Abstract

Hyperactivated glutaminase1 (GLS1) promotes the progression of cirrhosis via the reprogramming of hepatic stellate cells (HSCs). Hepatic encephalopathy (HE), the main complication of cirrhosis characterized by abnormal ammonia metabolism, is also associated with increased glutaminase activation in intestinal epithelial cells (IECs). The enzymatic activity of glutaminase depends on inorganic phosphate (Pi). In this study, a retrospective study of serum Pi levels was performed in 185 cirrhosis-HE patients. The pharmacology and pharmacodynamics of Pi binders (sevelamer and lanthanum carbonate) were evaluated in CCl4-induced cirrhosis and both type A and C HE murine models. The biological events downstream of Pi binders were evaluated via glutamate rescue in activated HSCs and GLS1-overexpressing IECs. We found that serum Pi is an independent risk factor for cirrhosis progression to HE. Both binders stimulated HSC senescence and rebalanced interorgan ammonia, alleviating cirrhosis and HE and reversing liver dysfunction. They had better therapeutic effects than L-ornithine L-aspartate (OA). Pi deprivation weakened glutaminase enzymatic activity, lowering collagen and Alpha-smooth muscle actin (α-SMA) production in HSCs and ammonia production in both wild-type and GLS1-overexpressing IECs. Since Pi deprivation alleviates glutaminolysis and ammonia production by decreasing glutaminase activity, Pi binders might hold great promising to treat cirrhosis and HE.