B-hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway. - Université de Lille Accéder directement au contenu
Article Dans Une Revue Journal of hepatology Année : 2018

B-hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway.

Yonglin Chen
  • Fonction : Auteur
Xinshou Ouyang
  • Fonction : Auteur
Rafaz Hoque
  • Fonction : Auteur
Irma Garcia-Martinez
  • Fonction : Auteur
Nadeem Yousaf Muhammad
  • Fonction : Auteur
Sarah Tonack
  • Fonction : Auteur
Stefan Offermanns
  • Fonction : Auteur
Veronica Massey
  • Fonction : Auteur
Bernd Schnabl
  • Fonction : Auteur
Ramon Bataller
  • Fonction : Auteur
Zafar Mehal Wajahat
  • Fonction : Auteur

Résumé

Background & Aims: Sterile inflammation resulting in alcoholic hepatitis (AH) occurs unpredictably after many years of excess alcohol intake. The factors responsible for the development of AH are not known but mitochondrial damage with loss of mitochondrial function are common features. Hcar2 is a G-protein coupled receptor which is activated by β-hydroxybutyrate (BHB). We aimed to determine the relevance of the BHB-Hcar2 pathway in alcoholic liver disease.Methods: We tested if loss of BHB production can result in increased liver inflammation. We further tested if BHB supplementation is protective in AH through interaction with Hcar2, and analyzed the immune and cellular basis for protection.Results: Humans with AH have reduced hepatic BHB, and inhibition of BHB production in mice aggravated ethanol-induced AH, with higher plasma alanine aminotransferase levels, increased steatosis and greater neutrophil influx. Conversely supplementation of BHB had the opposite effects with reduced alanine aminotransferase levels, reduced steatosis and neutrophil influx. This therapeutic effect of BHB is dependent on the receptor Hcar2. BHB treatment increased liver Il10 transcripts, and promoted the M2 phenotype of intrahepatic macrophages. BHB also increased the transcriptional level of M2 related genes in vitro bone marrow derived macrophages. This skewing towards M2 related genes is dependent on lower mitochondrial membrane potential (Δψ) induced by BHB.Conclusions: Collectively, our data shows that BHB production during excess alcohol consumption has an anti-inflammatory and hepatoprotective role through an Hcar2 dependent pathway. This introduces the concept of metabolite-based therapy for AH.Lay summary: Alcoholic hepatitis is a life-threatening condition with no approved therapy that occurs unexpectedly in people who consume excess alcohol. The liver makes many metabolites, and we demonstrate that loss of one such metabolite β-hydroxybutyrate occurs in patients with alcoholic hepatitis. This loss can increase alcohol-induced liver injury, and β-hydroxybutyrate can protect from alcohol-induced liver injury via a receptor on liver macrophages. This opens the possibility of metabolite-based therapy for alcoholic hepatitis.
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Dates et versions

hal-04315199 , version 1 (19-03-2024)

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Yonglin Chen, Xinshou Ouyang, Rafaz Hoque, Irma Garcia-Martinez, Nadeem Yousaf Muhammad, et al.. B-hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway.. Journal of hepatology, 2018, Journal of hepatology, 69, pp.687-696. ⟨10.1016/j.jhep.2018.04.004⟩. ⟨hal-04315199⟩

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