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Modulation of liver cholesterol homeostasis by choline supplementation during fibrosis resolution

ABSTRACT: Liver fibrosis is a critical global health challenge, often leading to severe liver diseases without timely intervention. Choline deficiency has been linked to metabolic dysfunction associated steatohepatitis (MASH) and liver fibrosis, suggesting choline supplementation as a potential therapeutic approach. This study aimed to explore the therapeutic potential of choline supplementation in liver fibrosis resolution and its effects on cholesterol homeostasis using a mouse model with induced liver fibrosis. Our findings reveal that choline supplementation significantly decreases blood lactate dehydrogenase (LDH) and non-high-density lipoprotein cholesterol (non-HDL-C) levels. Transcriptome analysis showed that choline supplementation primarily induces genes related to cholesterol homeostasis, suggesting a significant impact on liver cholesterol synthesis. However, choline supplementation did not significantly alter the expression of fibrosis-related, choline metabolism-related, or epigenetics-related genes. This study provides novel insights into the role of choline in liver health and cholesterol metabolism, potentially informing treatments for liver fibrosis and related conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE261310 | GEO | 2024/09/04

REPOSITORIES: GEO

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Project description:Metabolic Dysfunction Associated Steatohepatitis (MASH) is characterized by excess circulating toxic lipids, hepatic steatosis, and liver inflammation. Monocyte adhesion to the liver sinusoidal endothelial cells (LSEC) and transendothelial migration (TEM) are crucial in the inflammatory process. LSEC under lipotoxic stress develops a pro-inflammatory phenotype known as endotheliopathy. However, the mediators of endotheliopathy remain obscure. Primary mouse LSEC isolated from C57BL/6J mice on chow or MASH-inducing diets rich in fat, fructose, and cholesterol (FFC) were subjected to multi-omics profiling. Mice with established MASH, due to a choline-deficient high-fat diet (CDHFD) or FFC diet, were treated with two structurally distinct GSK3 inhibitors [LY2090314, elraglusib (9-ING-41)]. Integrated pathway analysis of mouse LSEC proteome and transcriptome indicates that leukocyte TEM and focal adhesion are major pathways altered in MASH. Kinome profiling of the LSEC phospho-proteome identified GSK3β as the major kinase hub in MASH. GSK3β activating phosphorylation was increased in primary human LSEC treated with the toxic lipid palmitate and in human MASH. Palmitate upregulated the expression of C-X-C motif chemokine ligand 2, intracellular adhesion molecule 1, and phosphorylated focal adhesion kinase, via a GSK3-dependant mechanism. Congruently, the adhesive and transendothelial migratory capacities of primary human neutrophils and THP-1 monocytes through LSEC monolayer under lipotoxic stress were reduced by GSK3 inhibition. Treatment with the GSK3 inhibitors LY2090314 and elraglusib ameliorated liver inflammation, injury, and fibrosis in FFC and CDHFD-fed mice, respectively. Immunophenotyping of intrahepatic leukocytes from CDHFD-fed mice treated with elraglusib using cytometry by the time of flight showed reduced proinflammatory monocyte-derived macrophages and monocyte-derived dendritic cells infiltration.GSK3 inhibition attenuates lipotoxicity-induced LSEC endotheliopathy and may serve as a potential therapeutic strategy in human MASH.

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Modulation of liver cholesterol homeostasis by choline supplementation during fibrosis resolution

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