Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression

Nisreen Nimer; Ibrahim Choucair; Zeneng Wang; Ina Nemet; Lin Li; Janet Gukasyan; Taylor L Weeks; Naim Alkhouri; Nizar Zein; W H Wilson Tang; Michael A Fischbach; J Mark Brown; Hooman Allayee; Srinivasan Dasarathy; Valentin Gogonea; Stanley L Hazen

doi:10.1016/j.metabol.2020.154457

Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression

Metabolism. 2021 Mar:116:154457. doi: 10.1016/j.metabol.2020.154457. Epub 2020 Dec 1.

Authors

Affiliations

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.

Keywords: Bile acids; Fibrosis; Metabolomics; NAFLD; NASH.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Bile Acids and Salts / blood*
Bile Acids and Salts / metabolism
Biopsy
Case-Control Studies
Disease Progression
Female
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Male
Metabolome / physiology
Metabolomics
Middle Aged
Non-alcoholic Fatty Liver Disease / blood*
Non-alcoholic Fatty Liver Disease / genetics*
Non-alcoholic Fatty Liver Disease / pathology*

Substances

Bile Acids and Salts

Abstract

Publication types

MeSH terms

Substances

Grants and funding