Induction of the hepatic aryl hydrocarbon receptor by alcohol dysregulates autophagy and phospholipid metabolism via PPP2R2D

Yun Seok Kim, Bongsub Ko, Da Jung Kim, Jihoon Tak, Chang Yeob Han, Joo-Youn Cho, Won Kim and Sang Geon Kim ()
Additional contact information
Yun Seok Kim: Seoul National University College of Medicine
Bongsub Ko: Seoul National University College of Medicine
Da Jung Kim: Seoul National University College of Medicine
Jihoon Tak: Seoul National University
Chang Yeob Han: Seoul National University
Joo-Youn Cho: Seoul National University College of Medicine
Won Kim: Seoul National University College of Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center
Sang Geon Kim: Dongguk University-Seoul

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Disturbed lipid metabolism precedes alcoholic liver injury. Whether and how AhR alters degradation of lipids, particularly phospho-/sphingo-lipids during alcohol exposure, was not explored. Here, we show that alcohol consumption in mice results in induction and activation of aryl hydrocarbon receptor (AhR) in the liver, and changes the hepatic phospho-/sphingo-lipids content. The levels of kynurenine, an endogenous AhR ligand, are elevated with increased hepatic tryptophan metabolic enzymes in alcohol-fed mice. Either alcohol or kynurenine treatment promotes AhR activation with autophagy dysregulation via AMPK. Protein Phosphatase 2 Regulatory Subunit-Bdelta (Ppp2r2d) is identified as a transcriptional target of AhR. Consequently, PPP2R2D-dependent AMPKα dephosphorylation causes autophagy inhibition and mitochondrial dysfunction. Hepatocyte-specific AhR ablation attenuates steatosis, which is associated with recovery of phospho-/sphingo-lipids content. Changes of AhR targets are corroborated using patient specimens. Overall, AhR induction by alcohol inhibits autophagy in hepatocytes through AMPKα, which is mediated by Ppp2r2d gene transactivation, revealing an AhR-dependent metabolism of phospho-/sphingo-lipids.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-33749-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33749-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-33749-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().