DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

INTERACTION BETWEEN ALCOHOL AND OBESITY IN THE SEVERITY OF FATTY LIVER DISEASE – HEPAMETOL

INTERACTION BETWEEN ALCOHOL AND OBESITY IN THE SEVERITY OF FATTY LIVER DISEASE

Alcoholic and Non-Alcoholic fatty liver disease (ALD, NAFLD) are leading causes of liver-related morbi-mortality and co-morbidities are emerging as factors accelerating disease progression. Studies of the interplay between obesity and alcohol on the severity and progression of liver lesions and identification of targets with therapeutic potential constitute a major issue.

General objective and main issues

The aim of HEPAMETOL is to study the molecular mechanisms underlying progression and severity of ALD in a context of obesity. We will 1) in humans, identify novel actors (i.e miRNA, gene expression), owing to an already constituted unique cohort of obese patients with ALD. The pertinence of these pathways will be compared with lean alcoholic patients and obese patients without alcohol consumption. 2) in alcohol-exposed obese mice, i.e in a context of insulin resistance and lipotoxicity, evaluate the relevance of i) metabolic targets in hepatocytes (ChREBP) and ii) immuno-metabolic regulators in immune cells (cannabinoids,CD44); 3) integrate results from human and mouse studies by investigating in mice, key targets identified in patients and validate, in humans, targets identified in animals.

In this project, experiments will combine studies in human samples, owing to the availability of liver and blood samples from a unique constituted cohort of overweight/obese patients with ALD, with studies in animal models and cultured cells, that will be shared by the three partners.

Our preliminary results at midterm indicate that 1) acute nicotinamide ribose (NR) treatment stimulates alcohol metabolism, decreases circulating and hepatic acetaldehyde levels and increases mitochondrial ALDH2 activity in binge alcohol mice. These promising data indicate that acute oral administration of NR would be an attractive therapeutic approach to antagonize deleterious effects of acute alcohol intoxication on the liver (manuscript in preparation). 2) CD44 is a marker and key player of hepatic inflammation and its targeting partially corrects NASH. We found that liver inflammation (including inflammatory foci number, macrophage and neutrophil infiltration and CCL2/CCR2 levels), liver injury and fibrosis strongly decreased in CD44KO mice compared to wild-type mice on MCDD. CD44 deficiency enhanced the M2 polarization and strongly decreased the activation of macrophages by lipopolysaccharide (LPS), hepatocyte damage-associated molecular patterns (DAMPs) and saturated fatty acids. Neutralization of CD44 in mice with steatohepatitis strongly decreased the macrophage infiltration and chemokine ligand (CCL)2 expression with a partial correction of liver inflammation and injury. In obese patients, hepatic CD44 was strongly upregulated in NASH patients and correlated with NAFLD activity score (NAS), ballooning , alanine transaminase and hepatic CCL2 and macrophage marker CD68 expression. Correction of NASH was associated with a strong decrease in liver CD44+ cells. Finally, the soluble form of CD44 increased with severe steatosis and NASH. The work has been recently accepted for publication (J Hepatol. 2017 Aug;67(2):328-33).

Over the coming months: -We will research of actors/pathways involved in progression of liver complications in alcoholic patients with obesity via high throughput sequencing for small and large RNA sequences. The most relevant miRNA and mRNA with the highest fold change will be validated in large number of patients and correlated with liver features complications, and metabolic parameters -We will set up set up a robust animal model of ALD in a context of obesity. -We will evaluate the relevance of i) metabolic targets in hepatocytes (ChREBP) and ii) immuno-metabolic regulators in immune cells (cannabinoids, CD44) in an animal model of ALD with obesity. We will study the role of hepatocyte ChREBP in ALD in a context of obesity, assess the contribution of SIRT1 to the ChREBP-induced phenotype and identify new targets of ChREBP by an array approach. We will determine if inhibition of CB1 (antagonist and CB1Mye-/-) in myeloïd cells regulates lipid metabolism (via autophagy) and prevents hepatic inflammation and liver complications. We will also evaluate the role of CD44 in ALD but also in a context of chronic alcohol exposure with obesity. We will target CD44 in all immune cells but also specifically in the myeloid cells. -Finally, we will integrate results from human and mouse studies by investigating in mice, key targets identified in patients and validate, in humans, targets identified in animals.

1- PUBLICATIONS. 1: Patouraux S, Rousseau D, Bonnafous S, Lebeaupin C, Luci C, Canivet CM, Schneck AS, Bertola A, Saint-Paul MC, Iannelli A, Gugenheim J, Anty R, Tran A, Bailly-Maitre B, Gual P. CD44 is a key player in non-alcoholic steatohepatitis. J Hepatol. 2017 Aug;67(2):328-338.. 2: Danin PE, Anty R, Patouraux S, Raucoules-Aimé M, Gugenheim J, Tran A, Gual P*, Iannelli A*.(*co-last author) Non-invasive Evaluation of NAFLD with Indocyanine Green Clearance Test: a Preliminary Study in Morbidly Obese Patients Undergoing Bariatric Surgery. Obes Surg. 2017 Sep 5 in press 3: Favre G, Anty R, Canivet C, Clément G, Ben-Amor I, Tran A, Gugenheim J, Gual P, Esnault VLM, Iannelli A. Determinants associated with the correction of glomerular hyper-filtration one year after bariatric surgery. Surg Obes Relat Dis. 2017 Jul 19. pii: S1550-7289(17)30344-1. 4: Schneck AS, Anty R, Patouraux S, Bonnafous S, Rousseau D, Lebeaupin C, Bailly-Maitre B, Sans A, Tran A, Gugenheim J, Iannelli A, Gual P. Roux-En Y Gastric Bypass Results in Long-Term Remission of Hepatocyte Apoptosis and Hepatic Histological Features of Non-alcoholic Steatohepatitis. Front Physiol. 2016 Aug 19;7:344. 2- REVUES, LETTRE A EDITEUR, EDITORIAL. 5: Gual P, Gilgenkrantz H, Lotersztajn S. Autophagy in chronic liver diseases: the two faces of Janus. Am J Physiol Cell Physiol. 2017 Mar 1;312(3):C263-C273 6: Gual P, Gilgenkrantz H, Lotersztajn S. L’autophagie dans les maladies chroniques du foie. Un ami qui vous veut (presque) toujours du bien! Med Sci (Paris), 2017 Mar;33(3):252-259. 7: Abdul-Wahed A, Guilmeau S, Postic C. Sweet Sixteenth for ChREBP: Established Roles and Future Goals. Cell Metab. 2017 Aug 1;26(2):324-341. 8: Canivet CM, Tran A, Gual P, Anty R. Génétique et épigénétique dans la non-alcoholic fatty liver disease. Hépato Gastro. 2017 ; 24 : 719-726.

Alcoholic and Non-Alcoholic fatty liver disease (ALD, NAFLD) are leading causes of liver-related morbi-mortality and co-morbidities are emerging as factors accelerating disease progression. Studies of the interplay between obesity and alcohol on the severity and progression of liver lesions and identification of targets with therapeutic potential constitute a major issue. The aim of HEPAMETOL is to study the molecular mechanisms underlying progression and severity of ALD in a context of obesity. We will

1) in humans, identify novel actors (i.e miRNA, gene expression), owing to an already constituted unique cohort of obese patients with ALD. The pertinence of these pathways will be compared with lean alcoholic patients and obese patients without alcohol consumption.

2) in alcohol-exposed obese mice, i.e in a context of insulin resistance and lipotoxicity, evaluate the relevance of i) metabolic targets in hepatocytes (ChREBP) and ii) immuno-metabolic regulators in immune cells (cannabinoids,CD44);

3) integrate results from human and mouse studies by investigating in mice, key targets identified in patients and validate, in humans, targets identified in animals.

Project coordinator

Monsieur Albert Tran (INSERM, U1065, Équipe 8 «Complications hépatiques de l’obésité»; Université de Nice-Sophia Antipolis, Faculté de Médecine; Centre Hospitalier Universitaire de Nice, Hôpital de l’Archet, Département Digestif, Nice, France)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM U1016 INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
U1149-CRI CENTRE DE RECHERCHE SUR L’INFLAMMATION
INSERM U1065 INSERM, U1065, Équipe 8 «Complications hépatiques de l’obésité»; Université de Nice-Sophia Antipolis, Faculté de Médecine; Centre Hospitalier Universitaire de Nice, Hôpital de l’Archet, Département Digestif, Nice, France

Help of the ANR 563,014 euros
Beginning and duration of the scientific project: September 2015 - 36 Months

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