RT Journal Article
T1 Targeting Hepatic Glutaminase 1 Ameliorates Non-alcoholic Steatohepatitis by Restoring Very-Low-Density Lipoprotein Triglyceride Assembly.
A1 Simon, Jorge
A1 Nuñez-García, Maitane
A1 Fernández-Tussy, Pablo
A1 Barbier-Torres, Lucía
A1 Fernández-Ramos, David
A1 Gómez-Santos, Beatriz
A1 Buqué, Xabier
A1 Lopitz-Otsoa, Fernando
A1 Goikoetxea-Usandizaga, Naroa
A1 Serrano-Macia, Marina
A1 Rodriguez-Agudo, Rubén
A1 Bizkarguenaga, Maider
A1 Zubiete-Franco, Imanol
A1 Gutiérrez-de Juan, Virginia
A1 Cabrera, Diana
A1 Alonso, Cristina
A1 Iruzubieta, Paula
A1 Romero-Gomez, Manuel
A1 van Liempd, Sebastiaan
A1 Castro, Azucena
A1 Nogueiras, Ruben
A1 Varela-Rey, Marta
A1 Falcón-Pérez, Juan Manuel
A1 Villa, Erica
A1 Crespo, Javier
A1 Lu, Shelly C
A1 Mato, Jose M
A1 Aspichueta, Patricia
A1 Delgado, Teresa C
A1 Martínez-Chantar, María Luz
K1 GLS1
K1 GLS2
K1 NAFLD
K1 NASH
K1 TCA cycle
K1 VLDL
K1 folate cycle
K1 glutaminase
K1 methionine cycle
K1 phospholipids
AB Non-alcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatic fat in an inflammatory/fibrotic background. Herein, we show that the hepatic high-activity glutaminase 1 isoform (GLS1) is overexpressed in NASH. Importantly, GLS1 inhibition reduces lipid content in choline and/or methionine deprivation-induced steatotic mouse primary hepatocytes, in human hepatocyte cell lines, and in NASH mouse livers. We suggest that under these circumstances, defective glutamine fueling of anaplerotic mitochondrial metabolism and concomitant reduction of oxidative stress promotes a reprogramming of serine metabolism, wherein serine is shifted from the generation of the antioxidant glutathione and channeled to provide one-carbon units to regenerate the methionine cycle. The restored methionine cycle can induce phosphatidylcholine synthesis from the phosphatidylethanolamine N-methyltransferase-mediated and CDP-choline pathways as well as by base-exchange reactions between phospholipids, thereby restoring hepatic phosphatidylcholine content and very-low-density lipoprotein export. Overall, we provide evidence that hepatic GLS1 targeting is a valuable therapeutic approach in NASH.
YR 2020
FD 2020-02-21
LK http://hdl.handle.net/10668/15143
UL http://hdl.handle.net/10668/15143
LA en
DS RISalud
RD Apr 7, 2025