Drug-like sphingolipid SH-BC-893 opposes ceramide-induced mitochondrial fission and corrects diet-induced obesity.

Autor: Jayashankar V; Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA., Selwan E; Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA., Hancock SE; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia., Verlande A; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA., Goodson MO; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA., Eckenstein KH; Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA., Milinkeviciute G; Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA., Hoover BM; Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA., Chen B; Department of Chemistry, Université de Montréal, Montréal, QC, Canada., Fleischman AG; Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA., Cramer KS; Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA., Hanessian S; Department of Chemistry, Université de Montréal, Montréal, QC, Canada., Masri S; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA., Turner N; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia., Edinger AL; Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2021 Aug 09; Vol. 13 (8), pp. e13086. Date of Electronic Publication: 2021 Jul 07.
DOI: 10.15252/emmm.202013086
Abstrakt: Ceramide-induced mitochondrial fission drives high-fat diet (HFD)-induced obesity. However, molecules targeting mitochondrial dynamics have shown limited benefits in murine obesity models. Here, we reveal that these compounds are either unable to block ceramide-induced mitochondrial fission or require extended incubation periods to be effective. In contrast, targeting endolysosomal trafficking events important for mitochondrial fission rapidly and robustly prevented ceramide-induced disruptions in mitochondrial form and function. By simultaneously inhibiting ARF6- and PIKfyve-dependent trafficking events, the synthetic sphingolipid SH-BC-893 blocked palmitate- and ceramide-induced mitochondrial fission, preserved mitochondrial function, and prevented ER stress in vitro. Similar benefits were observed in the tissues of HFD-fed mice. Within 4 h of oral administration, SH-BC-893 normalized mitochondrial morphology in the livers and brains of HFD-fed mice, improved mitochondrial function in white adipose tissue, and corrected aberrant plasma leptin and adiponectin levels. As an interventional agent, SH-BC-893 restored normal body weight, glucose disposal, and hepatic lipid levels in mice consuming a HFD. In sum, the sphingolipid analog SH-BC-893 robustly and acutely blocks ceramide-induced mitochondrial dysfunction, correcting diet-induced obesity and its metabolic sequelae.
(© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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