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Abstract Details
Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression
Metabolism. 2020 Dec 1;154457. doi: 10.1016/j.metabol.2020.154457. Online ahead of print.
Nisreen Nimer1, Ibrahim Choucair2, Zeneng Wang2, Ina Nemet2, Lin Li2, Janet Gukasyan3, Taylor L Weeks2, Naim Alkhouri4, Nizar Zein5, W H Wilson Tang6, Michael A Fischbach5, J Mark Brown2, Hooman Allayee3, Srinivasan Dasarathy7, Valentin Gogonea8, Stanley L Hazen9
Author information
1Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland, Clinic Cleveland, OH, 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH, 44195, USA; Department of Chemistry, Cleveland State University, Cleveland, OH, 44115, USA.
2Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland, Clinic Cleveland, OH, 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH, 44195, USA.
3Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
4Texas Liver Institute and University of Texas Health, San Antonio, TX, 78215, USA.
5Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA, 94305, USA.
6Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland, Clinic Cleveland, OH, 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH, 44195, USA; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
7Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, Clinic Cleveland, OH, 44195, USA.
8Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland, Clinic Cleveland, OH, 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH, 44195, USA; Department of Chemistry, Cleveland State University, Cleveland, OH, 44115, USA. Electronic address: v.gogonea@csuohio.edu.
9Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland, Clinic Cleveland, OH, 44195, USA; Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH, 44195, USA; Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, 44195, USA; Department of Chemistry, Cleveland State University, Cleveland, OH, 44115, USA. Electronic address: Hazens@ccf.org.
Abstract
Objective: Metabolomic studies suggest plasma levels of bile acids (BAs) are elevated amongst subjects with non-alcoholic fatty liver disease (NAFLD) compared to healthy controls. However, it remains unclear whether or not specific BAs are associated with the clinically relevant transition from nonalcoholic fatty liver (i.e. simple steatosis) to non-alcoholic steatohepatitis (NASH), or enhanced progression of hepatic fibrosis, or genetic determinants of NAFLD/NASH.
Methods: Among sequential subjects (n=102) undergoing diagnostic liver biopsy, we examined the associations of a broad panel of BAs with distinct histopathological features of NAFLD, the presence of NASH, and their associations with genetic variants linked to NAFLD and NASH.
Results: Plasma BA alterations were observed through the entire spectrum of NAFLD, with several glycine conjugated forms of the BAs demonstrating significant associations with higher grades of inflammation and fibrosis. Plasma 7-Keto-DCA levels showed the strongest associations with advanced stages of hepatic fibrosis [odds ratio(95% confidence interval)], 4.2(1.2-16.4), NASH 24.5(4.1-473), and ballooning 18.7(4.8-91.9). Plasma 7-Keto-LCA levels were associated with NASH 9.4(1.5-185) and ballooning 5.9(1.4-28.8). Genetic variants at several NAFLD/NASH loci were nominally associated with increased levels of 7-Keto- and glycine-conjugated forms of BAs, and the NAFLD risk allele at the TRIB1 locus showed strong tendency toward increased plasma levels of GCA (p=0.02) and GUDCA (p=0.009).
Conclusions: Circulating bile acid levels are associated with histopathological and genetic determinants of the transition from simple hepatic steatosis into NASH. Further studies exploring the potential involvement of bile acid metabolism in the development and/or progression of distinct histopathological features of NASH are warranted.