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Apolipoprotein O is mitochondrial and promotes lipotoxicity in heart
Annie Turkieh, … , Philippe Rouet, Fatima Smih
Annie Turkieh, … , Philippe Rouet, Fatima Smih
Published April 17, 2014
Citation Information: J Clin Invest. 2014;124(5):2277-2286. https://doi.org/10.1172/JCI74668.
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Research Article Cardiology

Apolipoprotein O is mitochondrial and promotes lipotoxicity in heart

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Abstract

Diabetic cardiomyopathy is a secondary complication of diabetes with an unclear etiology. Based on a functional genomic evaluation of obesity-associated cardiac gene expression, we previously identified and cloned the gene encoding apolipoprotein O (APOO), which is overexpressed in hearts from diabetic patients. Here, we generated APOO-Tg mice, transgenic mouse lines that expresses physiological levels of human APOO in heart tissue. APOO-Tg mice fed a high-fat diet exhibited depressed ventricular function with reduced fractional shortening and ejection fraction, and myocardial sections from APOO-Tg mice revealed mitochondrial degenerative changes. In vivo fluorescent labeling and subcellular fractionation revealed that APOO localizes with mitochondria. Furthermore, APOO enhanced mitochondrial uncoupling and respiration, both of which were reduced by deletion of the N-terminus and by targeted knockdown of APOO. Consequently, fatty acid metabolism and ROS production were enhanced, leading to increased AMPK phosphorylation and Ppara and Pgc1a expression. Finally, we demonstrated that the APOO-induced cascade of events generates a mitochondrial metabolic sink whereby accumulation of lipotoxic byproducts leads to lipoapoptosis, loss of cardiac cells, and cardiomyopathy, mimicking the diabetic heart–associated metabolic phenotypes. Our data suggest that APOO represents a link between impaired mitochondrial function and cardiomyopathy onset, and targeting APOO-dependent metabolic remodeling has potential as a strategy to adjust heart metabolism and protect the myocardium from impaired contractility.

Authors

Annie Turkieh, Céline Caubère, Manon Barutaut, Franck Desmoulin, Romain Harmancey, Michel Galinier, Matthieu Berry, Camille Dambrin, Carlo Polidori, Louis Casteilla, François Koukoui, Philippe Rouet, Fatima Smih

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Figure 2

In vitro analysis of APOO in cardiac myoblasts.

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In vitro analysis of APOO in cardiac myoblasts.
(A) Confocal microscopy ...
(A) Confocal microscopy of H9c2 cardiac myoblasts transfected with SNAP-tagged hAPOO. (B) Western blot for APOO (55 kDa) with membrane protein extracts prepared from APOO and control (C) cells. Equal lane loading and transfer were verified by probing the same membrane with calreticulin (CALR, 48 kDa) antibody. (C) Western blot analysis of cytoplasmic and mitochondrial fractions of control cells and cardiac myoblasts overexpressing APOO hybridized with APOO antibody. Mit, mitochondria; Cyto, cytoplasm. (D) Confocal microscopy of H9c2 cardiac myoblasts transfected with SNAP-tagged N-terminal deletion of 40 aa of APOO (APOO Δ1–40). (E) Western blot analysis of cytoplasmic and mitochondrial fractions of control cells and cardiac myoblasts overexpressing APOO Δ1–40 hybridized with APOO antibody. Recombinant (Recom) proteins were used for size control. Actin (42 kDa) and ANT (33 kDa) were used as cytosolic and mitochondrial purification controls, respectively. Mitochondria were stained with green mitotracker; SNAP-APOO and SNAP-APOO Δ1–40 were revealed with TMR-star. Shown are representative data from 1 experiment. Experiments were repeated 3 times. Scale bars: 10 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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