Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation

The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LP...

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Vydané v:Hepatology Ročník 81; číslo 2; s. 576 - 590
Hlavní autori: Moore, Mary P., Wang, Xiaobo, Kennelly, John Paul, Shi, Hongxue, Ishino, Yuki, Kano, Kuniyuki, Aoki, Junken, Cherubini, Alessandro, Ronzoni, Luisa, Guo, Xiuqing, Chalasani, Naga P., Khalid, Shareef, Saleheen, Danish, Mitsche, Matthew A., Rotter, Jerome I., Yates, Katherine P., Valenti, Luca, Kono, Nozomu, Tontonoz, Peter, Tabas, Ira
Médium: Journal Article
Jazyk:English
Japanese
Vydavateľské údaje: United States Ovid Technologies (Wolters Kluwer Health) 01.02.2025
Predmet:
Acyltransferases - genetics
Acyltransferases - metabolism
Adaptor Proteins, Signal Transducing
Animals
Disease Models, Animal
Genetic Predisposition to Disease
Hepatocytes - metabolism
Humans
Liver Cirrhosis - etiology
Liver Cirrhosis - genetics
Liver Cirrhosis - metabolism
Liver Cirrhosis - pathology
Male
Membrane Proteins
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease - genetics
Trans-Activators - metabolism
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Up-Regulation
ISSN:0270-9139, 1527-3350, 1527-3350
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Shrnutí:The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction-associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear. We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity and increased IHH mRNA. This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis, adds new insight into an established genetic locus for MASH, and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0270-9139
1527-3350
1527-3350
DOI:10.1097/hep.0000000000000933