PXD015553

PXD015553 is an original dataset announced via ProteomeXchange.

Title	Systems Proteomics of the Intermittent Fasting Response Identifies a Key Role for HNF4a
Description	Intermittent fasting (IF) increases lifespan, decreases metabolic disease phenotypes, and cancer risk in model organisms, but the mechanisms mediating these effects are not fully characterized. In particular, the altered transcriptional programming has yet to be defined in key fasting responsive tissues such as liver from animals undergoing intermittent fasting. In this study, we employed every-other-day-fasting (EODF) in mice and high-resolution proteome analysis of liver and blood plasma as a screening tool to identify key regulated pathways with comparison to ad libitum fed animals. We observed many changes in the liver proteome abundance profile that were distinct from those observed after a single bout of fasting. Key among these were the induction by EODF of de novo lipogenesis (DNL) and cholesterol biosynthesis pathway enzymes, which were mirrored by related metabolite changes such as increased triacylglycerides and HMG-CoA in EODF liver of fed mice. Paradoxically, we also observed the up-regulation of mitochondrial proteins associated with fatty-acid beta oxidation including ACOT2, which is known to accelerate this pathway in vivo. The most surprising observation was the EODF-mediated 16-fold down-regulation of alpha-1-antitrypsin (SERPINA1E) in liver, which is an abundant plasma protein made exclusively in this tissue. Plasma proteome analysis confirmed a 3-fold decrease in SERPINA1E after 2 weeks of EODF among other significant changes such as increased levels of APOA4, a finding in common with previous human EODF intervention studies. We determined that in liver the SREBP1c and HNF4A transcription factors were playing a major role in the up-regulation of lipid/cholesterol synthesis and down-regulation of AAT, respectively. Further characterization of HNF4A function suggested a global inhibition of its ability to bind promoters of target genes in livers from EODF animals, which we hypothesize is mediated by either increased linoleic acid binding, or post translational modifications of HNF4A protein in EODF animal liver tissue. Together these data provide a comprehensive Omics resource highlighting the key changes observed during the intermittent fasting response in a model animal.
HostingRepository	PRIDE
AnnounceDate	2024-10-07
AnnouncementXML	Submission_2024-10-07_13:31:27.663.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mark Larance
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	(R)-5-oxo-1,4-tetrahydrothiazine-3-carboxylic acid; deaminated residue; monohydroxylated residue; acetylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-09-23 08:49:32	ID requested
⏵ 1	2024-10-07 13:31:28	announced

Hatchwell L, Harney DJ, Cielesh M, Young K, Koay YC, O'Sullivan JF, Larance M, . Cell Rep, 30(10):3566-3582.e4(2020) [pubmed]

10.1016/j.celrep.2020.02.051;

submitter keyword: mouse, intermittent fasting, proteomics, metabolomics, SREBP1c, plasma, PPARA, liver, HNF4A

Mark Larance
contact affiliation	University of Sydney
contact email	mark.larance@sydney.edu.au
lab head
Mark Larance
contact affiliation	The University of Sydney
contact email	mark.larance@sydney.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD015553
     1. Label: PRIDE project
     2. Name: Systems Proteomics of the Intermittent Fasting Response Identifies a Key Role for HNF4a