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Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis.

Cell metabolism | 2019

Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [13C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[13C]β-hydroxybutyrate (D-βOHB) labeled almost none. [13C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.

Pubmed ID: 30449686 RIS Download

Research resources used in this publication

Additional research tools detected in this publication

Associated grants

  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK091538
  • Agency: NIH HHS, United States
    Id: R24 OD024624
  • Agency: NIDDK NIH HHS, United States
    Id: T32 DK007203
  • Agency: NIEHS NIH HHS, United States
    Id: R35 ES028365
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK115924
  • Agency: NCI NIH HHS, United States
    Id: U01 CA235482

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This is a list of tools and resources that we have found mentioned in this publication.


PRISM (tool)

RRID:SCR_005375

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on May 5,2022.Tool that predicts interactions between transcription factors and their regulated genes from binding motifs. Understanding vertebrate development requires unraveling the cis-regulatory architecture of gene regulation. PRISM provides accurate genome-wide computational predictions of transcription factor binding sites for the human and mouse genomes, and integrates the predictions with GREAT to provide functional biological context. Together, accurate computational binding site prediction and GREAT produce for each transcription factor: 1. putative binding sites, 2. putative target genes, 3. putative biological roles of the transcription factor, and 4. putative cis-regulatory elements through which the factor regulates each target in each functional role.

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PeproTech (tool)

RRID:SCR_006802

An Antibody supplier

View all literature mentions

mHMGCS (H-70) (antibody)

RRID:AB_2118322

This polyclonal targets HMGCS2

View all literature mentions

Goat Anti-Rabbit IgG-HRP (antibody)

RRID:AB_2687483

This polyclonal targets IgG

View all literature mentions

OXCT1 antibody (antibody)

RRID:AB_2157444

This polyclonal targets OXCT1

View all literature mentions

BDH1 antibody (antibody)

RRID:AB_2274683

This polyclonal targets BDH1

View all literature mentions

ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

View all literature mentions

TopHat (software resource)

RRID:SCR_013035

Software tool for fast and high throughput alignment of shotgun cDNA sequencing reads generated by transcriptomics technologies. Fast splice junction mapper for RNA-Seq reads. Aligns RNA-Seq reads to mammalian-sized genomes using ultra high-throughput short read aligner Bowtie, and then analyzes mapping results to identify splice junctions between exons.TopHat2 is accurate alignment of transcriptomes in presence of insertions, deletions and gene fusions.

View all literature mentions

MBRole (software resource)

RRID:SCR_014684

Software program for overrepresentation (enrichment) analysis of categorical annotations for a set of compounds. These categorical annotations correspond to biological and chemical information found in public databases and software. Annotations can be biological (pathways, enzyme interactions, pharmacological action) or chemical (taxonomy and chemical groups).

View all literature mentions

C57BL/6J (organism)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

View all literature mentions

BioCyc (software resource)

RRID:SCR_002298

A collection of Pathway/Genome Databases which describes the genome and metabolic pathways of a single organism. The BioCyc collection of Pathway/Genome Databases (PGDBs) provides an electronic reference source on the genomes and metabolic pathways of sequenced organisms. BioCyc PGDBs are generated by software that predicts the metabolic pathway complements of completely sequenced organisms from their genome sequences. They also include the results of a number of other computational inference procedures applied to these genomes, including predictions of which genes code for missing enzymes in metabolic pathways, and predicted operons. The BioCyc Web site provides a suite of software tools for database searching and visualization, for omics data analysis, and for comparative genomics and comparative pathway questions. The databases within the BioCyc collection are organized into tiers according to the amount of manual review and updating they have received. Tier 1 PGDBs have been created through intensive manual efforts, and receive continuous updating. Tier 2 PGDBs were computationally generated by the PathoLogic program, and have undergone moderate amounts of review and updating. Tier 3 PGDBs were computationally generated by the PathoLogic program, and have undergone no review and updating. There are 967 DBs in Tier 3. The downloadable version of BioCyc that includes the Pathway Tools software provides more speed and power than the BioCyc Web site.

View all literature mentions

GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

View all literature mentions

METLIN (data or information resource)

RRID:SCR_010500

A public repository of metabolite information as well as tandem mass spectrometry data is provided to facilitate metabolomics experiments. It contains structures and represents a data management system designed to assist in a broad array of metabolite research and metabolite identification. An annotated list of known metabolites and their mass, chemical formula, and structure are available. Each metabolite is linked to outside resources for further reference and inquiry. MS/MS data is also available on many of the metabolites.

View all literature mentions

XCMS (data or information resource)

RRID:SCR_015538

Cloud-based mass spectrometry data processing platform for metabolomics and lipidomics.

View all literature mentions

Thermo Xcalibur (software resource)

RRID:SCR_014593

A software which acquires and processes data sets, primarily through the Xcalibur system.

View all literature mentions

KEGG (software resource)

RRID:SCR_012773

Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.

View all literature mentions

Quantity One 1-D Analysis Software (software resource)

RRID:SCR_014280

Software used for Bio-Rad imaging systems to acquire, quantitate, and analyze a variety of data. The software allows automatic configuration of imaging systems with appropriate filters, lasers, LEDs, and other illumination sources. It also contains tools for automated analysis of tests and assays such as 1-D electrophoretic gels, western blots, and colony counts.

View all literature mentions

Cufflinks (software resource)

RRID:SCR_014597

Software tool for transcriptome assembly and differential expression analysis for RNA-Seq. Includes script called cuffmerge that can be used to merge together several Cufflinks assemblies. It also handles running Cuffcompare as well as automatically filtering a number of transfrags that are likely to be artifacts. If the researcher has a reference GTF file, the researcher can provide it to the script to more effectively merge novel isoforms and maximize overall assembly quality.

View all literature mentions

C57BL/6J (organism)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

View all literature mentions

METLIN (data or information resource)

RRID:SCR_010500

A public repository of metabolite information as well as tandem mass spectrometry data is provided to facilitate metabolomics experiments. It contains structures and represents a data management system designed to assist in a broad array of metabolite research and metabolite identification. An annotated list of known metabolites and their mass, chemical formula, and structure are available. Each metabolite is linked to outside resources for further reference and inquiry. MS/MS data is also available on many of the metabolites.

View all literature mentions

Thermo Xcalibur (software resource)

RRID:SCR_014593

A software which acquires and processes data sets, primarily through the Xcalibur system.

View all literature mentions

Goat Anti-Rabbit IgG-HRP (antibody)

RRID:AB_2687483

This polyclonal targets IgG

View all literature mentions

mHMGCS (H-70) (antibody)

RRID:AB_2118322

This polyclonal targets HMGCS2

View all literature mentions

OXCT1 antibody (antibody)

RRID:AB_2157444

This polyclonal targets OXCT1

View all literature mentions

BDH1 antibody (antibody)

RRID:AB_2274683

This polyclonal targets BDH1

View all literature mentions

Quantity One 1-D Analysis Software (software resource)

RRID:SCR_014280

Software used for Bio-Rad imaging systems to acquire, quantitate, and analyze a variety of data. The software allows automatic configuration of imaging systems with appropriate filters, lasers, LEDs, and other illumination sources. It also contains tools for automated analysis of tests and assays such as 1-D electrophoretic gels, western blots, and colony counts.

View all literature mentions

Cufflinks (software resource)

RRID:SCR_014597

Software tool for transcriptome assembly and differential expression analysis for RNA-Seq. Includes script called cuffmerge that can be used to merge together several Cufflinks assemblies. It also handles running Cuffcompare as well as automatically filtering a number of transfrags that are likely to be artifacts. If the researcher has a reference GTF file, the researcher can provide it to the script to more effectively merge novel isoforms and maximize overall assembly quality.

View all literature mentions

TopHat (software resource)

RRID:SCR_013035

Software tool for fast and high throughput alignment of shotgun cDNA sequencing reads generated by transcriptomics technologies. Fast splice junction mapper for RNA-Seq reads. Aligns RNA-Seq reads to mammalian-sized genomes using ultra high-throughput short read aligner Bowtie, and then analyzes mapping results to identify splice junctions between exons.TopHat2 is accurate alignment of transcriptomes in presence of insertions, deletions and gene fusions.

View all literature mentions

MBRole (software resource)

RRID:SCR_014684

Software program for overrepresentation (enrichment) analysis of categorical annotations for a set of compounds. These categorical annotations correspond to biological and chemical information found in public databases and software. Annotations can be biological (pathways, enzyme interactions, pharmacological action) or chemical (taxonomy and chemical groups).

View all literature mentions

XCMS (data or information resource)

RRID:SCR_015538

Cloud-based mass spectrometry data processing platform for metabolomics and lipidomics.

View all literature mentions

BioCyc (software resource)

RRID:SCR_002298

A collection of Pathway/Genome Databases which describes the genome and metabolic pathways of a single organism. The BioCyc collection of Pathway/Genome Databases (PGDBs) provides an electronic reference source on the genomes and metabolic pathways of sequenced organisms. BioCyc PGDBs are generated by software that predicts the metabolic pathway complements of completely sequenced organisms from their genome sequences. They also include the results of a number of other computational inference procedures applied to these genomes, including predictions of which genes code for missing enzymes in metabolic pathways, and predicted operons. The BioCyc Web site provides a suite of software tools for database searching and visualization, for omics data analysis, and for comparative genomics and comparative pathway questions. The databases within the BioCyc collection are organized into tiers according to the amount of manual review and updating they have received. Tier 1 PGDBs have been created through intensive manual efforts, and receive continuous updating. Tier 2 PGDBs were computationally generated by the PathoLogic program, and have undergone moderate amounts of review and updating. Tier 3 PGDBs were computationally generated by the PathoLogic program, and have undergone no review and updating. There are 967 DBs in Tier 3. The downloadable version of BioCyc that includes the Pathway Tools software provides more speed and power than the BioCyc Web site.

View all literature mentions

KEGG (software resource)

RRID:SCR_012773

Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.

View all literature mentions

ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

View all literature mentions

GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

View all literature mentions