FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2073168934> ?p ?o ?g. }

• W2073168934 endingPage "36827" @default.
• W2073168934 startingPage "36818" @default.
• W2073168934 abstract "The mechanisms underlying the protective effect of monounsaturated fatty acids (e.g. oleate) against the lipotoxic action of saturated fatty acids (e.g. palmitate) in skeletal muscle cells remain poorly understood. This study aimed to examine the role of mitochondrial long-chain fatty acid (LCFA) oxidation in mediating oleate's protective effect against palmitate-induced lipotoxicity. CPT1 (carnitine palmitoyltransferase 1), which is the key regulatory enzyme of mitochondrial LCFA oxidation, is inhibited by malonyl-CoA, an intermediate of lipogenesis. We showed that expression of a mutant form of CPT1 (CPT1mt), which is active but insensitive to malonyl-CoA inhibition, in C2C12 myotubes led to increased LCFA oxidation flux even in the presence of high concentrations of glucose and insulin. Furthermore, similar to preincubation with oleate, CPT1mt expression protected muscle cells from palmitate-induced apoptosis and insulin resistance by decreasing the content of deleterious palmitate derivates (i.e. diacylglycerols and ceramides). Oleate preincubation exerted its protective effect by two mechanisms: (i) in contrast to CPT1mt expression, oleate preincubation increased the channeling of palmitate toward triglycerides, as a result of enhanced diacylglycerol acyltransferase 2 expression, and (ii) oleate preincubation promoted palmitate oxidation through increasing CPT1 expression and modulating the activities of acetyl-CoA carboxylase and AMP-activated protein kinase. In conclusion, we demonstrated that targeting mitochondrial LCFA oxidation via CPT1mt expression leads to the same protective effect as oleate preincubation, providing strong evidence that redirecting palmitate metabolism toward oxidation is sufficient to protect against palmitate-induced lipotoxicity. The mechanisms underlying the protective effect of monounsaturated fatty acids (e.g. oleate) against the lipotoxic action of saturated fatty acids (e.g. palmitate) in skeletal muscle cells remain poorly understood. This study aimed to examine the role of mitochondrial long-chain fatty acid (LCFA) oxidation in mediating oleate's protective effect against palmitate-induced lipotoxicity. CPT1 (carnitine palmitoyltransferase 1), which is the key regulatory enzyme of mitochondrial LCFA oxidation, is inhibited by malonyl-CoA, an intermediate of lipogenesis. We showed that expression of a mutant form of CPT1 (CPT1mt), which is active but insensitive to malonyl-CoA inhibition, in C2C12 myotubes led to increased LCFA oxidation flux even in the presence of high concentrations of glucose and insulin. Furthermore, similar to preincubation with oleate, CPT1mt expression protected muscle cells from palmitate-induced apoptosis and insulin resistance by decreasing the content of deleterious palmitate derivates (i.e. diacylglycerols and ceramides). Oleate preincubation exerted its protective effect by two mechanisms: (i) in contrast to CPT1mt expression, oleate preincubation increased the channeling of palmitate toward triglycerides, as a result of enhanced diacylglycerol acyltransferase 2 expression, and (ii) oleate preincubation promoted palmitate oxidation through increasing CPT1 expression and modulating the activities of acetyl-CoA carboxylase and AMP-activated protein kinase. In conclusion, we demonstrated that targeting mitochondrial LCFA oxidation via CPT1mt expression leads to the same protective effect as oleate preincubation, providing strong evidence that redirecting palmitate metabolism toward oxidation is sufficient to protect against palmitate-induced lipotoxicity. IntroductionIt has long been recognized that increased plasma free fatty acids are associated with insulin resistance in humans (1Schalch D.S. Kipnis D.M. J. Clin. Invest. 1965; 44: 2010-2020Crossref PubMed Scopus (123) Google Scholar). Indeed, plasma free fatty acid concentrations are increased in obese subjects (2Adams 2nd, J.M. Pratipanawatr T. Berria R. Wang E. DeFronzo R.A. Sullards M.C. Mandarino L.J. Diabetes. 2004; 53: 25-31Crossref PubMed Scopus (511) Google Scholar) as well as in genetically obese or high fat diet-induced insulin-resistant mice (3Dentin R. Benhamed F. Hainault I. Fauveau V. Foufelle F. Dyck J.R. Girard J. Postic C. Diabetes. 2006; 55: 2159-2170Crossref PubMed Scopus (315) Google Scholar, 4Bonnard C. Durand A. Peyrol S. Chanseaume E. Chauvin M.A. Morio B. Vidal H. Rieusset J. J. Clin. Invest. 2008; 118: 789-800Crossref PubMed Scopus (639) Google Scholar). In such conditions, circulating free fatty acid concentrations are elevated, and FA 4The abbreviations used are: FAfatty acid(s)ASPacid-soluble product(s)CCCPcarbonyl cyanide m-chlorophenyl hydrazoneCPT1mtmutant CPT1A M593SDAGdiacylglycerol(s)LacZβ-galactosidaseLCFAlong-chain fatty acidMUFAmonounsaturated fatty acid(s)OApreincubation with oleatePLphospholipid(s)SFAsaturated fatty acid(s)SMsphingomyelin(s)TGtriglyceride(s)G55 mm glucoseG20+I20 mm glucose plus 100 nm insulin. metabolism is altered (5McGarry J.D. Diabetes. 2002; 51: 7-18Crossref PubMed Scopus (1205) Google Scholar, 6Hulver M.W. Berggren J.R. Cortright R.N. Dudek R.W. Thompson R.P. Pories W.J. MacDonald K.G. Cline G.W. Shulman G.I. Dohm G.L. Houmard J.A. Am. J. Physiol. Endocrinol. Metab. 2003; 284: E741-E747Crossref PubMed Scopus (276) Google Scholar, 7Kelley D.E. Goodpaster B. Wing R.R. Simoneau J.A. Am. J. Physiol. 1999; 277: E1130-E1141Crossref PubMed Google Scholar), leading to ectopic accumulation of FA in the liver, pancreatic β-cells, or skeletal muscle, where they interfere with normal cell function. For instance, FA overload induces skeletal muscle insulin resistance (6Hulver M.W. Berggren J.R. Cortright R.N. Dudek R.W. Thompson R.P. Pories W.J. MacDonald K.G. Cline G.W. Shulman G.I. Dohm G.L. Houmard J.A. Am. J. Physiol. Endocrinol. Metab. 2003; 284: E741-E747Crossref PubMed Scopus (276) Google Scholar), inflammation (8Coll T. Eyre E. Rodríguez-Calvo R. Palomer X. Sánchez R.M. Merlos M. Laguna J.C. Vázquez-Carrera M. J. Biol. Chem. 2008; 283: 11107-11116Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar), and cell death via apoptosis (4Bonnard C. Durand A. Peyrol S. Chanseaume E. Chauvin M.A. Morio B. Vidal H. Rieusset J. J. Clin. Invest. 2008; 118: 789-800Crossref PubMed Scopus (639) Google Scholar, 6Hulver M.W. Berggren J.R. Cortright R.N. Dudek R.W. Thompson R.P. Pories W.J. MacDonald K.G. Cline G.W. Shulman G.I. Dohm G.L. Houmard J.A. Am. J. Physiol. Endocrinol. Metab. 2003; 284: E741-E747Crossref PubMed Scopus (276) Google Scholar), a phenomenon commonly referred as “lipotoxicity.” The toxic effects of FA are known to depend on their chain length and degree of saturation. Long-chain saturated FA (SFA), such as palmitate (C16:0) and stearate (C18:0), are the most lipotoxic. Consistently, palmitate induces apoptosis in many cell types (9Sparagna G.C. Hickson-Bick D.L. Buja L.M. McMillin J.B. Antioxid. Redox Signal. 2001; 3: 71-79Crossref PubMed Scopus (36) Google Scholar, 10Shimabukuro M. Zhou Y.T. Levi M. Unger R.H. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 2498-2502Crossref PubMed Scopus (1006) Google Scholar, 11Turpin S.M. Lancaster G.I. Darby I. Febbraio M.A. Watt M.J. Am. J. Physiol. Endocrinol. Metab. 2006; 291: E1341-E1350Crossref PubMed Scopus (133) Google Scholar, 12Paumen M.B. Ishida Y. Muramatsu M. Yamamoto M. Honjo T. J. Biol. Chem. 1997; 272: 3324-3329Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar). In muscle cells, palmitate's cytotoxic effect is mediated by increased intracellular concentrations of diacylglycerols (DAG) and ceramides (11Turpin S.M. Lancaster G.I. Darby I. Febbraio M.A. Watt M.J. Am. J. Physiol. Endocrinol. Metab. 2006; 291: E1341-E1350Crossref PubMed Scopus (133) Google Scholar). In contrast, monounsaturated FA (MUFA), such as oleate (C18:1), protect against SFA-induced toxicity (8Coll T. Eyre E. Rodríguez-Calvo R. Palomer X. Sánchez R.M. Merlos M. Laguna J.C. Vázquez-Carrera M. J. Biol. Chem. 2008; 283: 11107-11116Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 13Miller T.A. LeBrasseur N.K. Cote G.M. Trucillo M.P. Pimentel D.R. Ido Y. Ruderman N.B. Sawyer D.B. Biochem. Biophys. Res. Commun. 2005; 336: 309-315Crossref PubMed Scopus (125) Google Scholar, 14Chavez J.A. Summers S.A. Arch. Biochem. Biophys. 2003; 419: 101-109Crossref PubMed Scopus (380) Google Scholar). Whether oleate exerts such a protective effect on palmitate-induced apoptosis in skeletal muscle cells has not been reported.The mechanisms by which oleate protects cells from palmitate toxicity are not well understood. SFA, which are reported to be less efficiently incorporated into triglycerides (TG) than MUFA, lead to increased accumulation of DAG (8Coll T. Eyre E. Rodríguez-Calvo R. Palomer X. Sánchez R.M. Merlos M. Laguna J.C. Vázquez-Carrera M. J. Biol. Chem. 2008; 283: 11107-11116Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 14Chavez J.A. Summers S.A. Arch. Biochem. Biophys. 2003; 419: 101-109Crossref PubMed Scopus (380) Google Scholar, 15Montell E. Turini M. Marotta M. Roberts M. Noé V. Ciudad C.J. Macé K. Gómez-Foix A.M. Am. J. Physiol. Endocrinol. Metab. 2001; 280: E229-E237Crossref PubMed Google Scholar). Oleate has been proposed to protect cells from palmitate-induced lipotoxicity by promoting its esterification into TG, a neutral form of FA storage (8Coll T. Eyre E. Rodríguez-Calvo R. Palomer X. Sánchez R.M. Merlos M. Laguna J.C. Vázquez-Carrera M. J. Biol. Chem. 2008; 283: 11107-11116Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 15Montell E. Turini M. Marotta M. Roberts M. Noé V. Ciudad C.J. Macé K. Gómez-Foix A.M. Am. J. Physiol. Endocrinol. Metab. 2001; 280: E229-E237Crossref PubMed Google Scholar, 16Listenberger L.L. Han X. Lewis S.E. Cases S. Farese Jr., R.V. Ory D.S. Schaffer J.E. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 3077-3082Crossref PubMed Scopus (1366) Google Scholar). However, it was recently hypothesized that oleate protects from palmitate-induced insulin resistance and inflammation by increasing its mitochondrial oxidation (as shown by increased CPT1 (carnitine palmitoyltransferase 1) gene expression) (8Coll T. Eyre E. Rodríguez-Calvo R. Palomer X. Sánchez R.M. Merlos M. Laguna J.C. Vázquez-Carrera M. J. Biol. Chem. 2008; 283: 11107-11116Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). CPT1 is a transmembrane enzyme of the mitochondrial outer membrane, which converts long-chain acyl-CoA to acylcarnitine, which enters the mitochondrial matrix and undergoes β-oxidation. Because of its inhibition by malonyl-CoA, an intermediate of lipogenesis synthesized by acetyl-CoA carboxylase (ACC), CPT1 is the key regulatory enzyme of long-chain fatty acid (LCFA) β-oxidation (17McGarry J.D. Brown N.F. Eur. J. Biochem. 1997; 244: 1-14Crossref PubMed Scopus (1322) Google Scholar). CPT1 exists in at least two isoforms, CPT1A (liver isoform) and CPT1B (muscle isoform), each of which is found in several tissue and cell types (17McGarry J.D. Brown N.F. Eur. J. Biochem. 1997; 244: 1-14Crossref PubMed Scopus (1322) Google Scholar, 18Perdomo G. Commerford S.R. Richard A.M. Adams S.H. Corkey B.E. O'Doherty R.M. Brown N.F. J. Biol. Chem. 2004; 279: 27177-27186Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar).Whether defects in muscle mitochondrial metabolism are a cause or a consequence of insulin resistance has been extensively investigated but remains controversial. In rodents, some argue against the concept that insulin resistance is mediated by muscle mitochondrial dysfunction (19Turner N. Bruce C.R. Beale S.M. Hoehn K.L. So T. Rolph M.S. Cooney G.J. Diabetes. 2007; 56: 2085-2092Crossref PubMed Scopus (417) Google Scholar, 20Hancock C.R. Han D.H. Chen M. Terada S. Yasuda T. Wright D.C. Holloszy J.O. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 7815-7820Crossref PubMed Scopus (396) Google Scholar). Others have demonstrated that skeletal muscles from obese and insulin-resistant patients exhibit diminished rates of palmitate oxidation, in association with a decrease in CPT1 activity (21Kim J.Y. Hickner R.C. Cortright R.L. Dohm G.L. Houmard J.A. Am. J. Physiol. Endocrinol. Metab. 2000; 279: E1039-E1044Crossref PubMed Google Scholar). Obese and insulin-resistant skeletal muscles also have fewer and dysmorphic mitochondria, which may decrease FA oxidative capacity (22Kelley D.E. He J. Menshikova E.V. Ritov V.B. Diabetes. 2002; 51: 2944-2950Crossref PubMed Scopus (1734) Google Scholar, 23He J. Watkins S. Kelley D.E. Diabetes. 2001; 50: 817-823Crossref PubMed Scopus (384) Google Scholar). Because accumulation of palmitate-derived metabolites within muscle cells is associated with decreased mitochondrial FA oxidative capacity, increasing LCFA oxidation may exert a protective effect. Additionally, contradictory results have been reported concerning the impact of a modulation of mitochondrial LCFA oxidation on palmitate-induced apoptosis in cardiomyocytes (11Turpin S.M. Lancaster G.I. Darby I. Febbraio M.A. Watt M.J. Am. J. Physiol. Endocrinol. Metab. 2006; 291: E1341-E1350Crossref PubMed Scopus (133) Google Scholar, 22Kelley D.E. He J. Menshikova E.V. Ritov V.B. Diabetes. 2002; 51: 2944-2950Crossref PubMed Scopus (1734) Google Scholar) and pancreatic β-cells (13Miller T.A. LeBrasseur N.K. Cote G.M. Trucillo M.P. Pimentel D.R. Ido Y. Ruderman N.B. Sawyer D.B. Biochem. Biophys. Res. Commun. 2005; 336: 309-315Crossref PubMed Scopus (125) Google Scholar, 24Kong J.Y. Rabkin S.W. Am. J. Physiol. Heart Circ. Physiol. 2002; 282: H717-H725Crossref PubMed Scopus (53) Google Scholar, 25Sol E.M. Sargsyan E. Akusjärvi G. Bergsten P. Biochem. Biophys. Res. Commun. 2008; 375: 517-521Crossref PubMed Scopus (24) Google Scholar). This question has never been addressed in skeletal muscle cells.In the present study, we aimed to determine whether oleate protects skeletal muscle cells from palmitate-induced apoptosis and to examine the role of mitochondrial LCFA in mediating any such effect of oleate. To this end, we expressed a mutant form of CPT1A (CPT1 M593S, CPT1mt), which is active but insensitive to malonyl-CoA inhibition (26Morillas M. Gómez-Puertas P. Bentebibel A. Sellés E. Casals N. Valencia A. Hegardt F.G. Asins G. Serra D. J. Biol. Chem. 2003; 278: 9058-9063Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar), in C2C12 myotubes. The metabolic and cellular consequences of an increased LCFA oxidation through CPT1mt expression were compared with the effects of preincubation with oleate (OA) to decipher the mechanisms underlying oleate's protective effect and to determine if direct manipulation of mitochondrial LCFA oxidation would lead to the same protective effect as OA.DISCUSSIONOur findings indicate that oleate preincubation protects skeletal muscle cells from palmitate-induced apoptosis by acting on its metabolism through two mechanisms. It promotes the clearance of DAG-containing palmitate moieties toward TG and palmitate oxidation. Second, because targeting mitochondrial LCFA oxidation directly, via the expression of a malonyl-CoA-insensitive CPT1 (CPT1mt), also has a protective effect, redirection of palmitate metabolism toward oxidation appears to be sufficient for protection against its lipotoxic effect (Fig. 7).Consistent with previous studies (11Turpin S.M. Lancaster G.I. Darby I. Febbraio M.A. Watt M.J. Am. J. Physiol. Endocrinol. Metab. 2006; 291: E1341-E1350Crossref PubMed Scopus (133) Google Scholar, 35Rachek L.I. Musiyenko S.I. LeDoux S.P. Wilson G.L. Endocrinology. 2007; 148: 293-299Crossref PubMed Scopus (105) Google Scholar), we showed that palmitate induced apoptosis in C2C12 myotubes. First, prolonged exposure of myotubes to palmitate promoted intracellular accumulation of TG (specifically TG species with at least two C16: C51 and C53), DAG (specifically 16-16 and 16-18), and ceramides (specifically Cer16:0). As previously suggested (11Turpin S.M. Lancaster G.I. Darby I. Febbraio M.A. Watt M.J. Am. J. Physiol. Endocrinol. Metab. 2006; 291: E1341-E1350Crossref PubMed Scopus (133) Google Scholar), these deleterious metabolites result from enhanced de novo ceramide synthesis rather than from SM degradation because cellular SM content was unaffected by palmitate treatment. Second, palmitate exposure increased SFA and decreased MUFA, leading to a decreased MUFA/SFA ratio. Previous studies have suggested that palmitate-induced DAG and TG accumulation might result from a higher esterification flux for palmitate than for oleate (15Montell E. Turini M. Marotta M. Roberts M. Noé V. Ciudad C.J. Macé K. Gómez-Foix A.M. Am. J. Physiol. Endocrinol. Metab. 2001; 280: E229-E237Crossref PubMed Google Scholar, 16Listenberger L.L. Han X. Lewis S.E. Cases S. Farese Jr., R.V. Ory D.S. Schaffer J.E. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 3077-3082Crossref PubMed Scopus (1366) Google Scholar), as we also observed. However, our metabolic investigations also revealed that palmitate is much less prone to oxidation than oleate, which could favor directing its metabolism toward esterification.We found that preincubation with oleate decreased palmitate esterification into DAG and TG after 3 h of palmitate exposure, resulting in a decreased DAG/TG ratio. However, oleate preincubation promoted intracellular TG accumulation, in particular TG species containing at least one C18 (C53, C55, and C57) after a 24-h palmitate exposure. This difference probably results from an enhanced expression of DGAT2, whose affinity is 50% higher for oleyl-CoA than for palmitoyl-CoA (36Cases S. Stone S.J. Zhou P. Yen E. Tow B. Lardizabal K.D. Voelker T. Farese Jr., R.V. J. Biol. Chem. 2001; 276: 38870-38876Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar, 37Lardizabal K.D. Mai J.T. Wagner N.W. Wyrick A. Voelker T. Hawkins D.J. J. Biol. Chem. 2001; 276: 38862-38869Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar). Indeed, oleate preincubation decreased TG and DAG species that contain solely C16 (i.e. C51 and DAG 16-16), suggesting that preincubation with oleate diverts DAG 16-16 to TG enriched with C18. Additionally, the lipidomic analysis revealed that oleate preincubation reduced palmitate content and increased the MUFA/SFA ratio. Interestingly, preincubation with oleate also reduced palmitoleate content in palmitate-exposed cells, which might be due to decreased SCD1 gene expression. Because oleate is a product of SCD1, we hypothesized that it can induce a negative feedback on SCD1 gene expression. It has been reported that oleate preincubation led to an increase in CPT1 mRNA level in skeletal muscle cells (8Coll T. Eyre E. Rodríguez-Calvo R. Palomer X. Sánchez R.M. Merlos M. Laguna J.C. Vázquez-Carrera M. J. Biol. Chem. 2008; 283: 11107-11116Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 38Wensaas A.J. Rustan A.C. Just M. Berge R.K. Drevon C.A. Gaster M. Diabetes. 2009; 58: 527-535Crossref PubMed Scopus (57) Google Scholar). We demonstrated that oleate preincubation enhanced mitochondrial oxidation of palmitate, as a consequence of increased CPT1 gene and protein expressions. Our findings also indicate that preincubation with oleate increases mitochondrial LCFA oxidation through a second mechanism, namely activation of AMPK, which leads to ACC inhibition and, thus, to increased CPT1 activity.We investigated whether acting directly on mitochondrial oxidation, by expressing CPT1mt, leads to the same protective effect as oleate preincubation. In agreement with the work of Sebastián et al. (34Sebastián D. Herrero L. Serra D. Asins G. Hegardt F.G. Am. J. Physiol. Endocrinol. Metab. 2007; 292: E677-E686Crossref PubMed Scopus (58) Google Scholar), we showed that CPT1mt expression induced an increase in LCFA oxidation at the expense of their esterification. Like oleate preincubation, DAG and ceramide contents are reduced by CPT1mt expression. In contrast to preincubation with oleate, CPT1mt expression decreased the rate of esterification of palmitate into TG (regarding the two species raised by palmitate) and had no impact on the nature or content of FA in myotubes. These results contrast with those of Perdomo et al. (18Perdomo G. Commerford S.R. Richard A.M. Adams S.H. Corkey B.E. O'Doherty R.M. Brown N.F. J. Biol. Chem. 2004; 279: 27177-27186Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar), who reported that expression of the wild-type CPT1 did not modify TG, DAG, or ceramide contents. This difference highlights the importance of malonyl-CoA in the regulation of CPT1 activity. It has been suggested that increased mitochondrial LCFA oxidation can lead to an accumulation of ASP (39Muoio D.M. Newgard C.B. Annu. Rev. Biochem. 2006; 75: 367-401Crossref PubMed Scopus (286) Google Scholar). However, in our study, the CO2/ASP ratio for palmitate was increased, not decreased, following CPT1mt expression, both in the presence of low glucose and high glucose/insulin concentrations. This indicates that CPT1mt expression permits the maintenance of complete oxidation of palmitate, thus avoiding accumulation of incompletely oxidized molecules.It is well established that skeletal muscle insulin resistance is associated with intramuscular lipid accumulation. Inhibition of CPT1 by etomoxir, an irreversible inhibitor, increased lipid deposition in skeletal muscle and exacerbated insulin resistance in high fat-fed animals (40Dobbins R.L. Szczepaniak L.S. Bentley B. Esser V. Myhill J. McGarry J.D. Diabetes. 2001; 50: 123-130Crossref PubMed Scopus (247) Google Scholar), indicating that alteration in LCFA flux into mitochondria is critical for regulating the deleterious effect of lipids on insulin sensitivity. Furthermore, it has been recently reported that in vivo wild-type CPT1 overexpression in rat skeletal muscle enhanced mitochondrial LCFA oxidation and decreased high fat diet-induced insulin resistance (41Bruce C.R. Brolin C. Turner N. Cleasby M.E. van der Leij F.R. Cooney G.J. Kraegen E.W. Am. J. Physiol. Endocrinol. Metab. 2007; 292: E1231-E1237Crossref PubMed Scopus (56) Google Scholar, 42Bruce C.R. Hoy A.J. Turner N. Watt M.J. Allen T.L. Carpenter K. Cooney G.J. Febbraio M.A. Kraegen E.W. Diabetes. 2009; 58: 550-558Crossref PubMed Scopus (249) Google Scholar). These effects were associated with a moderate decrease in both TG level and palmitate incorporation into DAG. We hypothesize that these mild effects may be due to the expression of wild-type CPT1, which is sensitive to malonyl-CoA inhibition. Indeed, it has been shown in muscle from obese and diabetic subjects that malonyl-CoA level is increased, leading to a decrease in mitochondrial LCFA oxidation (41Bruce C.R. Brolin C. Turner N. Cleasby M.E. van der Leij F.R. Cooney G.J. Kraegen E.W. Am. J. Physiol. Endocrinol. Metab. 2007; 292: E1231-E1237Crossref PubMed Scopus (56) Google Scholar, 42Bruce C.R. Hoy A.J. Turner N. Watt M.J. Allen T.L. Carpenter K. Cooney G.J. Febbraio M.A. Kraegen E.W. Diabetes. 2009; 58: 550-558Crossref PubMed Scopus (249) Google Scholar). Here we demonstrated that targeting mitochondrial LCFA oxidation, via the expression of a malonyl-CoA-insensitive CPT1, led to the same protective effect as preincubation with oleate, providing strong evidence that redirecting palmitate metabolism toward oxidation is sufficient to protect against palmitate-induced apoptosis and insulin resistance. In conclusion, we propose that increased CPT1 activity together with decreased malonyl-CoA sensitivity may be a promising strategy for the treatment of the deleterious effects of lipid accumulation caused by obesity, insulin resistance, or aging. IntroductionIt has long been recognized that increased plasma free fatty acids are associated with insulin resistance in humans (1Schalch D.S. Kipnis D.M. J. Clin. Invest. 1965; 44: 2010-2020Crossref PubMed Scopus (123) Google Scholar). Indeed, plasma free fatty acid concentrations are increased in obese subjects (2Adams 2nd, J.M. Pratipanawatr T. Berria R. Wang E. DeFronzo R.A. Sullards M.C. Mandarino L.J. Diabetes. 2004; 53: 25-31Crossref PubMed Scopus (511) Google Scholar) as well as in genetically obese or high fat diet-induced insulin-resistant mice (3Dentin R. Benhamed F. Hainault I. Fauveau V. Foufelle F. Dyck J.R. Girard J. Postic C. Diabetes. 2006; 55: 2159-2170Crossref PubMed Scopus (315) Google Scholar, 4Bonnard C. Durand A. Peyrol S. Chanseaume E. Chauvin M.A. Morio B. Vidal H. Rieusset J. J. Clin. Invest. 2008; 118: 789-800Crossref PubMed Scopus (639) Google Scholar). In such conditions, circulating free fatty acid concentrations are elevated, and FA 4The abbreviations used are: FAfatty acid(s)ASPacid-soluble product(s)CCCPcarbonyl cyanide m-chlorophenyl hydrazoneCPT1mtmutant CPT1A M593SDAGdiacylglycerol(s)LacZβ-galactosidaseLCFAlong-chain fatty acidMUFAmonounsaturated fatty acid(s)OApreincubation with oleatePLphospholipid(s)SFAsaturated fatty acid(s)SMsphingomyelin(s)TGtriglyceride(s)G55 mm glucoseG20+I20 mm glucose plus 100 nm insulin. metabolism is altered (5McGarry J.D. Diabetes. 2002; 51: 7-18Crossref PubMed Scopus (1205) Google Scholar, 6Hulver M.W. Berggren J.R. Cortright R.N. Dudek R.W. Thompson R.P. Pories W.J. MacDonald K.G. Cline G.W. Shulman G.I. Dohm G.L. Houmard J.A. Am. J. Physiol. Endocrinol. Metab. 2003; 284: E741-E747Crossref PubMed Scopus (276) Google Scholar, 7Kelley D.E. Goodpaster B. Wing R.R. Simoneau J.A. Am. J. Physiol. 1999; 277: E1130-E1141Crossref PubMed Google Scholar), leading to ectopic accumulation of FA in the liver, pancreatic β-cells, or skeletal muscle, where they interfere with normal cell function. For instance, FA overload induces skeletal muscle insulin resistance (6Hulver M.W. Berggren J.R. Cortright R.N. Dudek R.W. Thompson R.P. Pories W.J. MacDonald K.G. Cline G.W. Shulman G.I. Dohm G.L. Houmard J.A. Am. J. Physiol. Endocrinol. Metab. 2003; 284: E741-E747Crossref PubMed Scopus (276) Google Scholar), inflammation (8Coll T. Eyre E. Rodríguez-Calvo R. Palomer X. Sánchez R.M. Merlos M. Laguna J.C. Vázquez-Carrera M. J. Biol. Chem. 2008; 283: 11107-11116Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar), and cell death via apoptosis (4Bonnard C. Durand A. Peyrol S. Chanseaume E. Chauvin M.A. Morio B. Vidal H. Rieusset J. J. Clin. Invest. 2008; 118: 789-800Crossref PubMed Scopus (639) Google Scholar, 6Hulver M.W. Berggren J.R. Cortright R.N. Dudek R.W. Thompson R.P. Pories W.J. MacDonald K.G. Cline G.W. Shulman G.I. Dohm G.L. Houmard J.A. Am. J. Physiol. Endocrinol. Metab. 2003; 284: E741-E747Crossref PubMed Scopus (276) Google Scholar), a phenomenon commonly referred as “lipotoxicity.” The toxic effects of FA are known to depend on their chain length and degree of saturation. Long-chain saturated FA (SFA), such as palmitate (C16:0) and stearate (C18:0), are the most lipotoxic. Consistently, palmitate induces apoptosis in many cell types (9Sparagna G.C. Hickson-Bick D.L. Buja L.M. McMillin J.B. Antioxid. Redox Signal. 2001; 3: 71-79Crossref PubMed Scopus (36) Google Scholar, 10Shimabukuro M. Zhou Y.T. Levi M. Unger R.H. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 2498-2502Crossref PubMed Scopus (1006) Google Scholar, 11Turpin S.M. Lancaster G.I. Darby I. Febbraio M.A. Watt M.J. Am. J. Physiol. Endocrinol. Metab. 2006; 291: E1341-E1350Crossref PubMed Scopus (133) Google Scholar, 12Paumen M.B. Ishida Y. Muramatsu M. Yamamoto M. Honjo T. J. Biol. Chem. 1997; 272: 3324-3329Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar). In muscle cells, palmitate's cytotoxic effect is mediated by increased intracellular concentrations of diacylglycerols (DAG) and ceramides (11Turpin S.M. Lancaster G.I. Darby I. Febbraio M.A. Watt M.J. Am. J. Physiol. Endocrinol. Metab. 2006; 291: E1341-E1350Crossref PubMed Scopus (133) Google Scholar). In contrast, monounsaturated FA (MUFA), such as oleate (C18:1), protect against SFA-induced toxicity (8Coll T. Eyre E. Rodríguez-Calvo R. Palomer X. Sánchez R.M. Merlos M. Laguna J.C. Vázquez-Carrera M. J. Biol. Chem. 2008; 283: 11107-11116Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 13Miller T.A. LeBrasseur N.K. Cote G.M. Trucillo M.P. Pimentel D.R. Ido Y. Ruderman N.B. Sawyer D.B. Biochem. Biophys. Res. Commun. 2005; 336: 309-315Crossref PubMed Scopus (125) Google Scholar, 14Chavez J.A. Summers S.A. Arch. Biochem. Biophys. 2003; 419: 101-109Crossref PubMed Scopus (380) Google Scholar). Whether oleate exerts such a protective effect on palmitate-induced apoptosis in skeletal muscle cells has not been reported.The mechanisms by which oleate protects cells from palmitate toxicity are not well understood. SFA, which are reported to be less efficiently incorporated into triglycerides (TG) than MUFA, lead to increased accumulation of DAG (8Coll T. Eyre E. Rodríguez-Calvo R. Palomer X. Sánchez R.M. Merlos M. Laguna J.C. Vázquez-Carrera M. J. Biol. Chem. 2008; 283: 11107-11116Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 14Chavez J.A. Summers S.A. Arch. Biochem. Biophys. 2003; 419: 101-109Crossref PubMed Scopus (380) Google Scholar, 15Montell E. Turini M. Marotta M. Roberts M. Noé V. Ciudad C.J. Macé K. Gómez-Foix A.M. Am. J. Physiol. Endocrinol. Metab. 2001; 280: E229-E237Crossref PubMed Google Scholar). Oleate has been proposed to protect cells from palmitate-induced lipotoxicity by promoting its esterification into TG, a neutral form of FA storage (8Coll T. Eyre E. Rodríguez-Calvo R. Palomer X. Sánchez R.M. Merlos M. Laguna J.C. Vázquez-Carrera M. J. Biol. Chem. 2008; 283: 11107-11116Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 15Montell E. Turini M. Marotta M. Roberts M. Noé V. Ciudad C.J. Macé K. Gómez-Foix A.M. Am. J. Physiol. Endocrinol. Metab. 2001; 280: E229-E237Crossref PubMed Google Scholar, 16Listenberger L.L. Han X. Lewis S.E. Cases S. Farese Jr., R.V. Ory D.S. Schaffer J.E. Proc. Natl." @default.
• W2073168934 created "2016-06-24" @default.
• W2073168934 creator A5002222771 @default.
• W2073168934 creator A5004962893 @default.
• W2073168934 creator A5025030787 @default.
• W2073168934 creator A5037872466 @default.
• W2073168934 creator A5060418288 @default.
• W2073168934 creator A5072931338 @default.
• W2073168934 creator A5073345959 @default.
• W2073168934 creator A5081395403 @default.
• W2073168934 date "2010-11-01" @default.
• W2073168934 modified "2023-10-14" @default.
• W2073168934 title "Increased Mitochondrial Fatty Acid Oxidation Is Sufficient to Protect Skeletal Muscle Cells from Palmitate-induced Apoptosis" @default.
• W2073168934 cites W1963801361 @default.
• W2073168934 cites W1965718896 @default.
• W2073168934 cites W1970468997 @default.
• W2073168934 cites W1973186908 @default.
• W2073168934 cites W1982991739 @default.
• W2073168934 cites W1986654080 @default.
• W2073168934 cites W1995588427 @default.
• W2073168934 cites W1996248962 @default.
• W2073168934 cites W2020468088 @default.
• W2073168934 cites W2030901818 @default.
• W2073168934 cites W2031846075 @default.
• W2073168934 cites W2041836907 @default.
• W2073168934 cites W2043102772 @default.
• W2073168934 cites W2044131015 @default.
• W2073168934 cites W2055980308 @default.
• W2073168934 cites W2062365107 @default.
• W2073168934 cites W2076128586 @default.
• W2073168934 cites W2081922897 @default.
• W2073168934 cites W2088262190 @default.
• W2073168934 cites W2096217291 @default.
• W2073168934 cites W2099385136 @default.
• W2073168934 cites W2105244824 @default.
• W2073168934 cites W2106693109 @default.
• W2073168934 cites W2110135879 @default.
• W2073168934 cites W2110542127 @default.
• W2073168934 cites W2115693997 @default.
• W2073168934 cites W2133290655 @default.
• W2073168934 cites W2144007812 @default.
• W2073168934 cites W2149416112 @default.
• W2073168934 cites W2150090192 @default.
• W2073168934 cites W2154768987 @default.
• W2073168934 cites W2160524748 @default.
• W2073168934 cites W2160870282 @default.
• W2073168934 cites W2162794208 @default.
• W2073168934 cites W2171699473 @default.
• W2073168934 cites W2171977696 @default.
• W2073168934 cites W2172039605 @default.
• W2073168934 cites W2218250951 @default.
• W2073168934 cites W2300552860 @default.
• W2073168934 cites W2430143578 @default.
• W2073168934 cites W2613483351 @default.
• W2073168934 doi "https://doi.org/10.1074/jbc.m110.170431" @default.
• W2073168934 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2978610" @default.
• W2073168934 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20837491" @default.
• W2073168934 hasPublicationYear "2010" @default.
• W2073168934 type Work @default.
• W2073168934 sameAs 2073168934 @default.
• W2073168934 citedByCount "137" @default.
• W2073168934 countsByYear W20731689342012 @default.
• W2073168934 countsByYear W20731689342013 @default.
• W2073168934 countsByYear W20731689342014 @default.
• W2073168934 countsByYear W20731689342015 @default.
• W2073168934 countsByYear W20731689342016 @default.
• W2073168934 countsByYear W20731689342017 @default.
• W2073168934 countsByYear W20731689342018 @default.
• W2073168934 countsByYear W20731689342019 @default.
• W2073168934 countsByYear W20731689342020 @default.
• W2073168934 countsByYear W20731689342021 @default.
• W2073168934 countsByYear W20731689342022 @default.
• W2073168934 countsByYear W20731689342023 @default.
• W2073168934 crossrefType "journal-article" @default.
• W2073168934 hasAuthorship W2073168934A5002222771 @default.
• W2073168934 hasAuthorship W2073168934A5004962893 @default.
• W2073168934 hasAuthorship W2073168934A5025030787 @default.
• W2073168934 hasAuthorship W2073168934A5037872466 @default.
• W2073168934 hasAuthorship W2073168934A5060418288 @default.
• W2073168934 hasAuthorship W2073168934A5072931338 @default.
• W2073168934 hasAuthorship W2073168934A5073345959 @default.
• W2073168934 hasAuthorship W2073168934A5081395403 @default.
• W2073168934 hasBestOaLocation W20731689341 @default.
• W2073168934 hasConcept C134018914 @default.
• W2073168934 hasConcept C185592680 @default.
• W2073168934 hasConcept C190283241 @default.
• W2073168934 hasConcept C2779959927 @default.
• W2073168934 hasConcept C28859421 @default.
• W2073168934 hasConcept C543025807 @default.
• W2073168934 hasConcept C55493867 @default.
• W2073168934 hasConcept C82714985 @default.
• W2073168934 hasConcept C86803240 @default.
• W2073168934 hasConcept C95444343 @default.
• W2073168934 hasConceptScore W2073168934C134018914 @default.
• W2073168934 hasConceptScore W2073168934C185592680 @default.
• W2073168934 hasConceptScore W2073168934C190283241 @default.
• W2073168934 hasConceptScore W2073168934C2779959927 @default.
• W2073168934 hasConceptScore W2073168934C28859421 @default.

• next