Abstract
Background: The activation of hepatic stellate cells (HSCs) plays a central role in liver fibrosis. α-ketoglutarate is a natural metabolite and previous studies have shown that increase in intracellular α-ketoglutarate can inhibit HSC activation. Aim: The aim of the present study is to determine the changes and role of intracellular α-ketoglutarate in HSC activation and clarify its mechanism of action. Methods: A human HSC cell line (LX-2) and the primary mouse HSC were used in the present study. We detected the changes of intracellular α-ketoglutarate levels and the expression of enzymes involved in the metabolic processes during HSC activation. We used siRNA to determine the role of intracellular α-ketoglutarate in HSC activation and elucidate the mechanism of the metabolic changes. Results: Our results demonstrated that intracellular α-ketoglutarate levels decreased with an HSC cell line and primary mouse HSC activation, as well as the expression of isocitrate dehydrogenase 2 (IDH2), an enzyme that catalyzes the production of α-ketoglutarate. In addition, knockdown of IDH2 efficiently promoted the activation of HSCs, which was able to be reversed by introduction of an α-ketoglutarate analogue. Furthermore, we demonstrated that α-ketoglutarate regulated HSC activation is independent of transforming growth factor-β1 (TGF-β1). Conclusions: Our findings demonstrated that decrease in IDH2 expression limits the production of α-ketoglutarate during HSC activation and in turn promotes the activation of HSCs through a TGF-β1 independent pathway. The present study suggests that IDH2 and α-ketoglutarate may be potential new targets for the prevention and treatment of liver fibrosis.
Highlights
Liver fibrosis results from many chronic liver diseases, including viral hepatitis, autoimmune hepatitis, alcoholic liver disease, and non-alcoholic steatohepatitis
Intracellular α-ketoglutarate levels and isocitrate dehydrogenase 2 (IDH2) expression decreased with LX-2 hepatic stellate cell (HSC) cell line activation
Using a well validated immortalized human HSC cell line (LX-2), we first detected the changes of intracellular α-ketoglutarate levels when HSC activation was induced by transforming growth factor-β1 (TGF-β1)
Summary
Liver fibrosis results from many chronic liver diseases, including viral hepatitis, autoimmune hepatitis, alcoholic liver disease, and non-alcoholic steatohepatitis. Chronic inflammation despite the underlying cause may lead to liver cirrhosis, liver failure, and even hepatocellular carcinoma [1] It is currently unclear the mechanisms of liver fibrosis. Activation or transdifferentiation of hepatic stellate cells (HSCs) from a quiescent state into a myofibroblast-like phenotype plays a central role in liver fibrosis. Etiological treatments such as antiviral drugs that remove the underlying cause of viral-induced liver injury may halt the process of liver fibrosis. Results: Our results demonstrated that intracellular α-ketoglutarate levels decreased with an HSC cell line and primary mouse HSC activation, as well as the expression of isocitrate dehydrogenase 2 (IDH2), an enzyme that catalyzes the production of α-ketoglutarate. The present study suggests that IDH2 and α-ketoglutarate may be potential new targets for the prevention and treatment of liver fibrosis
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