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Fatty acid species differentially regulate macrophage polarization and oxidative stress with secondary effects on macrophage-HSC crosstalk.

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Title: Fatty acid species differentially regulate macrophage polarization and oxidative stress with secondary effects on macrophage-HSC crosstalk.
Authors: Nakanishi K; Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka, Japan., Shinkawa H; Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka, Japan., Takemura S; Department of Frontier Life-Science, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan., Nakagawa K; Department of Frontier Life-Science, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan., Minamiyama Y; Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka, Japan.; Food Hygiene and Environmental Health Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan., Ishizawa T; Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka, Japan.
Source: Physiological reports [Physiol Rep] 2026 Sep; Vol. 14 (17), pp. e71082.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society Country of Publication: United States NLM ID: 101607800 Publication Model: Print Cited Medium: Internet ISSN: 2051-817X (Electronic) Linking ISSN: 2051817X NLM ISO Abbreviation: Physiol Rep Subsets: MEDLINE
Imprint Name(s): Original Publication: [Malden MA] : published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society, 2013-
MeSH Terms: Macrophages*/metabolism , Macrophages*/drug effects , Oxidative Stress*/drug effects , Hepatic Stellate Cells*/metabolism , Hepatic Stellate Cells*/drug effects , Fatty Acids*/metabolism , Fatty Acids*/pharmacology , Palmitic Acid*/pharmacology , Oleic Acid*/pharmacology, Reactive Oxygen Species/metabolism ; PPAR gamma/metabolism ; Fatty Acids, Monounsaturated/pharmacology ; Animals ; Mice ; Macrophage Activation ; Mice, Inbred C57BL ; Cells, Cultured ; Cell Communication
Abstract: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by lipid accumulation, inflammation, and fibrosis. Macrophage-hepatic stellate cell (HSC) communication plays a key role in fibrogenesis; however, how fatty acid species influence macrophage polarization remains unclear. Bone marrow-derived macrophages (BMDMs) were polarized toward M1 or M2 phenotypes in the presence of palmitic acid (PA), oleic acid (OA), or palmitoleic acid (PO). Polarization markers, reactive oxygen species (ROS), and peroxisome proliferator-activated receptor gamma (PPARγ) expression were analyzed by RT-qPCR, Western blotting, and chemiluminescence. Primary HSCs were exposed to fatty acids or conditioned media from treated macrophages. PA enhanced selected inflammatory macrophage responses and increased ROS production under M1-polarizing conditions. OA enhanced ROS production in M1 macrophages and suppressed several M2-associated markers, whereas PO reduced inflammatory responses and ROS under M1-polarizing conditions. Direct fatty acid exposure did not significantly alter HSC activation markers. Conditioned media from polarized macrophages, particularly M1 macrophages, reduced α-SMA and cytoglobin protein expression in HSCs, while fatty acid-specific effects were modest and marker-dependent. Fatty acid species differentially modulate macrophage polarization and redox activity, partly in association with PPARγ signaling. These macrophage changes may secondarily affect macrophage-HSC communication and stellate cell redox-related responses, providing insight into lipid regulation of immune-stromal interactions in the liver.
(© 2026 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
References: Trends Endocrinol Metab. 2018 Mar;29(3):178-190. (PMID: 29290500)
Life Sci. 2018 Jun 15;203:291-304. (PMID: 29709653)
J Clin Invest. 2006 Nov;116(11):3015-25. (PMID: 17053832)
J Gastroenterol Hepatol. 2015 Feb;30(2):405-12. (PMID: 25089018)
J Lipid Res. 2013 Mar;54(3):725-733. (PMID: 23275648)
J Immunol Res. 2019 Nov 11;2019:1278301. (PMID: 31815149)
J Hepatol. 2020 Jul;73(1):202-209. (PMID: 32278004)
Clin Exp Pharmacol Physiol. 2017 May;44(5):566-575. (PMID: 28135761)
Diabetes. 2012 Aug;61(8):2074-83. (PMID: 22586586)
PLoS One. 2013 Sep 30;8(9):e75147. (PMID: 24098682)
PLoS One. 2015 Jun 01;10(6):e0128218. (PMID: 26030149)
J Biol Chem. 2015 Jul 3;290(27):16979-88. (PMID: 25987561)
Evid Based Complement Alternat Med. 2021 Jun 22;2021:6671129. (PMID: 34239589)
Nature. 2006 Dec 14;444(7121):860-7. (PMID: 17167474)
J Leukoc Biol. 2015 Jan;97(1):61-9. (PMID: 25359998)
ISRN Endocrinol. 2012;2012:237613. (PMID: 23251812)
Front Physiol. 2017 Nov 08;8:902. (PMID: 29167646)
J Hepatol. 2001 Aug;35(2):297-306. (PMID: 11580156)
Physiol Rev. 2008 Jan;88(1):125-72. (PMID: 18195085)
Hepatology. 2010 Nov;52(5):1836-46. (PMID: 21038418)
Cells. 2026 Feb 06;15(3):. (PMID: 41677671)
Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Oct;1865(10):158776. (PMID: 32738301)
Prostaglandins Leukot Essent Fatty Acids. 2021 Jun;169:102270. (PMID: 33930845)
J Hepatol. 2020 Oct;73(4):882-895. (PMID: 32330605)
Mediators Inflamm. 2014;2014:582197. (PMID: 25147439)
Med Sci Monit. 2018 Apr 10;24:2134-2141. (PMID: 29633755)
Sci Rep. 2018 Dec 14;8(1):17860. (PMID: 30552362)
Am J Physiol Gastrointest Liver Physiol. 2015 Aug 15;309(4):G270-8. (PMID: 26113297)
Free Radic Res. 2007 Apr;41(4):489-97. (PMID: 17454131)
Scand J Immunol. 2017 Mar;85(3):166-174. (PMID: 27491503)
Liver Int. 2005 Apr;25(2):420-8. (PMID: 15780068)
J Am Soc Nephrol. 2011 Feb;22(2):317-26. (PMID: 21289217)
Am J Physiol Gastrointest Liver Physiol. 2018 Feb 1;314(2):G150-G163. (PMID: 28971836)
Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1397-402. (PMID: 21415385)
Food Funct. 2021 Sep 7;12(17):7909-7922. (PMID: 34250536)
Chemotherapy. 2013;59(3):214-24. (PMID: 24356281)
Biochem Biophys Res Commun. 2021 Dec 10;582:77-85. (PMID: 34695754)
Grant Information: 21K08690 Japan Society for the Promotion of Science (JSPS KAKENHI)
Contributed Indexing: Keywords: PPARγ; hepatic stellate cells; lipid species; macrophage polarization; metabolic dysfunction–associated steatohepatitis
Substance Nomenclature: 0 (Reactive Oxygen Species)
0 (PPAR gamma)
0 (Fatty Acids)
209B6YPZ4I (palmitoleic acid)
2V16EO95H1 (Palmitic Acid)
2UMI9U37CP (Oleic Acid)
0 (Fatty Acids, Monounsaturated)
Entry Date(s): Date Created: 20260911 Date Completed: 20260911 Latest Revision: 20260914
Update Code: 20260914
PubMed Central ID: PMC13562811
DOI: 10.14814/phy2.71082
PMID: 42723224
Database: MEDLINE
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  Data: Fatty acid species differentially regulate macrophage polarization and oxidative stress with secondary effects on macrophage-HSC crosstalk.
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  Data: <i>Original Publication</i>: [Malden MA] : published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society, 2013-
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  Data: <searchLink fieldCode="MM" term="%22Macrophages%22">Macrophages*</searchLink>/<searchLink fieldCode="MM" term="%22Macrophages+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Macrophages%22">Macrophages*</searchLink>/<searchLink fieldCode="MM" term="%22Macrophages+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Oxidative+Stress%22">Oxidative Stress*</searchLink>/<searchLink fieldCode="MM" term="%22Oxidative+Stress+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Hepatic+Stellate+Cells%22">Hepatic Stellate Cells*</searchLink>/<searchLink fieldCode="MM" term="%22Hepatic+Stellate+Cells+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Hepatic+Stellate+Cells%22">Hepatic Stellate Cells*</searchLink>/<searchLink fieldCode="MM" term="%22Hepatic+Stellate+Cells+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Fatty+Acids%22">Fatty Acids*</searchLink>/<searchLink fieldCode="MM" term="%22Fatty+Acids+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Fatty+Acids%22">Fatty Acids*</searchLink>/<searchLink fieldCode="MM" term="%22Fatty+Acids+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Palmitic+Acid%22">Palmitic Acid*</searchLink>/<searchLink fieldCode="MM" term="%22Palmitic+Acid+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Oleic+Acid%22">Oleic Acid*</searchLink>/<searchLink fieldCode="MM" term="%22Oleic+Acid+pharmacology%22">pharmacology</searchLink><br /><searchLink fieldCode="MH" term="%22Reactive+Oxygen+Species%22">Reactive Oxygen Species</searchLink>/<searchLink fieldCode="MH" term="%22Reactive+Oxygen+Species+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22PPAR+gamma%22">PPAR gamma</searchLink>/<searchLink fieldCode="MH" term="%22PPAR+gamma+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Fatty+Acids%2C+Monounsaturated%22">Fatty Acids, Monounsaturated</searchLink>/<searchLink fieldCode="MH" term="%22Fatty+Acids%2C+Monounsaturated+pharmacology%22">pharmacology</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Macrophage+Activation%22">Macrophage Activation</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%2C+Inbred+C57BL%22">Mice, Inbred C57BL</searchLink> ; <searchLink fieldCode="MH" term="%22Cells%2C+Cultured%22">Cells, Cultured</searchLink> ; <searchLink fieldCode="MH" term="%22Cell+Communication%22">Cell Communication</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by lipid accumulation, inflammation, and fibrosis. Macrophage-hepatic stellate cell (HSC) communication plays a key role in fibrogenesis; however, how fatty acid species influence macrophage polarization remains unclear. Bone marrow-derived macrophages (BMDMs) were polarized toward M1 or M2 phenotypes in the presence of palmitic acid (PA), oleic acid (OA), or palmitoleic acid (PO). Polarization markers, reactive oxygen species (ROS), and peroxisome proliferator-activated receptor gamma (PPARγ) expression were analyzed by RT-qPCR, Western blotting, and chemiluminescence. Primary HSCs were exposed to fatty acids or conditioned media from treated macrophages. PA enhanced selected inflammatory macrophage responses and increased ROS production under M1-polarizing conditions. OA enhanced ROS production in M1 macrophages and suppressed several M2-associated markers, whereas PO reduced inflammatory responses and ROS under M1-polarizing conditions. Direct fatty acid exposure did not significantly alter HSC activation markers. Conditioned media from polarized macrophages, particularly M1 macrophages, reduced α-SMA and cytoglobin protein expression in HSCs, while fatty acid-specific effects were modest and marker-dependent. Fatty acid species differentially modulate macrophage polarization and redox activity, partly in association with PPARγ signaling. These macrophage changes may secondarily affect macrophage-HSC communication and stellate cell redox-related responses, providing insight into lipid regulation of immune-stromal interactions in the liver.<br /> (© 2026 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
– Name: Ref
  Label: References
  Group: RefInfo
  Data: Trends Endocrinol Metab. 2018 Mar;29(3):178-190. (PMID: <searchLink fieldCode="PM" term="%2229290500%22">29290500)</searchLink><br />Life Sci. 2018 Jun 15;203:291-304. (PMID: <searchLink fieldCode="PM" term="%2229709653%22">29709653)</searchLink><br />J Clin Invest. 2006 Nov;116(11):3015-25. (PMID: <searchLink fieldCode="PM" term="%2217053832%22">17053832)</searchLink><br />J Gastroenterol Hepatol. 2015 Feb;30(2):405-12. (PMID: <searchLink fieldCode="PM" term="%2225089018%22">25089018)</searchLink><br />J Lipid Res. 2013 Mar;54(3):725-733. (PMID: <searchLink fieldCode="PM" term="%2223275648%22">23275648)</searchLink><br />J Immunol Res. 2019 Nov 11;2019:1278301. (PMID: <searchLink fieldCode="PM" term="%2231815149%22">31815149)</searchLink><br />J Hepatol. 2020 Jul;73(1):202-209. (PMID: <searchLink fieldCode="PM" term="%2232278004%22">32278004)</searchLink><br />Clin Exp Pharmacol Physiol. 2017 May;44(5):566-575. (PMID: <searchLink fieldCode="PM" term="%2228135761%22">28135761)</searchLink><br />Diabetes. 2012 Aug;61(8):2074-83. (PMID: <searchLink fieldCode="PM" term="%2222586586%22">22586586)</searchLink><br />PLoS One. 2013 Sep 30;8(9):e75147. (PMID: <searchLink fieldCode="PM" term="%2224098682%22">24098682)</searchLink><br />PLoS One. 2015 Jun 01;10(6):e0128218. (PMID: <searchLink fieldCode="PM" term="%2226030149%22">26030149)</searchLink><br />J Biol Chem. 2015 Jul 3;290(27):16979-88. (PMID: <searchLink fieldCode="PM" term="%2225987561%22">25987561)</searchLink><br />Evid Based Complement Alternat Med. 2021 Jun 22;2021:6671129. (PMID: <searchLink fieldCode="PM" term="%2234239589%22">34239589)</searchLink><br />Nature. 2006 Dec 14;444(7121):860-7. (PMID: <searchLink fieldCode="PM" term="%2217167474%22">17167474)</searchLink><br />J Leukoc Biol. 2015 Jan;97(1):61-9. (PMID: <searchLink fieldCode="PM" term="%2225359998%22">25359998)</searchLink><br />ISRN Endocrinol. 2012;2012:237613. (PMID: <searchLink fieldCode="PM" term="%2223251812%22">23251812)</searchLink><br />Front Physiol. 2017 Nov 08;8:902. (PMID: <searchLink fieldCode="PM" term="%2229167646%22">29167646)</searchLink><br />J Hepatol. 2001 Aug;35(2):297-306. (PMID: <searchLink fieldCode="PM" term="%2211580156%22">11580156)</searchLink><br />Physiol Rev. 2008 Jan;88(1):125-72. (PMID: <searchLink fieldCode="PM" term="%2218195085%22">18195085)</searchLink><br />Hepatology. 2010 Nov;52(5):1836-46. (PMID: <searchLink fieldCode="PM" term="%2221038418%22">21038418)</searchLink><br />Cells. 2026 Feb 06;15(3):. (PMID: <searchLink fieldCode="PM" term="%2241677671%22">41677671)</searchLink><br />Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Oct;1865(10):158776. (PMID: <searchLink fieldCode="PM" term="%2232738301%22">32738301)</searchLink><br />Prostaglandins Leukot Essent Fatty Acids. 2021 Jun;169:102270. (PMID: <searchLink fieldCode="PM" term="%2233930845%22">33930845)</searchLink><br />J Hepatol. 2020 Oct;73(4):882-895. (PMID: <searchLink fieldCode="PM" term="%2232330605%22">32330605)</searchLink><br />Mediators Inflamm. 2014;2014:582197. (PMID: <searchLink fieldCode="PM" term="%2225147439%22">25147439)</searchLink><br />Med Sci Monit. 2018 Apr 10;24:2134-2141. (PMID: <searchLink fieldCode="PM" term="%2229633755%22">29633755)</searchLink><br />Sci Rep. 2018 Dec 14;8(1):17860. (PMID: <searchLink fieldCode="PM" term="%2230552362%22">30552362)</searchLink><br />Am J Physiol Gastrointest Liver Physiol. 2015 Aug 15;309(4):G270-8. (PMID: <searchLink fieldCode="PM" term="%2226113297%22">26113297)</searchLink><br />Free Radic Res. 2007 Apr;41(4):489-97. (PMID: <searchLink fieldCode="PM" term="%2217454131%22">17454131)</searchLink><br />Scand J Immunol. 2017 Mar;85(3):166-174. (PMID: <searchLink fieldCode="PM" term="%2227491503%22">27491503)</searchLink><br />Liver Int. 2005 Apr;25(2):420-8. (PMID: <searchLink fieldCode="PM" term="%2215780068%22">15780068)</searchLink><br />J Am Soc Nephrol. 2011 Feb;22(2):317-26. (PMID: <searchLink fieldCode="PM" term="%2221289217%22">21289217)</searchLink><br />Am J Physiol Gastrointest Liver Physiol. 2018 Feb 1;314(2):G150-G163. (PMID: <searchLink fieldCode="PM" term="%2228971836%22">28971836)</searchLink><br />Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1397-402. (PMID: <searchLink fieldCode="PM" term="%2221415385%22">21415385)</searchLink><br />Food Funct. 2021 Sep 7;12(17):7909-7922. (PMID: <searchLink fieldCode="PM" term="%2234250536%22">34250536)</searchLink><br />Chemotherapy. 2013;59(3):214-24. (PMID: <searchLink fieldCode="PM" term="%2224356281%22">24356281)</searchLink><br />Biochem Biophys Res Commun. 2021 Dec 10;582:77-85. (PMID: <searchLink fieldCode="PM" term="%2234695754%22">34695754)</searchLink>
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  Data: 21K08690 Japan Society for the Promotion of Science (JSPS KAKENHI)
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  Data: <i>Keywords: </i>PPARγ; hepatic stellate cells; lipid species; macrophage polarization; metabolic dysfunction–associated steatohepatitis
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  Data: 0 (Reactive Oxygen Species)<br />0 (PPAR gamma)<br />0 (Fatty Acids)<br />209B6YPZ4I (palmitoleic acid)<br />2V16EO95H1 (Palmitic Acid)<br />2UMI9U37CP (Oleic Acid)<br />0 (Fatty Acids, Monounsaturated)
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      – SubjectFull: Reactive Oxygen Species metabolism
        Type: general
      – SubjectFull: PPAR gamma metabolism
        Type: general
      – SubjectFull: Fatty Acids, Monounsaturated pharmacology
        Type: general
      – SubjectFull: Animals
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      – SubjectFull: Mice
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      – SubjectFull: Mice, Inbred C57BL
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      – SubjectFull: Macrophages drug effects
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      – SubjectFull: Oxidative Stress drug effects
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      – SubjectFull: Hepatic Stellate Cells metabolism
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      – SubjectFull: Hepatic Stellate Cells drug effects
        Type: general
      – SubjectFull: Fatty Acids metabolism
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      – SubjectFull: Fatty Acids pharmacology
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      – SubjectFull: Palmitic Acid pharmacology
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      – SubjectFull: Oleic Acid pharmacology
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      – TitleFull: Fatty acid species differentially regulate macrophage polarization and oxidative stress with secondary effects on macrophage-HSC crosstalk.
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            – D: 01
              M: 09
              Text: 2026 Sep
              Type: published
              Y: 2026
          Identifiers:
            – Type: issn-electronic
              Value: 2051-817X
          Numbering:
            – Type: volume
              Value: 14
            – Type: issue
              Value: 17
          Titles:
            – TitleFull: Physiological reports
              Type: main
ResultId 1