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 Fischbach7, J Mark Brown2, Hooman Allayee3, Srinivasan Dasarathy8, Valentin Gogonea9, Stanley L Hazen10. 1. Department 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. 2. Department 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. 3. Department 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. 4. Texas Liver Institute and University of Texas Health, San Antonio, TX 78215, USA. 5. Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA. 6. Department 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, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA. 7. Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA. 8. Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. 9. Department 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. 10. Department 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, Vascular and Thoracic 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.
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.
Authors: Ibrahim Choucair; Ina Nemet; Lin Li; Margaret A Cole; Sarah M Skye; Jennifer D Kirsop; Michael A Fischbach; Valentin Gogonea; J Mark Brown; W H Wilson Tang; Stanley L Hazen Journal: J Lipid Res Date: 2019-12-09 Impact factor: 5.922
Authors: Stefano Romeo; Julia Kozlitina; Chao Xing; Alexander Pertsemlidis; David Cox; Len A Pennacchio; Eric Boerwinkle; Jonathan C Cohen; Helen H Hobbs Journal: Nat Genet Date: 2008-09-25 Impact factor: 38.330
Authors: Siarhei A Dabravolski; Evgeny E Bezsonov; Mirza S Baig; Tatyana V Popkova; Ludmila V Nedosugova; Antonina V Starodubova; Alexander N Orekhov Journal: Int J Mol Sci Date: 2021-04-24 Impact factor: 5.923