Publication: Targeting Hepatic Glutaminase 1 Ameliorates Non-alcoholic Steatohepatitis by Restoring Very-Low-Density Lipoprotein Triglyceride Assembly.
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Date
2020-02-21
Authors
Simon, Jorge
Nuñez-García, Maitane
Fernández-Tussy, Pablo
Barbier-Torres, Lucía
Fernández-Ramos, David
Gómez-Santos, Beatriz
Buqué, Xabier
Lopitz-Otsoa, Fernando
Goikoetxea-Usandizaga, Naroa
Serrano-Macia, Marina
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Abstract
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.
Description
MeSH Terms
Adult
Animals
Choline
Disease Models, Animal
Female
Glutaminase
Hepatocytes
Humans
Lipid Metabolism
Lipoproteins, VLDL
Liver
Male
Methionine
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease
Oxidative Stress
Phospholipids
Triglycerides
Animals
Choline
Disease Models, Animal
Female
Glutaminase
Hepatocytes
Humans
Lipid Metabolism
Lipoproteins, VLDL
Liver
Male
Methionine
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease
Oxidative Stress
Phospholipids
Triglycerides
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Keywords
GLS1, GLS2, NAFLD, NASH, TCA cycle, VLDL, folate cycle, glutaminase, methionine cycle, phospholipids