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Arachidonoyl-taurine protects from diet-induced hepatic steatosis and inflammation -

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease and its progressive and inflamma-tory form metabolic dysfunction-associated steatohepatitis represents a global health challenge, with limited treatment options available. In this study we identified an endoge-nous, understudied omega-6 fatty acid metabolite, arachidonoyl-taurine (ARA-T), capable of mitigating liver disease. ARA-T levels increased in human plasma of chronic and acute fatty liver and their abundance can be driven in humans and mice by dietary supplementa-tion of arachidonic acid. Surprisingly, our genetic model of elevated circulating ARA-T levels prevented inflammation and hepatic steatosis by increased uptake and turnover of fatty ac-ids in the liver. Pharmacological administration of ARA-T reduced liver weight and diet-induced hepatic lipid deposition in mice, demonstrating its potential to protect against and reverse the progression of liver disease. Thus, ARA-T may represent a way to protect against pro-inflammatory actions of omega-6 fatty acids thereby contributing to regulation of in-flammation and accumulation of hepatic lipids.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte

SUBMITTER: Ivan Bradić

LAB HEAD: Trisha Jean Grevengoed

PROVIDER: PXD075585 | Pride | 2026-05-20

REPOSITORIES: Pride

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			Action	DRS
	20260217-0022_AS2_003363_250216_IVAN_MRL_HepKati_6.raw	Raw
	20260217-0142_AS2_003364_250216_IVAN_MRL_HepKati_7.raw	Raw
	20260217-0303_AS2_003365_250216_IVAN_MRL_HepKati_8.raw	Raw
	20260217-0423_AS2_003366_250216_IVAN_MRL_HepKati_9.raw	Raw
	20260217-0543_AS2_003367_250216_IVAN_MRL_HepKati_10.raw	Raw

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Project description:The optimal ratio of omega-6 to omega-3 polyunsaturated fatty acids (PUFAs) is important for keeping homeostasis of biological processes and metabolism, yet the underlying biological mechanism is poorly understood. The objective of this study was to identify changes in the pig liver transcriptome induced by a diet enriched with omega-6 and omega-3 fatty acids, and to characterize the biological mechanisms related to PUFA metabolism. Polish Landrace pigs (n =12) were fed diet enriched with linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3 family) or standard diet as a control. The fatty acids profiling was assayed in order to verify how feeding influenced the fatty acids content in liver, and subsequently next-generation sequencing (NGS) was used to identify differentially expressed genes (DEG) between transcriptomes between dietary groups. The biological mechanisms and pathway interaction networks were identified by analysis in DAVID and Cytoscape tools. Fatty acids profile analysis indicated a higher contribution of PUFAs in liver for LA and ALA-enriched diet group, particularly for the omega-3 fatty acids family, but not omega-6. Next-generation sequencing identified 3,565 DEG, 1,484 of which were induced and 2,081 were suppressed by PUFA supplemenation. Low ratio of omega-6/-3 fatty acids resulted in modulation of fatty acids metabolism pathways and over-representation of genes involved in membrane composition, signal transduction and immune response pathways. In conclusion, a diet enriched with omega-6 and omega-3 fatty acids altered the transcriptomic profile of the pig liver and affected a set of genes involved in metabolic pathways important to animal health status. Hepatic mRNA profiles of Polish Landrace pig breed fed two different diets, were generated by deep sequencing, using Illumina MiSeq. Experimental diet was enriched with polyunsaturated fatty acids (omega-6 and omega-3), while standard diet remain as a cotrol. 2 pooled samples each containing RNA extracts from 6 individuals livers were analyzed.

Project description:The mechanisms underlying the progression of non-alcoholic steatohepatitis (NASH) are not completely elucidated. In this study we have integrated gene expression profiling of liver biopsies of NASH patients with translational studies in a mouse model of steatohepatitis and with pharmacological interventions in isolated hepatocytes to identify a novel mechanism implicated in the pathogenesis of NASH. By using high-density oligonucleotide microarray analysis we identified a significant enrichment of known genes involved in the multi-step catalysis of long chain polyunsaturated fatty acids, including delta-5 and 6 desaturases. A combined inhibitor of delta-5 and delta-6 desaturases significantly reduced intracellular lipid accumulation and inflammatory gene expression in isolated hepatocytes. Gas chromatography analysis revealed impaired delta-5 desaturase activity toward the omega-3 pathway in livers from mice with high-fat diet (HFD)-induced NASH. Consistently, restoration of omega-3 index in transgenic fat-1 mice expressing an omega-3 desaturase, which allows the endogenous conversion of omega-6 into omega-3 fatty acids, produced a significant reduction in hepatic insulin resistance, hepatic steatosis, macrophage infiltration and necroinflammatory liver injury, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were comparable to those obtained in a group of mice receiving a HFD supplemented with EPA/DHA. Of interest, hepatocytes from fat-1 mice or supplemented with EPA exhibited synergistic anti-steatotic and anti-inflammatory actions with the delta-5/ delta-6 inhibitor. Conclusion: These findings indicate that both endogenous and exogenous restoration of the hepatic balance between omega-6 and omega-3 fatty acids and/or modulation of desaturase activities exert preventive actions in NASH. The complete database comprised the expression measurements of 18185 genes for liver sample groups: 8 non-alcoholic steatohepatitis (NASH ) and 7 control samples. This dataset is part of the TransQST collection.

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Arachidonoyl-taurine protects from diet-induced hepatic steatosis and inflammation -

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