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

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.

SUBMITTER: Kim YS

PROVIDER: S-EPMC9568535 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Kim Yun Seok YS Ko Bongsub B Kim Da Jung DJ Tak Jihoon J Han Chang Yeob CY Cho Joo-Youn JY Kim Won W Kim Sang Geon SG

Nature communications 20221014 1

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 a ...[more]

PMID: 36241614

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Project description:BackgroundThe aryl hydrocarbon receptor (AHR) is expressed in the intestine and liver, where it has pleiotropic functions and target genes. This study aims to explore the potential implication of AHR in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. Specifically, we tested the hypothesis that targeting AHR can alleviate cachectic features, particularly through the gut-liver axis.MethodsAHR pathways were explored in multiple tissues from four experimental mouse models of cancer cachexia (C26, BaF3, MC38 and APCMin/+ ) and from non-cachectic mice (sham-injected mice and non-cachexia-inducing [NC26] tumour-bearing mice), as well as in liver biopsies from cancer patients. Cachectic mice were treated with an AHR agonist (6-formylindolo(3,2-b)carbazole [FICZ]) or an antibody neutralizing interleukin-6 (IL-6). Key mechanisms were validated in vitro on HepG2 cells.ResultsAHR activation, reflected by the expression of Cyp1a1 and Cyp1a2, two major AHR target genes, was deeply reduced in all models (C26 and BaF3, P < 0.001; MC38 and APCMin/+ , P < 0.05) independently of anorexia. This reduction occurred early in the liver (P < 0.001; before the onset of cachexia), compared to the ileum and skeletal muscle (P < 0.01; pre-cachexia stage), and was intrinsically related to cachexia (C26 vs. NC26, P < 0.001). We demonstrate a differential modulation of AHR activation in the liver (through the IL-6/hypoxia-inducing factor 1α pathway) compared to the ileum (attributed to the decreased levels of indolic AHR ligands, P < 0.001), and the muscle. In cachectic mice, FICZ treatment reduced hepatic inflammation: expression of cytokines (Ccl2, P = 0.005; Cxcl2, P = 0.018; Il1b, P = 0.088) with similar trends at the protein levels, expression of genes involved in the acute-phase response (Apcs, P = 0.040; Saa1, P = 0.002; Saa2, P = 0.039; Alb, P = 0.003), macrophage activation (Cd68, P = 0.038) and extracellular matrix remodelling (Fga, P = 0.008; Pcolce, P = 0.025; Timp1, P = 0.003). We observed a decrease in blood glucose in cachectic mice (P < 0.0001), which was also improved by FICZ treatment (P = 0.026) through hepatic transcriptional promotion of a key marker of gluconeogenesis, namely, G6pc (C26 vs. C26 + FICZ, P = 0.029). Strikingly, these benefits on glycaemic disorders occurred independently of an amelioration of the gut barrier dysfunction. In cancer patients, the hepatic expression of G6pc was correlated to Cyp1a1 (Spearman's ρ = 0.52, P = 0.089) and Cyp1a2 (Spearman's ρ = 0.67, P = 0.020).ConclusionsWith this set of studies, we demonstrate that impairment of AHR signalling contributes to hepatic inflammatory and metabolic disorders characterizing cancer cachexia, paving the way for innovative therapeutic strategies in this context.

Dataset Information

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

Publications

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

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