RORα Induces KLF4-Mediated M2 Polarization in the Liver Macrophages that Protect against Nonalcoholic Steatohepatitis

Yong Hyun Han; Hyeon Ji Kim; Hyelin Na; Min Woo Nam; Ju Yeon Kim; Jun Seok Kim; Seung Hoi Koo; Mi Ock Lee

doi:10.1016/j.celrep.2017.06.017

RORα Induces KLF4-Mediated M2 Polarization in the Liver Macrophages that Protect against Nonalcoholic Steatohepatitis

Yong Hyun Han, Hyeon Ji Kim, Hyelin Na, Min Woo Nam, Ju Yeon Kim, Jun Seok Kim, Seung Hoi Koo, Mi Ock Lee

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104 Citations (Scopus)

Abstract

The regulation of M1/M2 polarization in liver macrophages is closely associated with the progression of nonalcoholic steatohepatitis (NASH); however, the mechanism involved in this process remains unclear. Here, we describe the orphan nuclear receptor retinoic-acid-related orphan receptor α (RORα) as a key regulator of M1/M2 polarization in hepatic residential Kupffer cells (KCs) and infiltrated monocyte-derived macrophages. RORα enhanced M2 polarization in KCs by inducing the kruppel-like factor 4. M2 polarization was defective in KCs and bone-marrow-derived macrophages of the myeloid-specific RORα null mice, and these mice were susceptible to HFD-induced NASH. We found that IL-10 played an important role in connecting the function of M2 KCs to lipid accumulation and apoptosis in hepatocytes. Importantly, M2 polarization was controlled by a RORα activator, JC1-40, which improved symptoms of NASH. Our results suggest that the M2-promoting effects of RORα in liver macrophages may provide better therapeutic strategies against NASH.

Original language	English
Pages (from-to)	124-135
Number of pages	12
Journal	Cell Reports
Volume	20
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2017.06.017
Publication status	Published - 2017 Jul 5

Keywords

KLF4
Kupffer cells
M2 polarity
RORα
non-alcoholic steatohepatitis

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2017.06.017

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title = "RORα Induces KLF4-Mediated M2 Polarization in the Liver Macrophages that Protect against Nonalcoholic Steatohepatitis",

abstract = "The regulation of M1/M2 polarization in liver macrophages is closely associated with the progression of nonalcoholic steatohepatitis (NASH); however, the mechanism involved in this process remains unclear. Here, we describe the orphan nuclear receptor retinoic-acid-related orphan receptor α (RORα) as a key regulator of M1/M2 polarization in hepatic residential Kupffer cells (KCs) and infiltrated monocyte-derived macrophages. RORα enhanced M2 polarization in KCs by inducing the kruppel-like factor 4. M2 polarization was defective in KCs and bone-marrow-derived macrophages of the myeloid-specific RORα null mice, and these mice were susceptible to HFD-induced NASH. We found that IL-10 played an important role in connecting the function of M2 KCs to lipid accumulation and apoptosis in hepatocytes. Importantly, M2 polarization was controlled by a RORα activator, JC1-40, which improved symptoms of NASH. Our results suggest that the M2-promoting effects of RORα in liver macrophages may provide better therapeutic strategies against NASH.",

keywords = "KLF4, Kupffer cells, M2 polarity, RORα, non-alcoholic steatohepatitis",

author = "Han, {Yong Hyun} and Kim, {Hyeon Ji} and Hyelin Na and Nam, {Min Woo} and Kim, {Ju Yeon} and Kim, {Jun Seok} and Koo, {Seung Hoi} and Lee, {Mi Ock}",

note = "Funding Information: This work was supported by grants from the Bio and Medical Technology Development Program (2012M3A9B6055338), the Korea Mouse Phenotyping Project (NRF-2014M3A9D5A01073556), and the National Research Foundation of Korea (2017R1A2B3011870). We thank the Institut Clinique de la Souris for establishment of the RORαfl/fl mouse mutant line. Publisher Copyright: {\textcopyright} 2017 The Authors",

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doi = "10.1016/j.celrep.2017.06.017",

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AU - Han, Yong Hyun

AU - Kim, Hyeon Ji

AU - Na, Hyelin

AU - Nam, Min Woo

AU - Kim, Ju Yeon

AU - Kim, Jun Seok

AU - Koo, Seung Hoi

AU - Lee, Mi Ock

N1 - Funding Information: This work was supported by grants from the Bio and Medical Technology Development Program (2012M3A9B6055338), the Korea Mouse Phenotyping Project (NRF-2014M3A9D5A01073556), and the National Research Foundation of Korea (2017R1A2B3011870). We thank the Institut Clinique de la Souris for establishment of the RORαfl/fl mouse mutant line. Publisher Copyright: © 2017 The Authors

PY - 2017/7/5

Y1 - 2017/7/5

N2 - The regulation of M1/M2 polarization in liver macrophages is closely associated with the progression of nonalcoholic steatohepatitis (NASH); however, the mechanism involved in this process remains unclear. Here, we describe the orphan nuclear receptor retinoic-acid-related orphan receptor α (RORα) as a key regulator of M1/M2 polarization in hepatic residential Kupffer cells (KCs) and infiltrated monocyte-derived macrophages. RORα enhanced M2 polarization in KCs by inducing the kruppel-like factor 4. M2 polarization was defective in KCs and bone-marrow-derived macrophages of the myeloid-specific RORα null mice, and these mice were susceptible to HFD-induced NASH. We found that IL-10 played an important role in connecting the function of M2 KCs to lipid accumulation and apoptosis in hepatocytes. Importantly, M2 polarization was controlled by a RORα activator, JC1-40, which improved symptoms of NASH. Our results suggest that the M2-promoting effects of RORα in liver macrophages may provide better therapeutic strategies against NASH.

AB - The regulation of M1/M2 polarization in liver macrophages is closely associated with the progression of nonalcoholic steatohepatitis (NASH); however, the mechanism involved in this process remains unclear. Here, we describe the orphan nuclear receptor retinoic-acid-related orphan receptor α (RORα) as a key regulator of M1/M2 polarization in hepatic residential Kupffer cells (KCs) and infiltrated monocyte-derived macrophages. RORα enhanced M2 polarization in KCs by inducing the kruppel-like factor 4. M2 polarization was defective in KCs and bone-marrow-derived macrophages of the myeloid-specific RORα null mice, and these mice were susceptible to HFD-induced NASH. We found that IL-10 played an important role in connecting the function of M2 KCs to lipid accumulation and apoptosis in hepatocytes. Importantly, M2 polarization was controlled by a RORα activator, JC1-40, which improved symptoms of NASH. Our results suggest that the M2-promoting effects of RORα in liver macrophages may provide better therapeutic strategies against NASH.

KW - KLF4

KW - Kupffer cells

KW - M2 polarity

KW - RORα

KW - non-alcoholic steatohepatitis

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SN - 2211-1247

VL - 20

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JO - Cell Reports

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ER -

RORα Induces KLF4-Mediated M2 Polarization in the Liver Macrophages that Protect against Nonalcoholic Steatohepatitis

Abstract

Keywords

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