Genetic Pathways in Nonalcoholic Fatty Liver Disease: Insights From Systems Biology.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
16
12
2019
revised:
12
02
2020
accepted:
06
03
2020
pubmed:
15
3
2020
medline:
7
5
2021
entrez:
15
3
2020
Statut:
ppublish
Résumé
Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here, we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as an NAFLD-Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in patatin-like phospholipase domain containing 3, transmembrane 6 superfamily member 2, membrane-bound O-acyltransferase domain containing 7, glucokinase regulator, and hydroxysteroid 17-beta dehydrogenase 13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell-based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de novo lipogenesis; mitochondrial energy use; lipid droplet assembly, lipolytic catabolism, and fatty acid compartmentalization; and very low-density lipoprotein assembly and secretion. The NAFLD-Reactome model expands these pathways and allows for hypothesis testing, as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice.
Identifiants
pubmed: 32170962
doi: 10.1002/hep.31229
pmc: PMC7363530
mid: NIHMS1592539
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
330-346Subventions
Organisme : NIDDK NIH HHS
ID : DK-119437
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK119437
Pays : United States
Organisme : NIDDK NIH HHS
ID : DK-112378
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020579
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK052574
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK112378
Pays : United States
Organisme : NIDDK NIH HHS
ID : DK-52574
Pays : United States
Informations de copyright
© 2020 by the American Association for the Study of Liver Diseases.
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