Date of Award

5-4-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Zhi-Ren Liu

Second Advisor

Ming-Hui Zou

Third Advisor

Jing Chen

Fourth Advisor

Ritu Aneja

Abstract

Fibrosis is a pathologic condition of abnormal accumulation of collagen fibrils. Collagen is synthesized and secreted from myofibroblasts. Collagen is a major extracellular matrix (ECM) protein composed of mainly (Gly-X-Y)n triplets repeats with >30% Gly residue. During fibrosis progression, myofibroblasts must upregulate glycine metabolism to meet the need for collagen synthesis. We report here that pyruvate kinase M2 (PKM2) is upregulated in myofibroblasts. Myofibroblast differentiation promotes dimerization of PKM2. Dimer PKM2 slows the flow rate of glycolysis. Dimer PKM2 channels glycolytic intermediates to de novo glycine synthesis, which facilitates collagen synthesis and secretion in myofibroblasts. Our results show that PKM2 activator that convert PKM2 dimer to tetramer inhibits fibrosis progression in mouse models of liver and lung fibrosis. Furthermore, PKM2 activator alters glycolysis pathway, which consequently affects the reverses fibrosis by reducing glycine production in vivo. Our study uncovers a novel role of PKM2 in tissue/organ, suggesting a possible strategy for treatment of fibrosis diseases. Furthermore, secreted collagen is crosslinked in the extracellular space by the lysyl oxidase (LOX) family proteins. LOX is secreted by the activated myofibroblasts under hypoxic conditions. PKM2 mediates Hif-1α activity in cells under hypoxic conditions. Here, we report that the PKM2- Hif-1α axis induces LOX expression in fibroblasts and cancer cells. PKM2-Hif-1α complex regulates LOX transcription by directly binding to LOX promoter. Here we show that PKM2 activators reduce PKM2-HIF1α association and thereby its nuclear localization. PKM2 activators reduce the production and hence the secretion and the crosslinking capacity of LOX family proteins.

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