Aryl hydrocarbon receptor promotes lipid droplet biogenesis and metabolic shift in respiratory Club cells

Hsueh Chun Wang*, Kwei Yan Liu, Li Ting Wang, Shih Hsien Hsu, Shao Chun Wang, Shau Ku Huang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Club cells are critical in maintaining airway integrity via, in part, secretion of immunomodulatory Club cell 10 kd protein (CC10) and xenobiotic detoxification. Aryl hydrocarbon receptor (AhR) is important in xenobiotic metabolism, but its role in Club cell function is unclear. To this end, an AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ, 10 nM) was found to induce, in a ligand and AhR-dependent manner, endoplasmic reticulum stress, phospholipid remodeling, free fatty acid and triglyceride synthesis, leading to perilipin 2-dependent lipid droplet (LD) biogenesis in a Club cell-like cell line, NL20. The increase in LDs was due, in part, to the blockade of adipose triglyceride lipase to LDs, while perilipin 5 facilitated LDs-mitochondria connection, leading to the breakdown of LDs via mitochondrial β-oxidation and acetyl-coA generation. In FICZ-treated cells, increased CC10 secretion and its intracellular association with LDs were noted. Administration of low (0.28 ng), medium (1.42 ng), and high (7.10 ng) doses of FICZ in C57BL/6 mice significantly enhanced lipopolysaccharide (LPS, 0.1 μg)-induced airway inflammation, mucin secretion, pro-inflammatory cytokines and CC10 in the bronchoalveolar lavage fluids, as compared to those seen in mice receiving LPS alone, suggesting the importance of AhR signaling in controlling the metabolic homeostasis and functions of Club cells.

Original languageEnglish
Pages (from-to)785-799
Number of pages15
JournalHuman Cell
Volume34
Issue number3
DOIs
Publication statusPublished - 2021 May
Externally publishedYes

Keywords

  • Aryl hydrocarbon receptor
  • Club cell
  • Club cell 10 kd protein
  • Lipid droplet
  • Perilipin

ASJC Scopus subject areas

  • Cell Biology
  • Cancer Research

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