Cardiolipin Remodeling by ALCAT1 Links Oxidative Stress and Mitochondrial Dysfunction to Obesity

Li, Jia; Romestaing, Caroline; Han, Xianlin; Li, Yuan; Hao, Xinbao; Wu, Yinyuan; Sun, Cheng; Liu, Xiaolei; Jefferson, Leonard S.; Xiong, Jing-Wei; LaNoue, Kathryn F.; Chen, Zhijie; Lynch, Christopher J.; Wang, Huayan; Shi, Yuguang

doi:10.1016/j.cmet.2010.07.003

Cited by 242 publications

(323 citation statements)

References 55 publications

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“…Defects in mitochondrial oxidative metabolism of fatty acids have been linked to diet-induced obesity and the development of insulin resistance in adipose tissue and skeletal muscle (1,2). Consistent with the observation that mitochondrial dysfunction is a risk factor for the development of metabolic syndrome, obese individuals have mitochondria with compromised bioenergetic capacity (3)(4)(5)(6).…”

mentioning

confidence: 74%

Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

Carrer

Liu²,

Grueter

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

263

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Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus, these miRNAs provide potential targets for pharmacologic intervention in obesity and metabolic syndrome.fatty acid oxidation | adipocytes | mitochondrial CO 2 production

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mentioning

confidence: 74%

Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

Carrer

Liu²,

Grueter

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

263

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“…Dysfunctional regulation of CL content and/or molecular species distribution represents a membrane-mediated mechanism underlying mitochondrial bioenergetic inefficiency in multiple disease states (5,24,31,33,57,58). However, due to the complex and interwoven nature of the multiple metabolic pathways involved in CL biosynthesis, remodeling, and meta- bolic flux, the mechanistic dissection of the roles of individual enzymes in the dysfunctional regulation of CL metabolism during the onset and progression of disease states has previously represented an intractable metabolomic problem (17,26,59,60).…”

Section: Discussionmentioning

confidence: 99%

Myocardial Regulation of Lipidomic Flux by Cardiolipin Synthase

Kiebish

Yang

Sims

et al. 2012

Journal of Biological Chemistry

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Background: Maintenance of cardiolipin molecular speciation by remodeling directly regulates mitochondrial bioenergetic efficiency. Results: Transgenic expression of cardiolipin synthase accelerates cardiolipin remodeling, improves mitochondrial function, modulates mitochondrial signaling, and attenuates mitochondrial dysfunction during diabetes. Conclusion: Cardiolipin synthase integrates multiple aspects of mitochondrial bioenergetic and signaling functions. Significance: Cardiolipin synthase expression attenuates mitochondrial dysfunction in diabetic myocardium.

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“…However, using the same type of cells, another study recovered recombinant fl ag-tagged mouse LYCAT from mitochondria and mitochondria-associated membranes but not from the microsomes ( 26 ). In the present study, we established a mouse LYCAT-specifi c monoclonal antibody YN1 and used it to analyze the subcellular localization of endogenous LYCAT.…”

Section: Lycat Defi Ciency Causes Reduced Acyltransferase Activity Tomentioning

confidence: 99%

LYCAT, a homologue of C. elegans acl-8,acl-9, and acl-10, determines the fatty acid composition of phosphatidylinositol in mice

Imae

Inoué

Nakasaki

et al. 2012

Journal of Lipid Research

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Phosphatidylinositol (PI) is a relatively minor component of membrane phospholipids but plays important roles in signal transduction through distinct phosphorylated derivatives of the inositol head group ( 1, 2 ). Threefourths or more of membrane PI obtained from mammalian tissues consist of the 1-stearoyl-2-arachidonoyl (18:0/20:4) species ( 3, 4 ), which is thought to be formed by a fatty acid remodeling reaction after the de novo synthesis of PI ( 5-10 ). The remodeling reaction involves the hydrolysis of a fatty acyl ester bond at the sn -1 or sn -2 position of the newly synthesized PI and subsequent incorporation of the appropriate fatty acid into the position. In an RNA interference (RNAi)-based genetic screen using Caenorhabditis elegans , we identifi ed mboa-7/ LPIAT1 as an acyltransferase that selectively incorporates arachidonic acid into the sn-2 position of PI ( 11 ). More recently, we demonstrated that C. elegans acl-8 , acl-9 , and acl-10 , which show signifi cant sequence homology to each other, encode acyltransferases that incorporate stearic acid (18:0) into the sn-1 position of PI ( 12 ). Stearic acid attached at the sn -1 position of PI Abstract Mammalian phosphatidylinositol (PI) has a unique fatty acid composition in that 1-stearoyl-2-arachidonoyl species is predominant. This fatty acid composition is formed through fatty acid remodeling by sequential deacylation and reacylation. We recently identifi ed three Caenorhabditis elegans acyltransferases (ACL-8, ACL-9, and ACL-10 ) that incorporate stearic acid into the sn-1 position of PI. Mammalian LYCAT, which is the closest homolog of ACL-8, ACL-9, and ACL-10, was originally identifi ed as a lysocardiolipin acyltransferase by an in vitro assay and was subsequently reported to possess acyltransferase activity toward various anionic lysophospholipids. However, the in vivo role of mammalian LYCAT in phospholipid fatty acid metabolism has not been well elucidated. In this study, we generated LYCAT-defi cient mice and demonstrated that LYCAT determined the fatty acid composition of PI in vivo. LYCATdefi cient mice were outwardly healthy and fertile. In the mice, stearoyl-CoA acyltransferase activity toward the sn -1 position of PI was reduced, and the fatty acid composition of PI, but not those of other major phospholipids, was altered. Furthermore, expression of mouse LYCAT rescued the phenotype of C. elegans acl-8 acl-9 acl-10 triple mutants. Our data indicate that LYCAT is a determinant of PI molecular species and its function is conserved in C. elegans and mammals. Abbreviations: AGPAT, 1-acylglycerol-3-phosphate O -acyltransferase; A-P axis, anterior-posterio axis; CL, cardiolipin; ER, endoplasmic reticulum; LPCAT, lysophosphatidylcholine acyltransferase; LPEAT, lysophosphatidylethanolamine acyltransferase; LPGAT, lysophosphatidylglycerol acyltransferase; LPIAT, lysophosphatidylinositol acyltransferase; LPSAT, lysophosphatidylserine acyltransferase; LYCAT, lysocardiolipin acyltransferase; MEF, mouse embryonic fi broblast; PC, phosphatidylcholi...

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Cardiolipin Remodeling by ALCAT1 Links Oxidative Stress and Mitochondrial Dysfunction to Obesity

Cited by 242 publications

References 55 publications

Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

Myocardial Regulation of Lipidomic Flux by Cardiolipin Synthase

LYCAT, a homologue of C. elegans acl-8,acl-9, and acl-10, determines the fatty acid composition of phosphatidylinositol in mice

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