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Carrasco Del Amor, A.* ; Hernandez-Bautista, R. ; Ussar, S. ; Cristobal, S.* ; Urbatzka, R.*

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.

Eur. J. Pharmacol. 960:176158 (2023)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Anti-obesity Activity ; Chlorophyll Derivatives ; Mechanism Of Action ; Thermal Proteome Profiling ; Zebrafish ; Brown Adipocytes; Gene-expression; Drug Discovery; Pyruvate; Obesity; Future
ISSN (print) / ISBN 0014-2999
e-ISSN 0014-2999
Zeitschrift European Journal of Pharmacology
Quellenangaben Band: 960, Heft: , Seiten: , Artikelnummer: 176158 Supplement: ,
Verlag Elsevier
Verlagsort Radarweg 29, 1043 Nx Amsterdam, Netherlands
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
Förderungen Magnus Bergvalls Foundations
Basque Government Research Grant
IKERBASQUE, Basque Foundation for Science
European Regional Development Fund (ERDF)