PXD023848

PXD023848 is an original dataset announced via ProteomeXchange.

Title	Non-transformed cells respond to fat by inducing glucose metabolism
Description	Hepatic fat accumulation has been widely associated with diabetes and hepatocellular carcinoma (HCC). Here, we aim to characterize the metabolic response that high fat availability elicits in livers prior to development of these diseases. We find that, after a short term on high fat diet, otherwise healthy mice show elevated hepatic glucose metabolization, activated glucose uptake, glycolysis and glucose contribution to serine as well as elevated pyruvate carboxylase activity compared to control diet mice. To understand other changes in the liver tissue after high fat diet exposure, we conducted untargeted transcriptomics and proteomics. This glucose phenotype occurred independent from transcriptional or proteomic programming, which identified increased peroxisomal and lipid metabolism pathways. Interestingly, we observe that high fat diet fed mice exhibit an increased lactate production when challenged with glucose. This trait seems to find a parallel in a human cohort, where we observe a correlation between waist circumference and lactate secretion after an oral glucose bolus across healthy individuals. In an in vitro model of hepatoma cells, we found physiologically relevant palmitate exposure stimulated production of reactive oxygen species (ROS) and glucose uptake, a similar glycolytic phenotype to the in vivo study. This effect is inhibited upon interference with peroxisomal lipid metabolism and ROS production. Furthermore, we find that with exposure to an HCC-inducing hepatic carcinogen, continuation of high fat diet enhances the formation of HCC (100% with resectable tumors) as compared to control (50% with resectable tumors) in mice. However, regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism compared to those identified in fat exposed non-transformed mouse livers. Further, the presence of tumors in high fat diet exposed mice normalized glucose tolerance. Lipidomics analysis of tumor tissue and liver tissue from high fat diet exposed mice identified tumor tissue enrichment of diacylglycerol (DG) and phosphatidylcholine (PC) species. Some of these species were also increased in high fat diet liver tissue compared to control diet liver tissue. These findings suggest that fat can induce similar metabolic changes in non-transformed liver cells than found in HCC, and that peroxisomal metabolism of lipids may be a factor in driving a glycolytic metabolism In conclusion, we show that normal, non-transformed livers respond to fat by inducing glucose metabolism.
HostingRepository	PRIDE
AnnounceDate	2021-03-08
AnnouncementXML	Submission_2021-03-07_22:30:31.018.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Delphi Van Haver
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-01-27 10:44:38	ID requested
⏵ 1	2021-03-07 22:30:31	announced

Dataset with its publication pending

submitter keyword: high fat diet, metabolism, cancer metabolism, liver metabolism, glucose metabolism, lipid metabolism, liver cancer, hepatocellular carcinoma, diethylnitrosamine (DEN)

Sarah-Maria Fendt
contact affiliation	KU Leuven-VIB Center for Cancer Biology
contact email	sarah-maria.fendt@kuleuven.be
lab head
Delphi Van Haver
contact affiliation	VIB Proteomics Core
contact email	delphi.vanhaver@vib-ugent.be
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD023848
     1. Label: PRIDE project
     2. Name: Non-transformed cells respond to fat by inducing glucose metabolism