USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages

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Ruuth , M , Soronen , J , Kaiharju , E , Merikanto , K , Perttilä , J , Metso , J , Lee-Rueckert , M , Taskinen , M-R , Kovanen , P T , Öörni , K , Olkkonen , V M , Jauhiainen , M S & Laurila , P-P 2018 , ' USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages ' , Lipids in Health and Disease , vol. 17 , 285 . https://doi.org/10.1186/s12944-018-0930-2

Title: USF1 deficiency alleviates inflammation, enhances cholesterol efflux and prevents cholesterol accumulation in macrophages
Author: Ruuth, Maija; Soronen, Jarkko; Kaiharju, Essi; Merikanto, Krista; Perttilä, Julia; Metso, Jari; Lee-Rueckert, Miriam; Taskinen, Marja-Riitta; Kovanen, Petri T.; Öörni, Katariina; Olkkonen, Vesa M.; Jauhiainen, Matti S.; Laurila, Pirkka-Pekka
Contributor organization: Medicum
Research Programs Unit
University of Helsinki
Clinicum
Diabetes and Obesity Research Program
Marja-Riitta Taskinen Research Group
Department of Anatomy
Department of Medical and Clinical Genetics
Institute for Molecular Medicine Finland
HUS Internal Medicine and Rehabilitation
HUS Heart and Lung Center
Date: 2018-12-13
Language: eng
Number of pages: 11
Belongs to series: Lipids in Health and Disease
ISSN: 1476-511X
DOI: https://doi.org/10.1186/s12944-018-0930-2
URI: http://hdl.handle.net/10138/287689
Abstract: BackgroundThe 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.MethodsWe 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.ResultsWe 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-1 and protection against inflammation-induced macrophage cholesterol accumulation in a cell-autonomous manner.ConclusionsOur 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.
Subject: USF1
High density lipoproteins
Cholesterol efflux
Cholesterol accumulation
Macrophage
Hepatocyte
Inflammation
FAMILIAL COMBINED HYPERLIPIDEMIA
UPSTREAM TRANSCRIPTION FACTOR-1
HIGH-DENSITY-LIPOPROTEINS
LYSOSOMAL ACID LIPASE
ESTER HYDROLASE 1
FOAM CELLS
HIGH-RISK
ATHEROSCLEROSIS
ASSOCIATION
CAPACITY
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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