Olfactory receptor 43 reduces hepatic lipid accumulation and adiposity in mice

Chunyan Wu, Trung Thanh Thach, Yeon Ji Kim, Sung-Joon Lee

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Olfactory receptors are primarily expressed in nasal olfactory epithelium, but these receptors are also ectopically expressed in diverse tissues. In this study, we investigated the biological functions of Olfr43, a mouse homolog of human OR1A1, in cultured hepatocytes and mice to assess its functionality in lipid metabolism. Olfr43 was expressed in mouse hepatocytes, and Olfr43 activation by a known ligand, (−)-carvone, stimulated cAMP response element-binding protein (CREB) activity. In ligand-receptor binding studies using site-directed mutagenesis, (−)-carvone binding required two residues, M257 and Y258, in Olfr43. In the mouse study, oral administration of (−)-carvone for 5 weeks in high-fat diet-fed mice improved energy metabolism, including reductions in hepatic steatosis and adiposity, and improved glucose and insulin tolerance. In mouse livers and cultured mouse hepatocytes, Olfr43 activation simulated the CREB-hairy and enhancer of split 1 (HES1)-peroxisome proliferator-activated receptor (PPAR)-γ signaling axis, leading to a reduction in hepatic triglyceride accumulation in the mouse liver. Thus, long-term administration of (−)-carvone reduces hepatic steatosis. The knockdown of Olfr43 gene expression in cultured hepatocytes negated these effects of (−)-carvone. In conclusion, an ectopic olfactory receptor, hepatic Olfr43, regulates energy metabolism via the CREB-HES1-PPARγ signaling axis.

Original languageEnglish
Pages (from-to)489-499
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1864
Issue number4
DOIs
Publication statusPublished - 2019 Apr 1

Keywords

  • (−)-carvone
  • cAMP response element-binding protein
  • Lipid accumulation
  • Olfactory receptor
  • Olfr43

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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