Mannose metabolism as a regulator of hepatic stellate cell activation and fibrosis

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PROJECT SUMMARY This proposal addresses the critical unmet need for effective anti-fibrotic therapies by elucidating an unexplored pathway regulating activation of the hepatic stellate cell (HSC), a resident perisinusoidal cell type that stores vitamin A in normal liver. However, among potential mechanisms driving HSC plasticity, sugar metabolism pathways have been largely overlooked. The role of mannose metabolism in HSC biology has not yet been examined, but recent high-impact studies, including ours (Shtraizent and DeRossi et al., eLife 2017), implicate mannose as a mediator of obesity, diabetes, and cancer. Mannose phosphate isomerase (MPI) is the key enzyme involved in catabolism of mannose; MPI glycosylation mutation in humans leads to a congenital disorder of N- characterized by early and progressive liver fibrosis in children. Our data and these clinical observations stimulated us to explore how the loss of MPI in this pediatric disorder leads to liver fibrosis. Our exciting data find that: 1) MPI expression is downregulated during HSC activation in primary human and rodent HSCs in vitro and in vivo, 2) decreased MPI correlates with advanced stages of liver fibrosis in human HBV and NAFLD cohorts, and 3) MPI depletion promotes HSC activation in human HSCs. Remarkably, mannose supplementation attenuates HSC activation in a dose-dependent manner. Our objective is to understand the regulatory role of mannose metabolism in HSCs and liver fibrosis. With the following aims, we will test our central hypotheses that mannose metabolism is a critical metabolic pathway mediating HSC activation and attenuation. Disruption of mannose metabolism, through loss of MPI, leads to HSC activation; conversely, exogeneous mannose supplementation can attenuate HSC activation and liver fibrosis in vivo. Specific Aims: Aim 1. Determine how MPI loss activates HSCs: By using primary rat HSCs and in vivo genetic zebrafish models, we will investigate the role of O-GlcNAcylation in HSC activation, determine the cell- specific effects of MPI-depletion, and test whether enhancing MPI activity can attenuate fibrogenesis following exposure to well-established HSC activators. Aim 2. Determine the efficacy of mannose supplementation in attenuating HSC activation in vitro and in vivo. This aim will use in vivo rodent models of fibrosis to investigate how mannose supplementation modulates the plasticity of HSC phenotypes and test the extent of mannose to attenuate liver fibrosis in vivo. Our long-term goal is to better understand the metabolic drivers of HSC activation to manipulate these fuel-generating mechanisms and attenuate liver fibrosis. We the and are will leverage our expertise in biology of a rare liver disease to advance our understanding of the metabolic regulation of HSC activation, to establish how this overlooked pathway of mannose metabolism can regulate HSC plasticity. These studies the first to investigate the antifibrotic roles of mannose supplementation andmay reveal a novel target and accessible therapeutic approach to suppress liver fibrosis.