USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages
Abstract Background The focus of studies on high-density lipoproteins (HDL) has shifted from HDL-cholesterol (HDL-C) to HDL function. We recently demonstrated that low USF1 expression in mice and humans associates with high plasma HDL-C and low triglyceride levels, as well as protection against obes...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-12-01
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| Series: | Lipids in Health and Disease |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12944-018-0930-2 |
| _version_ | 1819021221273010176 |
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| author | Maija Ruuth Jarkko Soronen Essi Kaiharju Krista Merikanto Julia Perttilä Jari Metso Miriam Lee-Rueckert Marja-Riitta Taskinen Petri T. Kovanen Katariina Öörni Vesa M. Olkkonen Matti S. Jauhiainen Pirkka-Pekka Laurila |
| author_facet | Maija Ruuth Jarkko Soronen Essi Kaiharju Krista Merikanto Julia Perttilä Jari Metso Miriam Lee-Rueckert Marja-Riitta Taskinen Petri T. Kovanen Katariina Öörni Vesa M. Olkkonen Matti S. Jauhiainen Pirkka-Pekka Laurila |
| author_sort | Maija Ruuth |
| collection | DOAJ |
| description | Abstract Background The focus of studies on high-density lipoproteins (HDL) has shifted from HDL-cholesterol (HDL-C) to HDL function. We recently demonstrated that low USF1 expression in mice and humans associates with high plasma HDL-C and low triglyceride levels, as well as protection against obesity, insulin resistance, and atherosclerosis. Here, we studied the impact of USF1 deficiency on HDL functional capacity and macrophage atherogenic functions, including inflammation, cholesterol efflux, and cholesterol accumulation. Methods We used a congenic Usf1 deficient mice in C57Bl/6JRccHsd background and blood samples were collected to isolate HDL for structural and functional studies. Lentiviral preparations containing the USF1 silencing shRNA expression vector were used to silence USF1 in human THP-1 and Huh-7 cells. Cholesterol efflux from acetyl-LDL loaded THP-1 macrophages was measured using HDL and plasma as acceptors. Gene expression analysis from USF1 silenced peritoneal macrophages was carried out using Affymetrix protocols. Results We show that Usf1 deficiency not only increases HDL-C levels in vivo, consistent with elevated ABCA1 protein expression in hepatic cell lines, but also improves the functional capacity of HDL particles. HDL particles derived from Usf1 deficient mice remove cholesterol more efficiently from macrophages, attributed to their higher contents of phospholipids. Furthermore, silencing of USF1 in macrophages enhanced the cholesterol efflux capacity of these cells. These findings are consistent with reduced inflammatory burden of USF1 deficient macrophages, manifested by reduced secretion of pro-inflammatory cytokines MCP-1 and IL-1β and protection against inflammation-induced macrophage cholesterol accumulation in a cell-autonomous manner. Conclusions Our findings identify USF1 as a novel factor regulating HDL functionality, showing that USF1 inactivation boosts cholesterol efflux, reduces macrophage inflammation and attenuates macrophage cholesterol accumulation, linking improved macrophage cholesterol metabolism and inflammatory pathways to the antiatherogenic function of USF1 deficiency. |
| first_indexed | 2024-12-21T04:03:39Z |
| format | Article |
| id | doaj.art-2cd6a50d4fb14b3aa27cb47c48a2f327 |
| institution | Directory Open Access Journal |
| issn | 1476-511X |
| language | English |
| last_indexed | 2024-12-21T04:03:39Z |
| publishDate | 2018-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Lipids in Health and Disease |
| spelling | doaj.art-2cd6a50d4fb14b3aa27cb47c48a2f3272022-12-21T19:16:39ZengBMCLipids in Health and Disease1476-511X2018-12-0117111110.1186/s12944-018-0930-2USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophagesMaija Ruuth0Jarkko Soronen1Essi Kaiharju2Krista Merikanto3Julia Perttilä4Jari Metso5Miriam Lee-Rueckert6Marja-Riitta Taskinen7Petri T. Kovanen8Katariina Öörni9Vesa M. Olkkonen10Matti S. Jauhiainen11Pirkka-Pekka Laurila12Wihuri Research InstituteGenomics and Biomarkers Unit, National Institute for Health and WelfareGenomics and Biomarkers Unit, National Institute for Health and WelfareGenomics and Biomarkers Unit, National Institute for Health and WelfareMinerva Foundation Institute for Medical ResearchGenomics and Biomarkers Unit, National Institute for Health and WelfareWihuri Research InstituteDiabetes and Obesity Research Program, University of HelsinkiWihuri Research InstituteWihuri Research InstituteMinerva Foundation Institute for Medical ResearchGenomics and Biomarkers Unit, National Institute for Health and WelfareGenomics and Biomarkers Unit, National Institute for Health and WelfareAbstract Background The focus of studies on high-density lipoproteins (HDL) has shifted from HDL-cholesterol (HDL-C) to HDL function. We recently demonstrated that low USF1 expression in mice and humans associates with high plasma HDL-C and low triglyceride levels, as well as protection against obesity, insulin resistance, and atherosclerosis. Here, we studied the impact of USF1 deficiency on HDL functional capacity and macrophage atherogenic functions, including inflammation, cholesterol efflux, and cholesterol accumulation. Methods We used a congenic Usf1 deficient mice in C57Bl/6JRccHsd background and blood samples were collected to isolate HDL for structural and functional studies. Lentiviral preparations containing the USF1 silencing shRNA expression vector were used to silence USF1 in human THP-1 and Huh-7 cells. Cholesterol efflux from acetyl-LDL loaded THP-1 macrophages was measured using HDL and plasma as acceptors. Gene expression analysis from USF1 silenced peritoneal macrophages was carried out using Affymetrix protocols. Results We show that Usf1 deficiency not only increases HDL-C levels in vivo, consistent with elevated ABCA1 protein expression in hepatic cell lines, but also improves the functional capacity of HDL particles. HDL particles derived from Usf1 deficient mice remove cholesterol more efficiently from macrophages, attributed to their higher contents of phospholipids. Furthermore, silencing of USF1 in macrophages enhanced the cholesterol efflux capacity of these cells. These findings are consistent with reduced inflammatory burden of USF1 deficient macrophages, manifested by reduced secretion of pro-inflammatory cytokines MCP-1 and IL-1β and protection against inflammation-induced macrophage cholesterol accumulation in a cell-autonomous manner. Conclusions Our findings identify USF1 as a novel factor regulating HDL functionality, showing that USF1 inactivation boosts cholesterol efflux, reduces macrophage inflammation and attenuates macrophage cholesterol accumulation, linking improved macrophage cholesterol metabolism and inflammatory pathways to the antiatherogenic function of USF1 deficiency.http://link.springer.com/article/10.1186/s12944-018-0930-2USF1High density lipoproteinsCholesterol effluxCholesterol accumulationMacrophageHepatocyte |
| spellingShingle | Maija Ruuth Jarkko Soronen Essi Kaiharju Krista Merikanto Julia Perttilä Jari Metso Miriam Lee-Rueckert Marja-Riitta Taskinen Petri T. Kovanen Katariina Öörni Vesa M. Olkkonen Matti S. Jauhiainen Pirkka-Pekka Laurila USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages Lipids in Health and Disease USF1 High density lipoproteins Cholesterol efflux Cholesterol accumulation Macrophage Hepatocyte |
| title | USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages |
| title_full | USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages |
| title_fullStr | USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages |
| title_full_unstemmed | USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages |
| title_short | USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages |
| title_sort | usf1 deficiency alleviates inflammation enhances cholesterol efflux and prevents cholesterol accumulation in macrophages |
| topic | USF1 High density lipoproteins Cholesterol efflux Cholesterol accumulation Macrophage Hepatocyte |
| url | http://link.springer.com/article/10.1186/s12944-018-0930-2 |
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