PMID- 32472585 OWN - NLM STAT- MEDLINE DCOM- 20201217 LR - 20201217 IS - 1096-9896 (Electronic) IS - 0022-3417 (Print) IS - 0022-3417 (Linking) VI - 251 IP - 4 DP - 2020 Aug TI - Sex-opposed inflammatory effects of 27-hydroxycholesterol are mediated via differences in estrogen signaling. PG - 429-439 LID - 10.1002/path.5477 [doi] AB - Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann-Pick disease type C1 mice (Npc1(nih) ) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17beta-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1(nih) mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1(nih) mice in contrast to male Npc1(nih) mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ERalpha expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ERalpha expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. (c) 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. CI - (c) 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. FAU - Houben, Tom AU - Houben T AD - Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands. FAU - Bitorina, Albert V AU - Bitorina AV AD - Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands. FAU - Oligschlaeger, Yvonne AU - Oligschlaeger Y AD - Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands. FAU - Jeurissen, Mike Lj AU - Jeurissen ML AD - Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands. FAU - Rensen, Sander AU - Rensen S AD - Department of Surgery, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands. FAU - Kohler, S Eleonore AU - Kohler SE AD - Department of Anatomy & Embryology, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands. FAU - Westerterp, Marit AU - Westerterp M AD - Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. FAU - Lutjohann, Dieter AU - Lutjohann D AD - Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany. FAU - Theys, Jan AU - Theys J AD - Department of Precision Medicine, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands. FAU - Romano, Andrea AU - Romano A AUID- ORCID: 0000-0002-5900-6883 AD - Department of Obstetrics & Gynaecology, School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands. FAU - Plat, Jogchum AU - Plat J AD - Department of Nutrition and Movement Sciences, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands. FAU - Shiri-Sverdlov, Ronit AU - Shiri-Sverdlov R AUID- ORCID: 0000-0002-6736-7814 AD - Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200707 PL - England TA - J Pathol JT - The Journal of pathology JID - 0204634 RN - 0 (Estrogen Receptor alpha) RN - 0 (Estrogens) RN - 0 (Hydroxycholesterols) RN - 6T2NA6P5SQ (27-hydroxycholesterol) SB - IM MH - Animals MH - Atherosclerosis/*pathology MH - Estrogen Receptor alpha/metabolism MH - Estrogens/*metabolism MH - Female MH - Humans MH - Hydroxycholesterols/*pharmacology MH - Inflammation/*pathology MH - Liver/metabolism/pathology MH - Macrophages/pathology MH - Male MH - Mice MH - Non-alcoholic Fatty Liver Disease/*pathology MH - Sex Factors MH - Signal Transduction/*drug effects PMC - PMC7497011 OTO - NOTNLM OT - 27-hydroxycholesterol OT - estrogen OT - inflammation OT - sex differences EDAT- 2020/05/31 06:00 MHDA- 2020/12/18 06:00 PMCR- 2020/09/17 CRDT- 2020/05/31 06:00 PHST- 2019/11/07 00:00 [received] PHST- 2020/04/28 00:00 [revised] PHST- 2020/05/19 00:00 [accepted] PHST- 2020/05/31 06:00 [pubmed] PHST- 2020/12/18 06:00 [medline] PHST- 2020/05/31 06:00 [entrez] PHST- 2020/09/17 00:00 [pmc-release] AID - PATH5477 [pii] AID - 10.1002/path.5477 [doi] PST - ppublish SO - J Pathol. 2020 Aug;251(4):429-439. doi: 10.1002/path.5477. Epub 2020 Jul 7.