Τίτλος:
Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10, GDF15, and PDGFA, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
Συγγραφείς:
Govaere, O.
Cockell, S.
Tiniakos, D.
Queen, R.
Younes, R.
Vacca, M.
Alexander, L.
Ravaioli, F.
Palmer, J.
Petta, S.
Boursier, J.
Rosso, C.
Johnson, K.
Wonders, K.
Day, C.P.
Ekstedt, M.
Orešič, M.
Darlay, R.
Cordell, H.J.
Marra, F.
Vidal-Puig, A.
Bedossa, P.
Schattenberg, J.M.
Clément, K.
Allison, M.
Bugianesi, E.
Ratziu, V.
Daly, A.K.
Anstee, Q.M.
Περιοδικό:
Science Translational Medicine
Εκδότης:
American Association for the Advancement of Science
Λέξεις-κλειδιά:
aldo keto reductase family 1 member B10; aspartate aminotransferase; growth differentiation factor 15; lipopolysaccharide; platelet derived growth factor A; transcriptome, adult; age; Article; blood sampling; disease activity; disease exacerbation; endoplasmic reticulum stress; female; gene; genetic variability; human; in vitro study; liver fibrosis; liver tissue; macrophage; major clinical study; male; non insulin dependent diabetes mellitus; nonalcoholic fatty liver; nonalcoholic steatohepatitis; pathophysiology; PNPLA3 gene; priority journal; RNA sequencing; transcriptomics; upregulation; clinical trial; genetics; liver; liver cirrhosis; multicenter study; non insulin dependent diabetes mellitus; nonalcoholic fatty liver; pathology, Diabetes Mellitus, Type 2; Humans; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Transcriptome
DOI:
10.1126/SCITRANSLMED.ABA4448
