β-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway

JOURNAL OF HEPATOLOGY

卷:69

Article

Chen, Yonglin¹  Ouyang, Xinshou¹  Hoque, Rafaz¹  Garcia-Martinez, Irma¹  Yousaf, Muhammad Nadeem¹  Tonack, Sarah^2,3  Offermanns, Stefan^2,3  Dubuquoy, Laurent⁵  Louvet, Alexandre⁴  Mathurin, Philippe^4,5  Massey, Veronica⁶  Schnabl, Bernd⁷  Bataller, Ramon Alberola⁸  Mehal, Wajahat Zafar^1,9 

[1] Yale Univ, Sch Med, Sect Digest Dis, New Haven, CT 06520 USA

[2] Max Planck Inst Heart & Lung Res, Dept Pharmacol, Ludwigstr 43, D-61231 Bad Nauheim, Germany

[3] JW Goethe Univ Frankfurt, Med Fac, Theodor Stern Kai 7, D-60590 Frankfurt, Germany

[4] Hop Huriez, Serv Malad Appareil Digestif, Lille, France

[5] INSERM, Unite 995, Fac Med, Lille, France

[6] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA

[7] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

[8] Univ Pittsburgh, Sch Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA

[9] USA West Haven Vet Med Ctr, West Haven, CT 06516 USA

关键词: beta-Hydroxybutyrate;    Therapy;    Alcohol;    induced liver injury;    Hcar2;   

DOI  :  10.1016/j.jhep.2018.04.004

来源: Elsevier

【 摘 要 】

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 beta-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 (Delta Psi) 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 beta-hydroxybutyrate occurs in patients with alcoholic hepatitis. This loss can increase alcohol-induced liver injury, and beta-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. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

Free