Hedgehog-YAP Signaling Pathway Regulates Glutaminolysis to Control Activation of Hepatic Stellate Cells

Abstract

Glutaminolysis controls accumulation of myofibroblast HSCs in mice and might be a therapeutic target for cirrhosis.

Mannose Phosphate Isomerase and Mannose Regulate Hepatic Stellate Cell Activation and Fibrosis in Zebrafish and Humans

“…Among the differentially regulated pathway analysis of total proteins and of phosphoproteins in mannose‐treated versus control experiments, glycolysis and glutamate metabolism were among the top pathways altered in HSCs treated with mannose (Table ). Regulation of glucose and glutamine metabolism are both important for HSC activation based on these data and previous studies . Together, our data suggest a model whereby reduction of MPI, either through an endogenous genetic mutation or during the process of HSC activation, is sufficient to promote HSC activation and indicate an antifibrotic role for mannose supplementation in HSC attenuation.…”

“…Regulation of glucose and glutamine metabolism are both important for HSC activation based on these data and previous studies. (30,31) Together, our data suggest a model whereby reduction of MPI, either through an endogenous genetic mutation or during the process of HSC activation, is sufficient to promote HSC activation and indicate an antifibrotic role for mannose supplementation in HSC attenuation.…”

“…As an alternative proposed mechanism, MPI reduction may activate HSCs through alterations in glycolysis and inter‐related biosynthetic pathways. Recent studies have demonstrated increased bioenergetic and biosynthetic demands required for HSC activation dependent on glycolysis and glutaminolysis, given that blocking either of these pathways halts HSC activation . Unbiased proteomics analysis suggests that these same pathways are altered in mannose supplementation of HSCs with decreased activation.…”

“…Recent studies have demonstrated increased bioenergetic and biosynthetic demands required for HSC activation dependent on glycolysis and glutaminolysis, given that blocking either of these pathways halts HSC activation. (30,31) Unbiased proteomics analysis suggests that these same pathways are altered in mannose supplementation of HSCs with decreased activation. Our group has indicated that MPI is a regulator of Warburg metabolism and directs glycolytic intermediates into the hexosamine biosynthetic pathway, (12) a key metabolic pathway which requires both glucose and glutamine as fuel.…”

Succinate‐GPR‐91 receptor signalling is responsible for nonalcoholic steatohepatitis‐associated fibrosis: Effects of DHA supplementation

“…Sections were blocked in Dako protein block solution for 1 hour and incubated overnight at 4°C with anti‐GRP91 primary antibodies. After vigorous washing with Tris‐buffered saline with Tween 20 (TBST), EnVision System horseradish peroxidase‐labelled polymer anti‐rabbit secondary antibodies from Dako were applied for 1 hour at room temperature, and Dako 3,3‐Diaminobenzidine Substrate Chromogen System was used for colour development as described in our previous study . Micrographs were taken under a microscope and positive area for GPR‐91 staining was morphometrically quantitated with Image J software as previously reported by us, and numeric data were converted to relative number using an average value of G1 group as a reference.…”