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Insights into the mechanism of action of the chlorophyll derivative 13-2-hydroxypheophytine a on reducing neutral lipid reserves in zebrafish larvae and mice adipocytes
Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Helmholtz Ctr Munich, Germany.
Helmholtz Ctr Munich, Germany.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Basque Country UPV EHU, Spain.ORCID iD: 0000-0002-3894-2218
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2023 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 960, article id 176158Article in journal (Refereed) Published
Abstract [en]

Obesity is a worldwide epidemic and natural products may hold promise in its treatment. The chlorophyll derivative 13-2-hydroxypheophytine (hpa) was isolated in a screen with zebrafish larvae to identify lipid reducing molecules from cyanobacteria. However, the mechanisms underlying the lipid-reducing effects of hpa in zebrafish larvae remain poorly understood. Thus, investigating the mechanism of action of hpa and validation in other model organisms such as mice represents important initial steps. 

In this study, we identified 14 protein targets of hpa in zebrafish larvae by thermal proteome profiling, and selected two targets (malate dehydrogenase and pyruvate kinase) involved in cellular metabolism for further validation by enzymatic measurements. Our findings revealed a dose-dependent inhibition of pyruvate kinase by hpa exposure using protein extracts of zebrafish larvae in vitro, and in exposure experiments from 3 to 5 days post fertilization in vivo. Analysis of untargeted metabolomics of zebrafish larvae detected 940 mass peaks (66 increased, 129 decreased) and revealed that hpa induced the formation of various phospholipid species (phosphoinositol, phosphoethanolamine, phosphatidic acid). Inter-species validation showed that brown adipocytes exposed to hpa significantly reduced the size of lipid droplets, increased maximal mitochondrial respiratory capacity, and the expression of PPARy during adipocyte differentiation. 

In line with our data, previous work described that reduced pyruvate kinase activity lowered hepatic lipid content via reduced pyruvate and citrate, and improved mitochondrial function via phospholipids. Thus, our data provide new insights into the molecular mechanism underlying the lipid reducing activities of hpa in zebrafish larvae, and species overlapping functions in reduction of lipids. 

Place, publisher, year, edition, pages
ELSEVIER , 2023. Vol. 960, article id 176158
Keywords [en]
Chlorophyll derivatives; brown adipocytes; Zebrafish; Anti-Obesity activity; Mechanism of action; Thermal proteome profiling
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:liu:diva-199720DOI: 10.1016/j.ejphar.2023.176158ISI: 001110873300001PubMedID: 37898286OAI: oai:DiVA.org:liu-199720DiVA, id: diva2:1821532
Note

Funding Agencies|European Regional Development Fund (ERDF); IKERBASQUE, Basque Foundation for Science; Basque Government Research Grant [IT-971-16, IT-476-22]; Magnus Bergvalls Foundations

Available from: 2023-12-20 Created: 2023-12-20 Last updated: 2024-09-20

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Carrasco Del Amor, Ana MariaCristobal, Susana
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