Alcohol withdrawal alleviates adipose tissue inflammation in patients with alcoholic liver disease.
OBJECTIVE
Patients with alcoholic liver disease (ALD) display inflammation of the subcutaneous adipose tissue (SAT) which correlates with liver lesions. We examined macrophage markers and polarization in the SAT of alcoholic patients and adipokine expression according to liver inflammation; we studied the consequences of alcohol withdrawal.


METHODS
Forty-seven patients with ALD were prospectively included. SAT and blood samples were collected at inclusion and after 1 week of alcohol withdrawal. Pro-inflammatory cytokines/chemokines, inflammasome components and products, adipokine expression levels, macrophage markers and polarization in liver and SAT samples were assessed by RT-PCR arrays.


RESULTS
mRNA expression level of chemokines (IL8, semaphorin 7A) correlated with hepatic steatosis in both liver and SAT. Liver expression of inflammasome components (IL1β, IL18, caspase-1) and SAT IL6 and CCL2 correlated with liver damage. In patients with mild ALD, 1 week of alcohol withdrawal was sufficient to decrease expression level of total macrophage markers in the adipose tissue, to orient adipose tissue macrophages (ATM) towards an anti-inflammatory M2 phenotype and to decrease the mRNA expression of cytokines/chemokines (IL18, CCL2, osteopontin, semaphorin 7A). In patients with severe ALD, 1 week of abstinence was also associated with an increase in CCL18 expression.


CONCLUSIONS
In alcoholic patients, upregulation of chemotactic factors in the liver and SAT is an early event that begins as early as the steatosis stage. The inflammasome pathway is upregulated in the liver of patients with ALD. One week of alcohol withdrawal alleviates macrophage infiltration in SAT and orients ATM towards a M2 anti-inflammatory phenotype; this implicates alcohol in adipose tissue inflammation (ClinicalTrials.gov NCT00388323).
INSERM U996, IPSIT, Clamart, F-92140, France; Univ Paris-Sud, Faculté de médecine Paris-Sud, Kremlin-Bicêtre, F-94270, France; AP-HP, Hôpital Antoine Béclère, Service d'hépato-gastroentérologie et nutrition, Clamart, F-92140, France; DHU Hépatinov, Clamart, F-92140, France.
Cosmin S
CS
Voican
Micheline
M
Njiké-Nakseu
Hédia
H
Boujedidi
Nadège
N
Barri-Ova
Laurence
L
Bouchet-Delbos
Hélène
H
Agostini
Sophie
S
Maitre
Sophie
S
Prévot
Anne-Marie
AM
Cassard-Doulcier
Sylvie
S
Naveau
Gabriel
G
Perlemuter
D054392:Adipokines / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D064829:Alcohol Abstinence; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015434:Panniculitis / Q000150:complications / Q000628:therapy*; D011446:Prospective Studies
D054392:Adipokines; D015415:Biomarkers; D016207:Cytokines
adipokine; adipose tissue; adipose tissue macrophage; alcohol withdrawal; alcoholic liver disease; cytokine; hepatic inflammation