims: Hepatic steatosis, characterized by lipid accumulation in hepatocytes, is a key diagnostic feature in patients with chronic hepatitis C virus (HCV) infection. This study aimed to clarify the involvement of phospholipid metabolic pathways in the pathogenesis of HCV-induced steatosis. Methods: The expression and distribution of lipid species in the livers of human liver chimeric mice were analyzed using imaging mass spectrometry. Triglyceride accumulation and lipid droplet formation were studied in phospholipase A2 group 4C (PLA2G4C) knockout or overexpressing cells. Results: Imaging mass spectrometry of the infected mouse model revealed increased lysophosphatidylcholine levels and decreased phosphatidylcholine levels in HCV-positive regions of the liver. Among the transcripts associated with phosphatidylcholine biosynthesis, upregulation of PLA2G4C mRNA was most pronounced following HCV infection. Activation of the transcription factor NF-κB and upregulation of c-Myc were important for activation of PLA2G4C transcription by HCV infection and expression of the viral proteins Core-NS2. The amount and size of lipid droplets were reduced in PLA2G4C-knockout cells. Inhibition of NF-κB or c-Myc activity suppressed lipid droplet formation in HCV-infected cells. HCV infection promoted the stabilization of lipid droplets, but this stability was reduced in PLA2G4C-knockout cells. Overexpression of PLA2G4C decreased the levels of phosphatidylcholine species in the lipid droplet fraction and led to lower levels of key factors involved in lipolysis (breakdown of triglycerides into glycerol and free fatty acids), such as ATGL, PLIN1 and ABHD5 on the lipid droplets. Conclusions: HCV infection markedly increases PLA2G4C expression. This may alter the phospholipid composition of the lipid droplet membrane, leading to stabilization and enlargement of the droplets. Impact and implications:: The involvement of phospholipid metabolism pathways in the pathogenesis of hepatitis C virus (HCV)-related liver diseases remains unclear. We found that PLA2G4C expression is upregulated through NF-κB and c-Myc activation upon HCV infection, and this upregulation is associated with a decrease in phosphatidylcholine species. The increased expression of PLA2G4C resulted in changes in the phospholipid composition of lipid droplets, led to the dissociation of lipolysis-related factors from the lipid droplet surface and the accumulation of lipid content within the droplets. These findings suggest that the disruption of the phospholipid metabolism pathway caused by HCV infection may contribute to the development of HCV-associated fatty liver. It would be interesting to determine whether alcohol- and/or metabolic dysfunction-associated steatohepatitis are also associated with increased PLA2 activity, altered phospholipid composition and decreased levels of ATGL and its cofactors in lipid droplet membranes.http://www.sciencedirect.com/science/article/pii/S2589555924002295HCVliver steatosishuman hepatocyte chimeric micelipidome analysisPLA2G4C |
| spellingShingle | Masahiko Ito Jie Liu Masayoshi Fukasawa Koji Tsutsumi Yumi Kanegae Mitsutoshi Setou Michinori Kohara Tetsuro Suzuki Induction of phospholipase A2 group 4C by HCV infection regulates lipid droplet formation JHEP Reports HCV liver steatosis human hepatocyte chimeric mice lipidome analysis PLA2G4C |
| title | Induction of phospholipase A2 group 4C by HCV infection regulates lipid droplet formation |
| title_full | Induction of phospholipase A2 group 4C by HCV infection regulates lipid droplet formation |
| title_fullStr | Induction of phospholipase A2 group 4C by HCV infection regulates lipid droplet formation |
| title_full_unstemmed | Induction of phospholipase A2 group 4C by HCV infection regulates lipid droplet formation |
| title_short | Induction of phospholipase A2 group 4C by HCV infection regulates lipid droplet formation |
| title_sort | induction of phospholipase a2 group 4c by hcv infection regulates lipid droplet formation |
| topic | HCV liver steatosis human hepatocyte chimeric mice lipidome analysis PLA2G4C |
| url | http://www.sciencedirect.com/science/article/pii/S2589555924002295 |
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