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Glutaminolysis Promotes Collagen Translation and Stability via &agr;‐Ketoglutarate‐mediated mTOR Activation and Proline Hydroxylation

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Abstract Glutaminolysis is the metabolic process of glutamine, aberration of which has been implicated in several pathogeneses. Although we and others recently found a diversity of metabolic dysregulation in organ… Click to show full abstract

Abstract Glutaminolysis is the metabolic process of glutamine, aberration of which has been implicated in several pathogeneses. Although we and others recently found a diversity of metabolic dysregulation in organ fibrosis, it is unknown if glutaminolysis regulates the profibrotic activities of myofibroblasts, the primary effector in this pathology. In this study, we found that lung myofibroblasts demonstrated significantly augmented glutaminolysis that was mediated by elevated glutaminase 1 (Gls1). Inhibition of glutaminolysis by specific Gls1 inhibitors CB‐839 and BPTES as well as Gls1 siRNA blunted the expression of collagens but not that of fibronectin, elastin, or myofibroblastic marker smooth muscle actin‐&agr;. We found that glutaminolysis enhanced collagen translation and stability, which were mediated by glutaminolysis‐dependent mTOR complex 1 activation and collagen proline hydroxylation, respectively. Furthermore, we found that the amount of the glutaminolytic end product &agr;‐ketoglutarate (&agr;‐KG) was increased in myofibroblasts. Similar to glutaminolysis, &agr;‐KG activated mTOR complex 1 and promoted the expression of collagens but not of fibronectin, elastin, or smooth muscle actin‐&agr;. &agr;‐KG also remarkably inhibited collagen degradation in fibroblasts. Taken together, our studies identified a previously unrecognized mechanism by which a major metabolic program regulates the exuberant production of collagens in myofibroblasts and suggest that glutaminolysis is a novel therapeutic target for treating organ fibrosis, including idiopathic pulmonary fibrosis.

Keywords: agr; collagen translation; proline hydroxylation; translation stability; mtor; glutaminolysis

Journal Title: American Journal of Respiratory Cell and Molecular Biology
Year Published: 2018

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