Induction of the hepatic aryl hydrocarbon receptor by alcohol dysregulates autophagy and phospholipid metabolism via PPP2R2D
Authors and Affiliations
Authors and Affiliations
Yun Seok Kim 1 2 3, Bongsub Ko 1, Da Jung Kim 1 4, Jihoon Tak 3 5, Chang Yeob Han 3 6, Joo-Youn Cho 1 2, Won Kim 7, Sang Geon Kim 8
1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, 03080, Korea.
2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
3College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
4Metabolomics Core Facility, Department of Transdisciplinary Research and Collaboration, Biomedical Research Institute, Seoul National University Hospital, Seoul, 03082, Korea.
5College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Kyeonggi-do, 10326, Republic of Korea.
6School of Pharmacy and Institute of New Drug Development, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do, 54896, Korea.
7Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea.
8College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Kyeonggi-do, 10326, Republic of Korea.
Corresponding author: Correspondence to Sang Geon Kim.
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.