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Cell Rep. 2017 Jul 5;20(1):124-135. doi: 10.1016/j.celrep.2017.06.017.

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

Author information

1
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
2
Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
3
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Bio-MAX Institute, Seoul National University, Seoul 08826, Republic of Korea; Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: molee@snu.ac.kr.

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

PMID:
28683306
DOI:
10.1016/j.celrep.2017.06.017
[Indexed for MEDLINE]
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