Insights into the mechanism of action of the chlorophyll derivative 13--hydroxypheophytine a on reducing neutral lipid reserves in zebrafish larvae and mice adipocytes
Year: 2023
Type: article
Abstract: -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.
Source: European Journal of Pharmacology
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,790
Funders: Skogs- och Jordbrukets Forskningsråd, Svenska Forskningsrådet Formas, Bundesministerium für Bildung und Forschung, Eusko Jaurlaritza, Ikerbasque, Basque Foundation for Science, Magnus Bergvalls Stiftelse, Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie, Fundação para a Ciência e a Tecnologia, European Regional Development Fund
Awards: G1103927107, G1319873162, G1516346500, G1735909041, Centro Interdisciplinar de Investigação Marinha e Ambiental, Cianobactérias como fonte de compostos bioativos com efeitos sobre obesidade e morbidades associadas à obesidade, ERA-NET Marine Biotechnologie: Identifizierung von bioaktiven Wirkstoffen aus Cyanobakterien für die Behandlung der Adipositas und des metabolischen Syndroms, G323769159, G3814299435, CYANOBESITY, Cyanobacteria as a source of bioactive compounds with effects on obesity and obesity-related co-morbidities, G4063455850, G4316116677, G5485649731, G562452873, G5840347571, G6413217827, Centro Interdisciplinar de Investigação Marinha e Ambiental, G7584003722, G8306709048, ATLANTIDA - Platform for the monitoring of the North Atlantic ocean and tools for the sustainable exploitation of the marine resources, G96847669
OpenAlex ID: W4387953756