AI Article Synopsis
- The study reveals that the harmful effects of TGF-β in promoting fibrosis are partly due to dysfunction in how cells process glutamine, and blocking an enzyme called GLS1 can reverse lung fibrosis.
- Researchers found GLS1 levels were significantly higher in fibrotic lung tissue compared to normal, and TGF-β's effects on fibrotic features required GLS1's activity.
- The study identifies SIRT7 and FOXO4 as natural regulators of GLS1 that TGF-β can inhibit, and using a GLS1 blocker (CB-839) showed promise in reducing lung fibrosis caused by bleomycin.
Article Abstract
In the current work we show that the profibrotic actions of TGF-β are mediated, at least in part, through a metabolic maladaptation in glutamine metabolism and how the inhibition of glutaminase 1 (GLS1) reverses pulmonary fibrosis. GLS1 was found to be highly expressed in fibrotic vs normal lung fibroblasts and the expression of profibrotic targets, cell migration, and soft agar colony formation stimulated by TGF-β required GLS1 activity. Moreover, knockdown of SMAD2 or SMAD3 as well as inhibition of PI3K, mTORC2, and PDGFR abrogated the induction of GLS1 by TGF-β. We further demonstrated that the NAD-dependent protein deacetylase, SIRT7, and the FOXO4 transcription factor acted as endogenous brakes for GLS1 expression, which are inhibited by TGF-β. Lastly, administration of the GLS1 inhibitor CB-839 attenuated bleomycin-induced pulmonary fibrosis. Our study points to an exciting and unexplored connection between epigenetic and transcriptional processes that regulate glutamine metabolism and fibrotic development in a TGF-β-dependent manner.
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| http://dx.doi.org/10.1096/fj.202000564R | DOI Listing |
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