PXD025268

PXD025268 is an original dataset announced via ProteomeXchange.

Title	Long-term adjustment of hepatic lipid metabolism after chronic stress and the role of FGF21
Description	Chronic stress leads post-traumatic stress disorder (PTSD) and to metabolic complications, including fatty liver. It is feasible, that stress immediately initiates molecular mechanisms to alter energy metabolism and glucose homeostasis which interfere with hepatic lipid accumulation after stress recovery. We aim to elucidate these molecular mechanisms of long term stress effects on metabolism and focus on physiological adaptation and the role of FGF21, which is protective in hepatic lipid accumulation. Methods FGF21 knockout and control mice were exposed to chronic variable stress (Cvs) and recovered for 3 months to simulate PTSD. We determined in vivo and ex vivo energy metabolism, mitochondrial function by extracellular flux analysis, alterations in DNA modifying enzymes and gene regulation immediately after stress and after the recovery period to determine long term alterations. Results Chronic stress leads to reduced insulin sensitivity and hepatic lipid accumulation with increased fatty acid uptake (FAU), stress-induced lipolysis, and reduction in NAD+/NAD ratio and Sirt activity. Immediately after stress, PPARa and SREBP-1 target genes are differentially regulated and are involved in the development of stress-induced fatty liver. After recovery, insulin sensitivity increases but insulin-induced de novo lipogenesis (DNL) is reduced and FAU is increased. HDAC and MT activity are suppressed, whereas HAT activity increases, linking metabolic adjustments to transcriptional regulators. Thus, key metabolic genes are differentially regulated and secreted proteins indicate the activation of liver disease by Cvs only in FGF21WT. GR binding to the Cd36 promoter is altered. After stress recovery, serum FGF21 is increased and protects against lipid accumulation. FGF21 interacts by attenuating DNL, increasing FAU and HAT activity, and balancing mitochondrial activity. Higher long-term stress-induced activation and binding of GR to the FGF21 promoter may contribute to the prolonged FGF21 release. Conclusions We show that previous stress exposure determines predisposition to fatty liver disease is regulated by FGF21. Immediately after Cvs, altered gene regulation and activity of DNA-modifying enzymes determine the metabolic late effects seen in PTSD. FGF21 functions after chronic stress exposure i) to protect against hepatic lipid accumulation, ii) to maintain mitochondrial capacity, and iii) to mediate in the modulation of DNA-modifying enzymes. These findings highlight the protective role of FGF21 even in stress-induced hepatic lipid accumulation.
HostingRepository	PRIDE
AnnounceDate	2022-03-10
AnnouncementXML	Submission_2022-03-09_23:52:13.158.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Birgit Knebel
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-04-08 06:14:45	ID requested
⏵ 1	2022-03-09 23:52:14	announced

Dille M, Nikolic A, Wahlers N, Fahlbusch P, Jacob S, Hartwig S, Lehr S, Kabra D, Klymenko O, Al-Hasani H, Kotzka J, Knebel B, Long-term adjustment of hepatic lipid metabolism after chronic stress and the role of FGF21. Biochim Biophys Acta Mol Basis Dis, 1868(1):166286(2022) [pubmed]

submitter keyword: mouse hepatocytes, secreted proteins, long-term effects of chronic stress, fatty liver

Birgit Knebel
contact affiliation	Dr. rer. nat. Birgit Knebel Institute for Clinical Biochemistry and Pathobiochemistry German Diabetes Center (DDZ) Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf Auf´m Hennekamp 65 40225 Düsseldorf, Germany Tel.: +49-(0)-211-33-82-536 birgit.knebel@ddz.de www.ddz.de
contact email	birgit.knebel@ddz.de
lab head
Birgit Knebel
contact affiliation	Institute for Clinical Biochemistry and Pathobiochemistry German Diabetes Center (DDZ) Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf
contact email	birgit.knebel@ddz.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD025268
     1. Label: PRIDE project
     2. Name: Long-term adjustment of hepatic lipid metabolism after chronic stress and the role of FGF21