Hematopoietic overexpression of Cyp27a1 reduces hepatic inflammation independently of 27-hydroxycholesterol levels in Ldlr(-/-) mice

Tim Hendrikx; Mike L.J. Jeurissen; V. Bieghs; Sofie M.A. Walenbergh; Patrick J. van Gorp; F. Verheyen; Tom Houben; Y. D. Guichot; M.J. Gijbels; E. Leitersdorf; M.H. Hofker; D. Luetjohann; Ronit Shiri-Sverdlov

doi:10.1016/j.jhep.2014.09.027

Hematopoietic overexpression of Cyp27a1 reduces hepatic inflammation independently of 27-hydroxycholesterol levels in Ldlr(-/-) mice

Tim Hendrikx, Mike L.J. Jeurissen, V. Bieghs, Sofie M.A. Walenbergh, Patrick J. van Gorp, F. Verheyen, Tom Houben, Y. D. Guichot, M.J. Gijbels, E. Leitersdorf, M.H. Hofker, D. Luetjohann, Ronit Shiri-Sverdlov^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background & Aims: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation and inflammation. Currently, the underlying mechanisms, leading to hepatic inflammation, are still unknown. The breakdown of free cholesterol inside Kupffer cells (KCs) by the mitochondrial enzyme CYP27A1 produces 27-hydroxycholesterol (27HC). We recently demonstrated that administration of 27HC to hyperlipidemic mice reduced hepatic inflammation. In line, hematopoietic deletion of Cyp27a1 resulted in increased hepatic inflammation. In the current manuscript, the effect of hematopoietic overexpression of Cyp27a1 on the development of NASH and cholesterol trafficking was investigated. We hypothesized that Cyp27a1 overexpression in KCs will lead to reduced hepatic inflammation.

Methods: Irradiated Ldlr(-/-) mice were transplanted (tp) with bone marrow from mice overexpressing Cyp27a1 (Cyp27a1(over)) and wild type (Wt) mice and fed either chow or a high-fat, high-cholesterol (HFC) diet for 3 months. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) from Cyp27a1(over) and Wt mice.

Results: In line with our hypothesis, hepatic inflammation in HFC-fed Cyp27a1(over)-tp mice was reduced and KCs were less foamy compared to Wt-tp mice. Remarkably, these changes occurred even though plasma and liver levels of 27HC did not differ between both groups. BMDM from Cyp27a1(over) mice revealed reduced inflammatory gene expression and increased expression of cholesterol transporters compared to Wt BMDM after lipopolysaccharide (LPS) stimulation.

Conclusions: Our data suggest that overexpression of Cyp27a1 in KCs reduces hepatic inflammation independently of 27HC levels in plasma and liver, further pointing towards KCs as specific target for improving the therapy of NASH. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Original language	English
Pages (from-to)	430-436
Number of pages	7
Journal	Journal of Hepatology
Volume	62
Issue number	2
DOIs	https://doi.org/10.1016/j.jhep.2014.09.027
Publication status	Published - Feb 2015

Keywords

Hepatic inflammation
Cholesterol
CYP27A1
Kupffer cells
ESTROGEN-RECEPTOR MODULATOR
LOW-DENSITY-LIPOPROTEIN
LIVER-X-RECEPTOR
CHOLESTERYL ESTER
TRANSGENIC EXPRESSION
BONE HOMEOSTASIS
CELLS
EFFLUX
NPC2
ACCUMULATION

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Hendrikx, T., Jeurissen, M. L. J., Bieghs, V., Walenbergh, S. M. A., van Gorp, P. J., Verheyen, F., Houben, T., Guichot, Y. D., Gijbels, M. J., Leitersdorf, E., Hofker, M. H., Luetjohann, D., & Shiri-Sverdlov, R. (2015). Hematopoietic overexpression of Cyp27a1 reduces hepatic inflammation independently of 27-hydroxycholesterol levels in Ldlr(-/-) mice. Journal of Hepatology, 62(2), 430-436. https://doi.org/10.1016/j.jhep.2014.09.027

@article{77a52e1e822b4f7f8f8f8e43c5fb633e,

title = "Hematopoietic overexpression of Cyp27a1 reduces hepatic inflammation independently of 27-hydroxycholesterol levels in Ldlr(-/-) mice",

abstract = "Background & Aims: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation and inflammation. Currently, the underlying mechanisms, leading to hepatic inflammation, are still unknown. The breakdown of free cholesterol inside Kupffer cells (KCs) by the mitochondrial enzyme CYP27A1 produces 27-hydroxycholesterol (27HC). We recently demonstrated that administration of 27HC to hyperlipidemic mice reduced hepatic inflammation. In line, hematopoietic deletion of Cyp27a1 resulted in increased hepatic inflammation. In the current manuscript, the effect of hematopoietic overexpression of Cyp27a1 on the development of NASH and cholesterol trafficking was investigated. We hypothesized that Cyp27a1 overexpression in KCs will lead to reduced hepatic inflammation.Methods: Irradiated Ldlr(-/-) mice were transplanted (tp) with bone marrow from mice overexpressing Cyp27a1 (Cyp27a1(over)) and wild type (Wt) mice and fed either chow or a high-fat, high-cholesterol (HFC) diet for 3 months. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) from Cyp27a1(over) and Wt mice.Results: In line with our hypothesis, hepatic inflammation in HFC-fed Cyp27a1(over)-tp mice was reduced and KCs were less foamy compared to Wt-tp mice. Remarkably, these changes occurred even though plasma and liver levels of 27HC did not differ between both groups. BMDM from Cyp27a1(over) mice revealed reduced inflammatory gene expression and increased expression of cholesterol transporters compared to Wt BMDM after lipopolysaccharide (LPS) stimulation.Conclusions: Our data suggest that overexpression of Cyp27a1 in KCs reduces hepatic inflammation independently of 27HC levels in plasma and liver, further pointing towards KCs as specific target for improving the therapy of NASH. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.",

keywords = "Hepatic inflammation, Cholesterol, CYP27A1, Kupffer cells, ESTROGEN-RECEPTOR MODULATOR, LOW-DENSITY-LIPOPROTEIN, LIVER-X-RECEPTOR, CHOLESTERYL ESTER, TRANSGENIC EXPRESSION, BONE HOMEOSTASIS, CELLS, EFFLUX, NPC2, ACCUMULATION",

author = "Tim Hendrikx and Jeurissen, {Mike L.J.} and V. Bieghs and Walenbergh, {Sofie M.A.} and {van Gorp}, {Patrick J.} and F. Verheyen and Tom Houben and Guichot, {Y. D.} and M.J. Gijbels and E. Leitersdorf and M.H. Hofker and D. Luetjohann and Ronit Shiri-Sverdlov",

year = "2015",

month = feb,

doi = "10.1016/j.jhep.2014.09.027",

language = "English",

volume = "62",

pages = "430--436",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier Science",

number = "2",

}

Hendrikx, T, Jeurissen, MLJ, Bieghs, V, Walenbergh, SMA, van Gorp, PJ, Verheyen, F, Houben, T, Guichot, YD, Gijbels, MJ, Leitersdorf, E, Hofker, MH, Luetjohann, D & Shiri-Sverdlov, R 2015, 'Hematopoietic overexpression of Cyp27a1 reduces hepatic inflammation independently of 27-hydroxycholesterol levels in Ldlr(-/-) mice', Journal of Hepatology, vol. 62, no. 2, pp. 430-436. https://doi.org/10.1016/j.jhep.2014.09.027

TY - JOUR

T1 - Hematopoietic overexpression of Cyp27a1 reduces hepatic inflammation independently of 27-hydroxycholesterol levels in Ldlr(-/-) mice

AU - Hendrikx, Tim

AU - Jeurissen, Mike L.J.

AU - Bieghs, V.

AU - Walenbergh, Sofie M.A.

AU - van Gorp, Patrick J.

AU - Verheyen, F.

AU - Houben, Tom

AU - Guichot, Y. D.

AU - Gijbels, M.J.

AU - Leitersdorf, E.

AU - Hofker, M.H.

AU - Luetjohann, D.

AU - Shiri-Sverdlov, Ronit

PY - 2015/2

Y1 - 2015/2

N2 - Background & Aims: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation and inflammation. Currently, the underlying mechanisms, leading to hepatic inflammation, are still unknown. The breakdown of free cholesterol inside Kupffer cells (KCs) by the mitochondrial enzyme CYP27A1 produces 27-hydroxycholesterol (27HC). We recently demonstrated that administration of 27HC to hyperlipidemic mice reduced hepatic inflammation. In line, hematopoietic deletion of Cyp27a1 resulted in increased hepatic inflammation. In the current manuscript, the effect of hematopoietic overexpression of Cyp27a1 on the development of NASH and cholesterol trafficking was investigated. We hypothesized that Cyp27a1 overexpression in KCs will lead to reduced hepatic inflammation.Methods: Irradiated Ldlr(-/-) mice were transplanted (tp) with bone marrow from mice overexpressing Cyp27a1 (Cyp27a1(over)) and wild type (Wt) mice and fed either chow or a high-fat, high-cholesterol (HFC) diet for 3 months. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) from Cyp27a1(over) and Wt mice.Results: In line with our hypothesis, hepatic inflammation in HFC-fed Cyp27a1(over)-tp mice was reduced and KCs were less foamy compared to Wt-tp mice. Remarkably, these changes occurred even though plasma and liver levels of 27HC did not differ between both groups. BMDM from Cyp27a1(over) mice revealed reduced inflammatory gene expression and increased expression of cholesterol transporters compared to Wt BMDM after lipopolysaccharide (LPS) stimulation.Conclusions: Our data suggest that overexpression of Cyp27a1 in KCs reduces hepatic inflammation independently of 27HC levels in plasma and liver, further pointing towards KCs as specific target for improving the therapy of NASH. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

AB - Background & Aims: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation and inflammation. Currently, the underlying mechanisms, leading to hepatic inflammation, are still unknown. The breakdown of free cholesterol inside Kupffer cells (KCs) by the mitochondrial enzyme CYP27A1 produces 27-hydroxycholesterol (27HC). We recently demonstrated that administration of 27HC to hyperlipidemic mice reduced hepatic inflammation. In line, hematopoietic deletion of Cyp27a1 resulted in increased hepatic inflammation. In the current manuscript, the effect of hematopoietic overexpression of Cyp27a1 on the development of NASH and cholesterol trafficking was investigated. We hypothesized that Cyp27a1 overexpression in KCs will lead to reduced hepatic inflammation.Methods: Irradiated Ldlr(-/-) mice were transplanted (tp) with bone marrow from mice overexpressing Cyp27a1 (Cyp27a1(over)) and wild type (Wt) mice and fed either chow or a high-fat, high-cholesterol (HFC) diet for 3 months. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) from Cyp27a1(over) and Wt mice.Results: In line with our hypothesis, hepatic inflammation in HFC-fed Cyp27a1(over)-tp mice was reduced and KCs were less foamy compared to Wt-tp mice. Remarkably, these changes occurred even though plasma and liver levels of 27HC did not differ between both groups. BMDM from Cyp27a1(over) mice revealed reduced inflammatory gene expression and increased expression of cholesterol transporters compared to Wt BMDM after lipopolysaccharide (LPS) stimulation.Conclusions: Our data suggest that overexpression of Cyp27a1 in KCs reduces hepatic inflammation independently of 27HC levels in plasma and liver, further pointing towards KCs as specific target for improving the therapy of NASH. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KW - Hepatic inflammation

KW - Cholesterol

KW - CYP27A1

KW - Kupffer cells

KW - ESTROGEN-RECEPTOR MODULATOR

KW - LOW-DENSITY-LIPOPROTEIN

KW - LIVER-X-RECEPTOR

KW - CHOLESTERYL ESTER

KW - TRANSGENIC EXPRESSION

KW - BONE HOMEOSTASIS

KW - CELLS

KW - EFFLUX

KW - NPC2

KW - ACCUMULATION

U2 - 10.1016/j.jhep.2014.09.027

DO - 10.1016/j.jhep.2014.09.027

M3 - Article

SN - 0168-8278

VL - 62

SP - 430

EP - 436

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 2

ER -