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Palmitoleic acid reduces high fat diet-induced liver inflammation by promoting PPAR-γ-independent M2a polarization of myeloid cells

Palmitoleic acid reduces high fat diet-induced liver inflammation by promoting PPAR-γ-independent M2a polarization of myeloid cells
Palmitoleic acid reduces high fat diet-induced liver inflammation by promoting PPAR-γ-independent M2a polarization of myeloid cells

Palmitoleic acid (POA, 16:1n-7) is a lipokine that has potential nutraceutical use to treat non-alcoholic fatty liver disease. We tested the effects of POA supplementation (daily oral gavage, 300 mg/Kg, 15 days) on murine liver inflammation induced by a high fat diet (HFD, 59% fat, 12 weeks). In HFD-fed mice, POA supplementation reduced serum insulin and improved insulin tolerance compared with oleic acid (OA, 300 mg/Kg). The livers of POA-treated mice exhibited less steatosis and inflammation than those of OA-treated mice with lower inflammatory cytokine levels and reduced toll-like receptor 4 protein content. The anti-inflammatory effects of POA in the liver were accompanied by a reduction in liver macrophages (LM, CD11c+; F4/80+; CD86+), an effect that could be triggered by peroxisome proliferator activated receptor (PPAR)-γ, a lipogenic transcription factor upregulated in livers of POA-treated mice. We also used HFD-fed mice with selective deletion of PPAR-γ in myeloid cells (PPAR-γ KOLyzCre+) to test whether the beneficial anti-inflammatory effects of POA are dependent on macrophages PPAR-γ. POA-mediated improvement of insulin tolerance was tightly dependent on myeloid PPAR-γ, while POA anti-inflammatory actions including the reduction in liver inflammatory cytokines were preserved in mice bearing myeloid cells deficient in PPAR-γ. This overlapped with increased CD206+ (M2a) cells and downregulation of CD86+ and CD11c+ liver macrophages. Moreover, POA supplementation increased hepatic AMPK activity and decreased expression of the fatty acid binding scavenger receptor, CD36. We conclude that POA controls liver inflammation triggered by fat accumulation through induction of M2a macrophages independently of myeloid cell PPAR-γ.

Animals, B7-2 Antigen/genetics, CD11c Antigen/genetics, Diet, High-Fat/adverse effects, Fatty Acids, Monounsaturated/metabolism, Humans, Inflammation/drug therapy, Insulin Resistance/genetics, Lectins, C-Type/genetics, Liver/drug effects, Mannose-Binding Lectins/genetics, Mice, Myeloid Cells/drug effects, Non-alcoholic Fatty Liver Disease/drug therapy, Oleic Acid/metabolism, PPAR gamma/genetics, Protein Kinases/genetics, Receptors, Cell Surface/genetics
1388-1981
158776
Souza, Camila O
b2b1f1be-0e79-4663-9f21-e08cb11f97b9
Teixeira, Alexandre A S
50e835c2-0dce-445c-80b3-b940b847317a
Biondo, Luana Amorim
d9ac2a7c-339c-40e4-b658-2d412e8a7066
Silveira, Loreana Sanches
35cb3181-3cac-4b9a-9473-4c18d72e835c
de Souza Breda, Cristiane N
4fec750f-bef7-4f06-9b19-7d0996cf6dd7
Braga, Tarcio T
04825dd7-7314-4310-b3f4-870bbf3bacc5
Camara, Niels O S
e9a7acb3-cb46-47bc-b4c6-0cc2ef2ef01b
Belchior, Thiago
4de23afd-27db-4933-90aa-28c0d330db72
Festuccia, William T
28170e32-1e09-4fdc-aaf9-b34ba9f1c3da
Diniz, Tiego A
13245131-2e2c-42bc-9a7f-87cf352e61db
Ferreira, Glaucio Monteiro
64780b0c-a5a6-45da-89d3-659906c90e64
Hirata, Mario Hiroyuki
df1c2e89-985f-468b-a68e-a3c7befaaa20
Chaves-Filho, Adriano B
e7a16019-3e0e-4bc0-9e75-2461c9f4231b
Yoshinaga, Marcos Y
e475017e-461b-4d67-8994-3d42cc9e81eb
Miyamoto, Sayuri
e6bca72c-35d8-4455-96ce-db53a0e8c52c
Calder, Philip C
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Sethi, Jaswinder K
923f1a81-91e4-46cd-8853-bb4a979f5a85
Rosa Neto, José C
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Souza, Camila O
b2b1f1be-0e79-4663-9f21-e08cb11f97b9
Teixeira, Alexandre A S
50e835c2-0dce-445c-80b3-b940b847317a
Biondo, Luana Amorim
d9ac2a7c-339c-40e4-b658-2d412e8a7066
Silveira, Loreana Sanches
35cb3181-3cac-4b9a-9473-4c18d72e835c
de Souza Breda, Cristiane N
4fec750f-bef7-4f06-9b19-7d0996cf6dd7
Braga, Tarcio T
04825dd7-7314-4310-b3f4-870bbf3bacc5
Camara, Niels O S
e9a7acb3-cb46-47bc-b4c6-0cc2ef2ef01b
Belchior, Thiago
4de23afd-27db-4933-90aa-28c0d330db72
Festuccia, William T
28170e32-1e09-4fdc-aaf9-b34ba9f1c3da
Diniz, Tiego A
13245131-2e2c-42bc-9a7f-87cf352e61db
Ferreira, Glaucio Monteiro
64780b0c-a5a6-45da-89d3-659906c90e64
Hirata, Mario Hiroyuki
df1c2e89-985f-468b-a68e-a3c7befaaa20
Chaves-Filho, Adriano B
e7a16019-3e0e-4bc0-9e75-2461c9f4231b
Yoshinaga, Marcos Y
e475017e-461b-4d67-8994-3d42cc9e81eb
Miyamoto, Sayuri
e6bca72c-35d8-4455-96ce-db53a0e8c52c
Calder, Philip C
1797e54f-378e-4dcb-80a4-3e30018f07a6
Sethi, Jaswinder K
923f1a81-91e4-46cd-8853-bb4a979f5a85
Rosa Neto, José C
4befc2f8-f896-43dc-b922-8ef738946931

Souza, Camila O, Teixeira, Alexandre A S, Biondo, Luana Amorim, Silveira, Loreana Sanches, de Souza Breda, Cristiane N, Braga, Tarcio T, Camara, Niels O S, Belchior, Thiago, Festuccia, William T, Diniz, Tiego A, Ferreira, Glaucio Monteiro, Hirata, Mario Hiroyuki, Chaves-Filho, Adriano B, Yoshinaga, Marcos Y, Miyamoto, Sayuri, Calder, Philip C, Sethi, Jaswinder K and Rosa Neto, José C (2020) Palmitoleic acid reduces high fat diet-induced liver inflammation by promoting PPAR-γ-independent M2a polarization of myeloid cells. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1865 (10), 158776, [158776]. (doi:10.1016/j.bbalip.2020.158776).

Record type: Article

Abstract

Palmitoleic acid (POA, 16:1n-7) is a lipokine that has potential nutraceutical use to treat non-alcoholic fatty liver disease. We tested the effects of POA supplementation (daily oral gavage, 300 mg/Kg, 15 days) on murine liver inflammation induced by a high fat diet (HFD, 59% fat, 12 weeks). In HFD-fed mice, POA supplementation reduced serum insulin and improved insulin tolerance compared with oleic acid (OA, 300 mg/Kg). The livers of POA-treated mice exhibited less steatosis and inflammation than those of OA-treated mice with lower inflammatory cytokine levels and reduced toll-like receptor 4 protein content. The anti-inflammatory effects of POA in the liver were accompanied by a reduction in liver macrophages (LM, CD11c+; F4/80+; CD86+), an effect that could be triggered by peroxisome proliferator activated receptor (PPAR)-γ, a lipogenic transcription factor upregulated in livers of POA-treated mice. We also used HFD-fed mice with selective deletion of PPAR-γ in myeloid cells (PPAR-γ KOLyzCre+) to test whether the beneficial anti-inflammatory effects of POA are dependent on macrophages PPAR-γ. POA-mediated improvement of insulin tolerance was tightly dependent on myeloid PPAR-γ, while POA anti-inflammatory actions including the reduction in liver inflammatory cytokines were preserved in mice bearing myeloid cells deficient in PPAR-γ. This overlapped with increased CD206+ (M2a) cells and downregulation of CD86+ and CD11c+ liver macrophages. Moreover, POA supplementation increased hepatic AMPK activity and decreased expression of the fatty acid binding scavenger receptor, CD36. We conclude that POA controls liver inflammation triggered by fat accumulation through induction of M2a macrophages independently of myeloid cell PPAR-γ.

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Accepted/In Press date: 25 July 2020
e-pub ahead of print date: 30 July 2020
Published date: October 2020
Keywords: Animals, B7-2 Antigen/genetics, CD11c Antigen/genetics, Diet, High-Fat/adverse effects, Fatty Acids, Monounsaturated/metabolism, Humans, Inflammation/drug therapy, Insulin Resistance/genetics, Lectins, C-Type/genetics, Liver/drug effects, Mannose-Binding Lectins/genetics, Mice, Myeloid Cells/drug effects, Non-alcoholic Fatty Liver Disease/drug therapy, Oleic Acid/metabolism, PPAR gamma/genetics, Protein Kinases/genetics, Receptors, Cell Surface/genetics

Identifiers

Local EPrints ID: 442909
URI: http://eprints.soton.ac.uk/id/eprint/442909
ISSN: 1388-1981
PURE UUID: 332f5038-2dbb-4c4b-94b0-3f1c05a01252
ORCID for Philip C Calder: ORCID iD orcid.org/0000-0002-6038-710X
ORCID for Jaswinder K Sethi: ORCID iD orcid.org/0000-0003-4157-0475

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Date deposited: 31 Jul 2020 16:30
Last modified: 15 Sep 2021 02:13

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Contributors

Author: Camila O Souza
Author: Alexandre A S Teixeira
Author: Luana Amorim Biondo
Author: Loreana Sanches Silveira
Author: Cristiane N de Souza Breda
Author: Tarcio T Braga
Author: Niels O S Camara
Author: Thiago Belchior
Author: William T Festuccia
Author: Tiego A Diniz
Author: Glaucio Monteiro Ferreira
Author: Mario Hiroyuki Hirata
Author: Adriano B Chaves-Filho
Author: Marcos Y Yoshinaga
Author: Sayuri Miyamoto
Author: Philip C Calder ORCID iD
Author: José C Rosa Neto

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