Inflammation-induced cholestasis in cancer cachexia.

Autor: Thibaut MM; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Sboarina M; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Roumain M; Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Pötgens SA; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Neyrinck AM; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Destrée F; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Gillard J; Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Leclercq IA; Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Dachy G; Experimental Medicine Unit, de Duve Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Demoulin JB; Experimental Medicine Unit, de Duve Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Tailleux A; Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France., Lestavel S; Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France., Rastelli M; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.; Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Everard A; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.; Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Cani PD; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.; Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Porporato PE; Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Center, University of Turin, Turin, Italy., Loumaye A; Endocrinology, Diabetology and Nutrition Department, Institut de Recherche Expérimentale et Clinique, UCLouvain, Université catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium., Thissen JP; Endocrinology, Diabetology and Nutrition Department, Institut de Recherche Expérimentale et Clinique, UCLouvain, Université catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium., Muccioli GG; Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Delzenne NM; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium., Bindels LB; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.
Jazyk: angličtina
Zdroj: Journal of cachexia, sarcopenia and muscle [J Cachexia Sarcopenia Muscle] 2021 Feb; Vol. 12 (1), pp. 70-90. Date of Electronic Publication: 2020 Dec 22.
DOI: 10.1002/jcsm.12652
Abstrakt: Background: Cancer cachexia is a debilitating metabolic syndrome contributing to cancer death. Organs other than the muscle may contribute to the pathogenesis of cancer cachexia. This work explores new mechanisms underlying hepatic alterations in cancer cachexia.
Methods: We used transcriptomics to reveal the hepatic gene expression profile in the colon carcinoma 26 cachectic mouse model. We performed bile acid, tissue mRNA, histological, biochemical, and western blot analyses. Two interventional studies were performed using a neutralizing interleukin 6 antibody and a bile acid sequestrant, cholestyramine. Our findings were evaluated in a cohort of 94 colorectal cancer patients with or without cachexia (43/51).
Results: In colon carcinoma 26 cachectic mice, we discovered alterations in five inflammatory pathways as well as in other pathways, including bile acid metabolism, fatty acid metabolism, and xenobiotic metabolism (normalized enrichment scores of -1.97, -2.16, and -1.34, respectively; all Padj < 0.05). The hepatobiliary transport system was deeply impaired in cachectic mice, leading to increased systemic and hepatic bile acid levels (+1512 ± 511.6 pmol/mg, P = 0.01) and increased hepatic inflammatory cytokines and neutrophil recruitment to the liver of cachectic mice (+43.36 ± 16.01 neutrophils per square millimetre, P = 0.001). Adaptive mechanisms were set up to counteract this bile acid accumulation by repressing bile acid synthesis and by enhancing alternative routes of basolateral bile acid efflux. Targeting bile acids using cholestyramine reduced hepatic inflammation, without affecting the hepatobiliary transporters (e.g. tumour necrosis factor α signalling via NFκB and inflammatory response pathways, normalized enrichment scores of -1.44 and -1.36, all Padj < 0.05). Reducing interleukin 6 levels counteracted the change in expression of genes involved in the hepatobiliary transport, bile acid synthesis, and inflammation. Serum bile acid levels were increased in cachectic vs. non-cachectic cancer patients (e.g. total bile acids, +5.409 ± 1.834 μM, P = 0.026) and were strongly correlated to systemic inflammation (taurochenodeoxycholic acid and C-reactive protein: ρ = 0.36, Padj = 0.017).
Conclusions: We show alterations in bile acid metabolism and hepatobiliary secretion in cancer cachexia. In this context, we demonstrate the contribution of systemic inflammation to the impairment of the hepatobiliary transport system and the role played by bile acids in the hepatic inflammation. This work paves the way to a better understanding of the role of the liver in cancer cachexia.
(© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)
Databáze: MEDLINE
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