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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24 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



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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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