Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis

Abstract

Glutamine metabolism plays an essential role in cell growth, and glutamate dehydrogenase (GDH) is a key enzyme. GDH promotes the metabolism of glutamate and glutamine to generate ATP, which is profoundly increased in multiple human cancers. Through in vitro and in vivo experiments, we verified that the small-molecule GDH inhibitor EGCG slowed the progression of fibrosis by inhibiting GDH enzyme activity and glutamine metabolism. SIRT4 is a mitochondrial enzyme with NAD that promotes ADP ribosylation and downregulates GDH activity. The role of SIRT4 in liver fibrosis and the related mechanisms are unknown. In this study, we measured the expression of SIRT4 and found that it was downregulated in liver fibrosis. Modest overexpression of SIRT4 protected the liver from fibrosis by inhibiting the transformation of glutamate to 2-ketoglutaric acid (α-KG) in the tricarboxylic acid cycle (TCA), thereby reducing the proliferative activity of hepatic stellate cells (HSCs). Collectively, our study reveals that SIRT4 controls GDH enzyme activity and expression, targeting glutamine metabolism in HSCs and alleviating liver fibrosis.

Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy

“…We used epigallocatechin-3-gallate (EGCG), an inhibitor of GDH 47 , to reverse Sirt4 knockout effects, i.e., preserving and directing glutamate to GABA. Oral gavage of EGCG (100 mg/kg) and BHB (500 mg/kg) for 4 weeks 48 , which had no impact on body weight (Supplementary Fig. S10a ) and food intake (Supplementary Fig.…”

Emodin promotes hepatic stellate cell senescence and alleviates liver fibrosis via a nuclear receptor (Nur77)‐mediated epigenetic regulation of glutaminase 1

“…Here, HSC senescence was significantly induced by emodin at 20 μM consistent with the observation that emodin at 20 μM stimulated senescence in breast cancer cells (Zu et al, 2018), indicating that induction of senescence could be a common pharmacological action of emodin. We explored the reasons for emodin-induction of HSC senescence focusing on glutaminolysis, because glutaminolytic activity can fuel anapleurosis to satisfy the high bioenergetic and biosynthetic demands for maintaining the myofibroblastic phenotype (Yin et al, 2022). A recent study demonstrated that GLS1 was accumulated in hepatic fibrotic septa and inhibition of GLS1 reduced the fibrogenic activity of HSCs in nonalcoholic steatohepatitis patients (Du et al, 2020).…”

“…We explored the reasons for emodin‐induction of HSC senescence focusing on glutaminolysis, because glutaminolytic activity can fuel anapleurosis to satisfy the high bioenergetic and biosynthetic demands for maintaining the myofibroblastic phenotype (Yin et al, 2022). A recent study demonstrated that GLS1 was accumulated in hepatic fibrotic septa and inhibition of GLS1 reduced the fibrogenic activity of HSCs in nonalcoholic steatohepatitis patients (Du et al, 2020).…”

“…HSC activation is a process characterized by metabolic reprogramming, allowing these cells to meet the high demands of bioenergy and biosynthesis (Yin et al, 2022). Recent evidence has revealed that glutaminolysis is required for HSC activation and liver fibrogenesis (Du et al, 2018).…”

Sirtuins in kidney diseases: potential mechanism and therapeutic targets

“…Glutamine metabolism plays a crucial role in cell growth, and glutamate dehydrogenase (GDH) is a critical enzyme that promotes the metabolism of glutamate and glutamine to produce adenosine triphosphate (ATP). Sirt4 promotes adenosine diphosphate (ADP) ribosylation and downregulates GDH activity, inhibiting the conversion of glutamate to α-ketoglutarate during the tricarboxylic acid cycle [ 96 ]. In addition, Sirt4 deficiency leads to decreased expression and function of the glutamate transporter [ 97 ], which may be more important than Sirt4 deacetylation.…”