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

Research output: Contribution to journalArticlepeer-review

106 Citations (Scopus)


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 languageEnglish
Pages (from-to)124-135
Number of pages12
JournalCell Reports
Issue number1
Publication statusPublished - 2017 Jul 5

Bibliographical 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:
© 2017 The Authors


  • KLF4
  • Kupffer cells
  • M2 polarity
  • RORα
  • non-alcoholic steatohepatitis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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