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 thephosphatidylethanolamine 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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a global health problem with an estimated worldwide prevalence of 30%–40% of the adult population (Younossi et al, 2016)
Whereas there are no significant differences in serum glutamine levels between controls (n = 90) and Non-alcoholic steatohepatitis (NASH) patients (n = 131), serum glutamate levels are significantly increased in NASH patients (Figure 1A), suggesting that glutamine catabolism may be aberrant in NASH
Whereas GLS2 is the major isoform expressed in the healthy liver, a switch from GLS2 to Glutaminase 1 (GLS1) occurs in liver fibrosis (Du et al, 2018), cirrhosis, and liver cancer (Yu et al, 2015; Yuneva et al, 2012)
Summary
Non-alcoholic fatty liver disease (NAFLD) is a global health problem with an estimated worldwide prevalence of 30%–40% of the adult population (Younossi et al, 2016). They show that a liver enzyme involved in glutamine metabolism, glutaminase 1, is elevated in hepatic biopsies of NASH patients and in mouse models of the disease. They reveal that GLS1 inhibition in pre-clinical models reduces liver steatosis and oxidative stress without side effects. GLS1 targeting could be a valuable therapeutic approach for the clinical management of NASH
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