TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models.
Acyltransferases
/ genetics
Carcinoma, Hepatocellular
/ genetics
Genetic Predisposition to Disease
Genotype
Humans
Lipase
/ genetics
Liver Neoplasms
/ genetics
Membrane Proteins
/ genetics
Non-alcoholic Fatty Liver Disease
/ genetics
Phospholipases A2, Calcium-Independent
Polymorphism, Single Nucleotide
/ genetics
ER Stress
HCC
Mitochondrial Dynamics
NAFLD
TM6SF2
Journal
Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302
Informations de publication
Date de publication:
2022
2022
Historique:
received:
26
02
2021
revised:
16
11
2021
accepted:
16
11
2021
pubmed:
26
11
2021
medline:
5
4
2022
entrez:
25
11
2021
Statut:
ppublish
Résumé
The I148M Patatin-like Phospholipase Domain-containing 3 (PNPLA3), the rs641738 in the Membrane bound O-acyltransferase domain containing 7-transmembrane channel-like 4 (MBOAT7-TMC4) locus, and the E167K Transmembrane 6 Superfamily Member 2 (TM6SF2) polymorphisms represent the main predisposing factors to nonalcoholic fatty liver disease (NAFLD) development and progression. We previously generated a full knockout of MBOAT7 in HepG2 cells (MBOAT7 NAFLD patients (n = 1380), of whom 121 had HCC, were stratified with a semiquantitative score ranging from 0 to 3 according to the number of PNPLA3, TM6SF2, and MBOAT7 at-risk variants. TM6SF2 was silenced in HepG2 (TM6SF2 In NAFLD patients, the additive weight of these mutations was associated with liver disease severity and an increased risk of developing HCC. In HepG2 cells, TM6SF2 silencing altered lipid composition and induced the accumulation of microvesicular lipid droplets (LDs), whereas the MBOAT7 The co-presence of the 3 at-risk variants impacts the NAFLD course in both patients and experimental models, affecting LD accumulation, mitochondrial functionality, and metabolic reprogramming toward HCC.
Sections du résumé
BACKGROUND & AIMS
The I148M Patatin-like Phospholipase Domain-containing 3 (PNPLA3), the rs641738 in the Membrane bound O-acyltransferase domain containing 7-transmembrane channel-like 4 (MBOAT7-TMC4) locus, and the E167K Transmembrane 6 Superfamily Member 2 (TM6SF2) polymorphisms represent the main predisposing factors to nonalcoholic fatty liver disease (NAFLD) development and progression. We previously generated a full knockout of MBOAT7 in HepG2 cells (MBOAT7
METHODS
NAFLD patients (n = 1380), of whom 121 had HCC, were stratified with a semiquantitative score ranging from 0 to 3 according to the number of PNPLA3, TM6SF2, and MBOAT7 at-risk variants. TM6SF2 was silenced in HepG2 (TM6SF2
RESULTS
In NAFLD patients, the additive weight of these mutations was associated with liver disease severity and an increased risk of developing HCC. In HepG2 cells, TM6SF2 silencing altered lipid composition and induced the accumulation of microvesicular lipid droplets (LDs), whereas the MBOAT7
CONCLUSIONS
The co-presence of the 3 at-risk variants impacts the NAFLD course in both patients and experimental models, affecting LD accumulation, mitochondrial functionality, and metabolic reprogramming toward HCC.
Identifiants
pubmed: 34823063
pii: S2352-345X(21)00241-1
doi: 10.1016/j.jcmgh.2021.11.007
pmc: PMC8783129
pii:
doi:
Substances chimiques
Membrane Proteins
0
TM6SF2 protein, human
0
Acyltransferases
EC 2.3.-
MBOAT7 protein, human
EC 2.3.-
Lipase
EC 3.1.1.3
adiponutrin, human
EC 3.1.1.3
Phospholipases A2, Calcium-Independent
EC 3.1.1.4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
759-788Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.