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B-cell Translocation Gene 2 Inhibits UFMylation Modification of FMO1 thus Restricting Taurine Synthesis and Exacerbating Ferroptosis in Hepatic Ischemia-Reperfusion Injury

ABSTRACT:

Hepatic ischemia-reperfusion (I/R) injury is a common complication occurs during liver transplantation. However, the mechanisms underlying hepatic I/R injury have not been fully elucidated. B-cell translocation gene 2 (Btg2) has been implicated in the development of various diseases. However, its involvement in hepatic I/R injury remains unclear. The present study aimed to explore the role of Btg2 in hepatic I/R injury. We observed that Btg2 expression was elevated alongside the progress of hepatic I/R injury in mice liver tissues and primary hepatocytes. Systemic Btg2 knock-out (KO) substantially alleviated inflammation and mitochondrial stress, while conditional hepatocyte Btg2 knock-in (KI) largely aggravated inflammation and mitochondrial oxidative stress in hepatic I/R injury. Metabolomics analysis revealed that taurine metabolism was significantly enriched in Btg2-KO mice after hepatic I/R injury. Mechanistically, Btg2 binds to FMO1 to restrict the UFMylation of FMO1 by the E3 ligase UFM1-specific ligase 1 (UFL1), which in turn promoting K48 ubiquitination-mediated degradation of FMO1. Our study results demonstrate that Btg2 exacerbates hepatic I/R injury by restricting the UFMylation and degradation of FMO1, which in turn aggravates ferroptosis. These results suggest that Btg2 may be a potential therapeutic target for hepatic I/R injury.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS11677 | MetaboLights | 2026-03-07

REPOSITORIES: MetaboLights

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Project description:Post-translational acetylation of proteins at lysine side chains by the central metabolite acetyl-CoA, is a crucial regulator of proteostasis. Ethanol metabolism in the liver induces protein acetylation and disrupts hepatic substrate metabolism. While acetylation can influence gene transcription, enzyme activity, and stability of proteins, the role of ethanol-induced acetylation in hepatic metabolism is still unclear. We used a 2H2O-based metabolic labeling approach to investigate the impact of ethanol-induced acetylation on liver metabolism in a murine model of chronic ethanol-induced liver injury. Mice were fed an ethanol containing diet for 25 days; liver proteins and acetylation patterns were monitored during the final 21 days of 2H2O labeling. The proteome, acetylome, and targeted metabolic profiling were conducted to evaluate ethanol-induced alterations in hepatic metabolism. Ethanol consumption induced hepatic steatosis, inflammation, and oxidative stress. It led to reduced turnover of mitochondrial proteins and increased turnover of cytosolic stress response proteins and metabolic enzymes. Ethanol elevated acetylation levels of mitochondrial metabolic enzymes and nuclear histones, with no significant changes in the cytosol. Acetylation stabilized mitochondrial proteins but destabilized histones. Ethanol-induced reduced mitochondrial protein turnover, linked to increased acetylation, led to hepatic protein accumulation. Impaired proteasomal and lysosomal degradation contributed to alcohol-induced hepatic proteopathy. These changes were associated with altered levels of acyl-CoAs and acyl-carnitines, amino acids, and tricarboxylic acid (TCA) cycle intermediates, reflecting impaired fatty acid oxidation, nitrogen disposal and citric acid cycle activities. In conclusion, ethanol-induced alterations in acetylome dynamics could modify hepatic substrate metabolism and contribute to liver injury in alcohol-associated liver disease through acetylation-dependent epigenetic changes and the regulation of metabolic enzymes.

Project description:Methionine adenosyltransferase (MAT) enzymes generate SAMe (S-adenosylmethionine), the main biological methyl donor. There are two MAT encoding genes in mammals (Mat1a and Mat2a), which show different activities and cellular distribution. Mat1a encodes the enzyme mainly expressed in normal liver. Mat1a ablation in mice results in the spontaneous development of non-alcoholic steatohepatitis (NASH). We observed that SAMe depletion in Mat1a KO mice had three main effects on hepatic lipid metabolism: 1) impaired TG (triglyceride) export via VLDL; 2) impaired mitochondrial FA (fatty acid) oxidation (as evidenced by membrane depolarization, downregulation of Phb1 (prohibitin 1, a mitochondrial chaperone protein) and Mcj/Dnajc15 (endogenous mitochondrial repressor of respiratory chain), and accumulation of long-chain acylcarnitines); and 3) increased FA uptake. The convergence of these three factors induced TG accumulation in LD (lipid droplets). LD expansion confronts hepatocytes with a high demand of PC (phosphatidylcholine) molecules to cover the LD surface since other phospholipids, such as PE (phosphatidylethanolamine), cannot stabilize LD and prevent coalescence. In Mat1a KO this situation is aggravated, since SAMe-dependent PC synthesis via PE methylation is decreased, the PC/PE ratio reduced and mitochondrial FA oxidation impaired. To put a brake to this drain of PC molecules to LD, FA are rerouted in Mat1a KO mice liver to other catabolic (endoplasmic reticulum and peroxisome oxidation) and biosynthetic (ceramides synthesis) pathways, causing oxidative stress, inflammation and fibrosis. SAMe treatment for two months in 8-9 month old Mat1a KO mice ameliorated mitochondrial dysfunction (reduces membrane depolarization, improves Phb1 and Mcj expression, and increases SAMe transport to mitochondria) improving FA oxidation efficiency (FA and acylcarnitine levels decrease), which results in a drastic reduction in TG accumulation. SAMe treatment in Mat1a KO mice resulted in more PC available for proper membrane function, improving liver lipid homeostasis, histology (H&E, Sudan red, Sirius red) and liver injury (ALT, AST).

			Action	DRS
	HIRI-Btg2-KO-1_NEG.raw	Raw
	HIRI-Btg2-KO-2_NEG.raw	Raw
	HIRI-Btg2-KO-3_NEG.raw	Raw
	HIRI-Btg2-KO-4_NEG.raw	Raw
	HIRI-Btg2-KO-5_NEG.raw	Raw

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B-cell Translocation Gene 2 Inhibits UFMylation Modification of FMO1 thus Restricting Taurine Synthesis and Exacerbating Ferroptosis in Hepatic Ischemia-Reperfusion Injury

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