Until recently, intracellular triacylglycerols (TAG) stored in the form of cytoplasmic lipid droplets have been considered to be only passive "energy conserves". Nevertheless, degradation of TAG gives rise to a pleiotropic spectrum of bioactive intermediates, which may function as potent co-factors of transcription factors or enzymes and contribute to the regulation of numerous cellular processes. From this point of view, the process of lipolysis not only provides energy-rich equivalents but also acquires a new regulatory function. In this review, we will concentrate on the role that fatty acids liberated from intracellular TAG stores play as signaling molecules. The first part provides an overview of the transcription factors, which are regulated by fatty acids derived from intracellular stores. The second part is devoted to the role of fatty acid signaling in different organs/tissues. The specific contribution of free fatty acids released by particular lipases, hormone-sensitive lipase, adipose triacylglycerol lipase and lysosomal lipase will also be discussed.

Centre for Experimental Medicine Department of Metabolism and Diabetes Institute for Clinical and Experimental Medicine Prague 140 21 Czech Republic

See more in PubMed

Aoun M., Feillet-Coudray C., Fouret G., Chabi B., Crouzier D., Ferreri C., Chatgilialoglu C., Wrutniak-Cabello C., Cristol J.P., Carbonneau M.A., et al. Rat liver mitochondrial membrane characteristics and mitochondrial functions are more profoundly altered by dietary lipid quantity than by dietary lipid quality: Effect of different nutritional lipid patterns. Br. J. Nutr. 2012;107:647–659. doi: 10.1017/S000711451100331X. PubMed DOI

Body D.R. The lipid composition of adipose tissue. Prog. Lipid Res. 1988;27:39–60. doi: 10.1016/0163-7827(88)90004-5. PubMed DOI

Field C.J., Clandinin M.T. Modulation of adipose tissue fat composition by diet: A review. Nutr. Res. 1984;4:743–755. doi: 10.1016/S0271-5317(84)80050-0. DOI

Vessby B., Gustafsson I.B., Tengblad S., Boberg M., Andersson A. Desaturation and elongation of fatty acids and insulin action. Ann. N. Y. Acad. Sci. 2002;967:183–189. doi: 10.1111/j.1749-6632.2002.tb04275.x. PubMed DOI

Jump D.B. The biochemistry of n-3 polyunsaturated fatty acids. J. Biol. Chem. 2002;277:8755–8758. doi: 10.1074/jbc.R100062200. PubMed DOI

Ma D.W., Seo J., Davidson L.A., Callaway E.S., Fan Y.Y., Lupton J.R., Chapkin R.S. n-3 PUFA alter caveolae lipid composition and resident protein localization in mouse colon. FASEB J. 2004;18:1040–1042. doi: 10.1096/fj.03-0732com. PubMed DOI

Jump D.B., Tripathy S., Depner C.M. Fatty acid-regulated transcription factors in the liver. Annu. Rev. Nutr. 2013;33:249–269. doi: 10.1146/annurev-nutr-071812-161139. PubMed DOI PMC

Ma D.W., Seo J., Switzer K.C., Fan Y.Y., McMurray D.N., Lupton J.R., Chapkin R.S. n-3 PUFA and membrane microdomains: A new frontier in bioactive lipid research. J. Nutr. Biochem. 2004;15:700–706. doi: 10.1016/j.jnutbio.2004.08.002. PubMed DOI

Adkins Y., Kelley D.S. Mechanisms underlying the cardioprotective effects of omega-3 polyunsaturated fatty acids. J. Nutr. Biochem. 2010;21:781–792. doi: 10.1016/j.jnutbio.2009.12.004. PubMed DOI

Bagga D., Wang L., Farias-Eisner R., Glaspy J.A., Reddy S.T. Differential effects of prostaglandin derived from omega-6 and omega-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc. Natl. Acad. Sci. USA. 2003;100:1751–1756. doi: 10.1073/pnas.0334211100. PubMed DOI PMC

Novak T.E., Babcock T.A., Jho D.H., Helton W.S., Espat N.J. NF-κB inhibition by omega-3 fatty acids modulates LPS-stimulated macrophage TNF-α transcription. Am. J. Physiol. Lung Cell. Mol. Physiol. 2003;284:L84–L89. PubMed

Malhi H., Gores G.J. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin. Liver Dis. 2008;28:360–369. doi: 10.1055/s-0028-1091980. PubMed DOI PMC

Legrand-Poels S., Esser N., L’homme L., Scheen A., Paquot N., Piette J. Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes. Biochem. Pharmacol. 2014;92:131–141. doi: 10.1016/j.bcp.2014.08.013. PubMed DOI

Jackson Kim G., Jackson K.G., Maitin V., Leake D.S., Yaqoob P., Williams Ch.M. Saturated fat-induced changes in Sf 60–400 particle composition reduces uptake of LDL by HepG2 cells. J. Lipid Res. 2006;47:393–403. doi: 10.1194/jlr.M500382-JLR200. PubMed DOI

Lin J., Yang R., Tarr P.T., Wu P.H., Handschin C., Li S., Yang W., Pei L., Uldry M., Tontonoz P., et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1b coactivation of SREBP. Cell. 2005;120:261–273. doi: 10.1016/j.cell.2004.11.043. PubMed DOI

Jump D.B., Botolin D., Wang Y., Xu J., Christian B., Demeure O. Fatty acid regulation of hepatic gene transcription. J. Nutr. 2005;135:2503–2506. PubMed

Furuhashi M., Hotamisligil G.S. Fatty acid-binding proteins: Role in metabolic diseases and potential as drug targets. Nat. Rev. Drug Discov. 2008;7:489–503. doi: 10.1038/nrd2589. PubMed DOI PMC

Kersten S., Desvergne B., Wahli W. Roles of PPARs in health and disease. Nature. 2000;405:421–424. doi: 10.1038/35013000. PubMed DOI

Mangelsdorf D.J., Thummel C., Beato M., Herrlich P., Schutz G., Umesono K., Blumberg B., Kastner P., Mark M., Chambon P., et al. The nuclear receptor superfamily: The second decade. Cell. 1995;83:835–839. doi: 10.1016/0092-8674(95)90199-X. PubMed DOI PMC

Forman B.M., Tontonoz P., Chen J., Brun R.P., Spiegelman B.M., Evans R.M. 15-Deoxy-Δ12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ. Cell. 1995;83:803–812. doi: 10.1016/0092-8674(95)90193-0. PubMed DOI

Schmitz G., Ecker J. The opposing effects of n-3 and n-6 fatty acids. Prog. Lipid Res. 2008;47:147–55. doi: 10.1016/j.plipres.2007.12.004. PubMed DOI

Nakamura M.T., Yudell B.E., Loor J.J. Regulation of energy metabolism by long-chain fatty acids. Prog. Lipid Res. 2014;53:124–144. doi: 10.1016/j.plipres.2013.12.001. PubMed DOI

Rakhshandehroo M., Knoch B., Muller M., Kersten S. Peroxisome proliferator-activated receptor α target genes. Cell. Mol. Life Sci. 2004;61:393–416. doi: 10.1007/s00018-003-3216-3. PubMed DOI PMC

Kersten S., Seydoux J., Peters J.M., Gonzalez F.J., Desvergne B., Wahli W. Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting. J. Clin. Investig. 1999;103:1489–1498. doi: 10.1172/JCI6223. PubMed DOI PMC

Luquet S., Lopez-Soriano J., Holst D., Fredenrich A., Melki J., Rassoulzadegan M., Grimaldi P.A. Peroxisome proliferator-activated receptor δ controls muscle development and oxidative capability. FASEB J. 2003;17:2299–2301. PubMed

Kannisto K., Chibalin A., Glinghammar B., Zierath J.R., Hamsten A., Ehrenborg E. Differential expression of peroxisomal proliferator activated receptors α and δ in skeletal muscle in response to changes in diet and exercise. Int. J. Mol. Med. 2006;17:45–52. PubMed

Pilegaard H., Osada T., Andersen L.T., Helge J.W., Saltin B., Neufer P.D. Substrate availability and transcriptional regulation of metabolic genes in human skeletal muscle during recovery from exercise. Metabolism. 2005;54:1048–1055. doi: 10.1016/j.metabol.2005.03.008. PubMed DOI

Motojima K., Passilly P., Peters J.M., Gonzalez F.J., Latruffe N. Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor α and γ activators in a tissue- and inducer-specific manner. J. Biol. Chem. 1998;273:16710–16714. doi: 10.1074/jbc.273.27.16710. PubMed DOI

Tontonoz P., Hu E., Spiegelman B.M. Stimulation of adipogenesis in fibroblasts by PPAR γ2, a lipid-activated transcription factor. Cell. 1994;79:1147–1156. doi: 10.1016/0092-8674(94)90006-X. PubMed DOI

Dalen K.T., Schoonjans K., Ulven S.M., Weedon-Fekjaer M.S., Bentzen T.G., Koutnikova H., Auwerx J., Nebb H.I. Adipose tissue expression of the lipid droplet-associating proteins S3–12 and perilipin is controlled by peroxisome proliferator-activated receptor-γ. Diabetes. 2004;53:1243–1252. doi: 10.2337/diabetes.53.5.1243. PubMed DOI

Sears D.D., Hsiao A., Ofrecio J.M., Chapman J., He W., Olefsky J.M. Selective modulation of promoter recruitment and transcriptional activity of PPARγ. Biochem. Biophys. Res. Commun. 2007;364:515–521. doi: 10.1016/j.bbrc.2007.10.057. PubMed DOI PMC

Devine J.H., Eubank D.W., Clouthier D.E., Tontonoz P., Spiegelman B.M., Hammer R.E., Beale E.G. Adipose expression of the phosphoenolpyruvate carboxykinase promoter requires peroxisome proliferator-activated receptor γ and 9-cis-retinoic acid receptor binding to an adipocyte-specific enhancer in vivo. J. Biol. Chem. 1999;274:13604–13612. doi: 10.1074/jbc.274.19.13604. PubMed DOI

Guan Y. Targeting peroxisome proliferator-activated receptors (PPARs) in kidney and urologic disease. Minerva Urol. Nefrol. 2002;54:65–79. PubMed

Grey S.L., Nora E.D., Vidal-Puig A.J. Mouse model of PPAR-γ deficiency: Dissecting PPAR-γ’s role in metabolic homeostasis. Biochem. Soc. Trans. 2005;33:1053–1058. doi: 10.1042/BST20051053. PubMed DOI

Matsusue K., Haluzik M., Lambert G., Yim S.H., Gavrilova O., Ward J.M., Brewer B., Jr., Reitman M.L., Gonzalez F.J. Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J. Clin. Investig. 2003;111:737–747. doi: 10.1172/JCI200317223. PubMed DOI PMC

Gavrilova O., Haluzik M., Matsusue K., Cutson J.J., Johnson L., Dietz K.R., Nicol C.J., Vinson C., Gonzalez F.J., Reitman M.L. Liver peroxisome proliferator-activated receptor γ contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J. Biol. Chem. 2003;278:34268–34276. doi: 10.1074/jbc.M300043200. PubMed DOI

Akiyama T.E., Sakai S., Lambert G., Nicol C.J., Matsusue K., Pimprale S., Lee Y.H., Ricote M., Glass C.K., Brewer H.B., Jr., et al. Conditional disruption of the peroxisome proliferator-activated receptor γ gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux. Mol. Cell. Biol. 2002;22:2607–2619. doi: 10.1128/MCB.22.8.2607-2619.2002. PubMed DOI PMC

Rosen E.D., Kulkarni R.N., Sarraf P., Ozcan U., Okada T., Hsu C.H., Eisenman D., Magnuson M.A., Gonzalez F.J., Kahn C.R., et al. Targeted elimination of peroxisome proliferator-activated receptor γ in β cells leads to abnormalities in islet mass without compromising glucose homeostasis. Mol. Cell. Biol. 2003;23:7222–7229. doi: 10.1128/MCB.23.20.7222-7229.2003. PubMed DOI PMC

Horton J.D., Goldstein J.L., Brown M.S. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Investig. 2002;109:1125–1131. doi: 10.1172/JCI0215593. PubMed DOI PMC

Clarke S.D., Gasperikova D., Nelson C., Lapillonne A., Heird W.C. Fatty acid regulation of gene expression: A genomic explanation for the benefits of the mediterranean diet. Ann. N. Y. Acad. Sci. 2002;967:283–298. doi: 10.1111/j.1749-6632.2002.tb04284.x. PubMed DOI

Bennett M.K., Toth J.I., Osborne T.F. Selective association of sterol regulatory element-binding protein isoforms with target promoters in vivo. J. Biol. Chem. 2004;279:37360–37367. doi: 10.1074/jbc.M404693200. PubMed DOI

Hirano Y., Yoshida M., Shimizu M., Sato R. Direct demonstration of rapid degradation of nuclear sterol regulatory element-binding proteins by the ubiquitin-proteasome pathway. J. Biol. Chem. 2001;276:36431–36437. doi: 10.1074/jbc.M105200200. PubMed DOI

Xu J., Nakamura M.T., Cho H.P., Clarke S.D. Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J. Biol. Chem. 1999;274:23577–23583. PubMed

Worgall T.S., Sturley S.L., Seo T., Osborne T.F., Deckelbaum R.J. Polyunsaturated fatty acids decrease expression of promoters with sterol regulatory elements by decreasing levels of mature sterol regulatory element-binding protein. J. Biol. Chem. 1998;273:25537–25540. doi: 10.1074/jbc.273.40.25537. PubMed DOI

Xu J., Teran-Garcia M., Park J.H., Nakamura M.T., Clarke S.D. Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay. J. Biol. Chem. 2001;276:9800–9807. doi: 10.1074/jbc.M008973200. PubMed DOI

Botolin D., Wang Y., Christian B., Jump D.B. Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways. J. Lipid Res. 2006;47:181–192. doi: 10.1194/jlr.M500365-JLR200. PubMed DOI PMC

Yoshikawa T., Shimano H., Yahagi N., Ide T., Amemiya-Kudo M., Matsuzaka T., Nakakuki M., Tomita S., Okazaki H., Tamura Y., et al. Polyunsaturated fatty acids suppress sterol regulatory element-binding protein 1c promoter activity by inhibition of liver X receptor (LXR) binding to LXR response elements. J. Biol. Chem. 2002;277:1705–1711. doi: 10.1074/jbc.M105711200. PubMed DOI

Repa J.J., Liang G., Ou J., Bashmakov Y., Lobaccaro J.M., Shimomura I., Shan B., Brown M.S., Goldstein J.L., Mangelsdorf D.J. Regulation of mouse sterol regulatory element binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev. 2000;14:2819–2830. doi: 10.1101/gad.844900. PubMed DOI PMC

Ou J.F., Tu H., Shan B., Luk A., DeBose-Boyd R.A., Bashmakov Y., Goldstein J.L., Brown M.S. Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c) gene by antagonizing ligand-dependent activation of the LXR. Proc. Natl. Acad. Sci. USA. 2001;98:6027–6032. doi: 10.1073/pnas.111138698. PubMed DOI PMC

Anderson E.J., Thayne K., Harris M., Carraway K., Shaikh S.R. Aldehyde stress and up-regulation of Nrf2-mediated antioxidant systems accompany functional adaptations in cardiac mitochondria from mice fed N-3 polyunsaturated fatty acids. Biochem. J. 2012;441:359–366. doi: 10.1042/BJ20110626. PubMed DOI PMC

Tang W., Jiang Y.F., Ponnusamy M., Diallo M. Role of Nrf2 in chronic liver disease. World J. Gastroenterol. 2014;20:13079–13087. doi: 10.3748/wjg.v20.i36.13079. PubMed DOI PMC

Georgiadi A., Kersten S. Mechanism of gene regulation by fatty acids. Adv. Nutr. 2012;3:127–134. doi: 10.3945/an.111.001602. PubMed DOI PMC

Fan M., Wang X., Xu G., Yan Q., Huang W. Bile acid signaling and liver regeneration. Biochim. Biophys. Acta. 2015;1849:196–200. doi: 10.1016/j.bbagrm.2014.05.021. PubMed DOI PMC

Li Y., Jadhav K., Zhang Y. Bile acid receptors in non-alcoholic fatty liver disease. Biochem. Pharmacol. 2013;86:1517–1524. doi: 10.1016/j.bcp.2013.08.015. PubMed DOI PMC

Zhao A., Yu J., Lew J.L., Huang L., Wright S.D., Cui J. Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets. DNA Cell Biol. 2004;23:519–526. doi: 10.1089/1044549041562267. PubMed DOI

Chmurzyńska A. The multigene family of fatty acid-binding proteins (FABPs): Function, structure and polymorphism. J. Appl. Genet. 2006;47:39–48. doi: 10.1007/BF03194597. PubMed DOI

Hanhoff T., Lücke C., Spener F. Insights into binding of fatty acids by fatty acid binding proteins. Mol. Cell. Biochem. 2002;239:45–54. doi: 10.1023/A:1020502624234. PubMed DOI

Xu L.Z., Sánchez R., Sali A., Heintz N. Ligand specificity of brain lipid-binding protein. J. Biol. Chem. 1996;271:24711–24719. doi: 10.1074/jbc.271.40.24711. PubMed DOI

Wolfrum C., Borrmann C.M., Borchers T., Spener F. Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors α—And γ-mediated gene expression via liver fatty acid binding protein: A signaling path to the nucleus. Proc. Natl. Acad. Sci. USA. 2001;98:2323–2328. doi: 10.1073/pnas.051619898. PubMed DOI PMC

Tan N.S., Shaw N.S., Vinckenbosch N., Liu P., Yasmin R., Desvergne B., Wahli W., Noy N. Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription. Mol. Cell. Biol. 2002;22:5114–5127. doi: 10.1128/MCB.22.14.5114-5127.2002. PubMed DOI PMC

Khan S.H., Sorof S. Liver fatty acid-binding protein: Specific mediator of the mitogenesis induced by two classes of carcinogenic peroxisome proliferators. Proc. Natl. Acad. Sci. USA. 1994;91:848–852. doi: 10.1073/pnas.91.3.848. PubMed DOI PMC

Boneva N.B., Kikuchi M., Minabe Y., Yamashima T. Neuroprotective and ameliorative actions of polyunsaturated fatty acids against neuronal diseases: Implication of fatty acid-binding proteins (FABP) and G protein-coupled receptor 40 (GPR40) in adult neurogenesis. J. Pharmacol. Sci. 2011;116:163–172. doi: 10.1254/jphs.10R34FM. PubMed DOI

Raclot T., Groscolas R. Differential mobilization of white adipose tissue fatty acids according to chain length, unsaturation, and positional isomerism. J. Lipid Res. 1993;34:1515–1526. PubMed

Raclot T., Oudart H. Selectivity of fatty acids on lipid metabolism and gene expression. Proc. Nutr. Soc. 1999;58:633–646. doi: 10.1017/S002966519900083X. PubMed DOI

Pinent M., Hackl H., Burkard T.R., Prokesch A., Papak C., Scheideler M., Hämmerle G., Zechner R., Trajanoski Z., Strauss J.G. Differential transcriptional modulation of biological processes in adipocyte triglyceride lipase and hormone-sensitive lipase-deficient mice. Genomics. 2008;92:26–32. doi: 10.1016/j.ygeno.2008.03.010. PubMed DOI

Haemmerle G., Zimmermann R., Strauss J.G., Kratky D., Riederer M., Knipping G., Zechner R. Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle. J. Biol. Chem. 2002;277:12946–12952. doi: 10.1074/jbc.M108640200. PubMed DOI

Osuga J., Ishibashi S., Oka T., Yagyu H., Tozawa R., Fujimoto A., Shionoiri F., Yahagi N., Kraemer F.B., Tsutsumi O., et al. Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. Proc. Natl. Acad. Sci. USA. 2000;97:787–792. doi: 10.1073/pnas.97.2.787. PubMed DOI PMC

Harada K., Shen W.J., Patel S., Natu V., Wang J., Osuga J., Ishibashi S., Kraemer F.B. Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice. Am. J. Physiol. Endocrinol. Metab. 2003;285:E1182–E1195. PubMed

Wang S.P., Laurin N., Himms-Hagen J., Rudnicki M.A., Levy E., Robert M.F., Pan L., Oligny L., Mitchell G.A. The adipose tissue phenotype of hormone-sensitive lipase deficiency in mice. Obes. Res. 2001;9:119–128. doi: 10.1038/oby.2001.15. PubMed DOI

Roduit R., Masiello P., Wang S.P., Li H., Mitchell G.A., Prentki M. A role for hormone-sensitive lipase in glucose-stimulated insulin secretion: A study in hormone-sensitive lipase-deficient mice. Diabetes. 2001;50:1970–1975. doi: 10.2337/diabetes.50.9.1970. PubMed DOI

Du H., Heur M., Duanmu M., Grabowski G.A., Hui D.Y., Witte D.P., Mishra J. Lysosomal acid lipase-deficient mice: Depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span. J. Lipid Res. 2001;42:489–500. PubMed

Finn P.F., Dice J.F. Proteolytic and lipolytic responses to starvation. Nutrition. 2006;22:830–844. doi: 10.1016/j.nut.2006.04.008. PubMed DOI

Singh R., Kaushik S., Wang Y., Xiang Y., Novak I., Komatsu M., Tanaka K., Cuervo A.M., Czaja M.J. Autophagy regulates lipid metabolism. Nature. 2009;458:1131–1135. doi: 10.1038/nature07976. PubMed DOI PMC

Dolinsky V.W., Gilham D., Alam M., Vance D.E., Lehner R. Triacylglycerol hydrolase: Role in intracellular lipid metabolism. Cell. Mol. Life Sci. 2004;61:1633–1651. doi: 10.1007/s00018-004-3426-3. PubMed DOI PMC

Wei E., Ben Ali Y., Lyon J., Wang H., Nelson R., Dolinsky V.W., Dyck J.R., Mitchell G., Korbutt G.S., Lehner R. Loss of TGH/Ces3 in mice decreases blood lipids, improves glucose tolerance, and increases energy expenditure. Cell Metab. 2010;11:183–193. doi: 10.1016/j.cmet.2010.02.005. PubMed DOI

Lian J., Wei E., Wang S.P., Quiroga A.D., Li L., di Pardo A., van der Veen J., Sipione S., Mitchell G.A., Lehner R. Liver specific inactivation of carboxylesterase 3/triacylglycerol hydrolase decreases blood lipids without causing severe steatosis in mice. Hepatology. 2012;56:2154–2162. doi: 10.1002/hep.25881. PubMed DOI

Wang H., Wei E., Quiroga A.D., Sun X., Touret N., Lehner R. Altered lipid droplet dynamics in hepatocytes lacking triacylglycerol hydrolase expression. Mol. Biol. Cell. 2010;21:1991–2000. doi: 10.1091/mbc.E09-05-0364. PubMed DOI PMC

Yeaman S.J. Hormone-sensitive lipase—New roles for an old enzyme. Biochem. J. 2004;379:11–22. doi: 10.1042/BJ20031811. PubMed DOI PMC

Tansey J.T., Sztalryd C., Hlavin E.M., Kimmel A.R., Londos C. The central role of perilipin a in lipid metabolism and adipocyte lipolysis. IUBMB Life. 2004;56:379–385. doi: 10.1080/15216540400009968. PubMed DOI

Londos C., Brasaemle D.L., Schultz C.J., Segrest J.P., Kimmel A.R. Perilipins, ADRP, and other proteins that associate with intracellular neutral lipid droplets in animal cells. Semin. Cell Dev. Biol. 1999;10:51–58. doi: 10.1006/scdb.1998.0275. PubMed DOI

Su C.L., Sztalryd C., Contreras J.A., Holm C., Kimmel A.R., Londos C. Mutational analysis of the hormone-sensitive lipase translocation reaction in adipocytes. J. Biol. Chem. 2003;278:43615–43619. doi: 10.1074/jbc.M301809200. PubMed DOI

Sztalryd C., Xu G., Dorward H., Tansey J.T., Contreras J.A., Kimmel A.R., Londos C. Perilipin A is essential for the translocation of hormone-sensitive lipase during lipolytic activation. J. Cell Biol. 2003;161:1093–1103. doi: 10.1083/jcb.200210169. PubMed DOI PMC

Sengenes C., Bouloumie A., Hauner H., Berlan M., Busse R., Lafontan M., Galitzky J. Involvement of a cGMP-dependent pathway in the natriuretic peptidemediated hormone-sensitive lipase phosphorylation in human adipocytes. J. Biol. Chem. 2003;278:48617–48626. doi: 10.1074/jbc.M303713200. PubMed DOI

Lampidonis A.D., Rogdakis E., Voutsinas G.E., Stravopodis D.J. The resurgence of Hormone-Sensitive Lipase (HSL) in mammalian lipolysis. Gene. 2011;477:1–11. doi: 10.1016/j.gene.2011.01.007. PubMed DOI

Daval M., Diot-Dupuy F., Bazin R., Hainault I., Viollet B., Vaulont S., Hajduch E., Ferré P., Foufelle F. Antilipolytic action of AMP-activated protein kinase in rodent adipocytes. J. Biol. Chem. 2005;280:25250–25257. doi: 10.1074/jbc.M414222200. PubMed DOI

Castro-Chavez F., Yechoor V.K., Saha P.K., Martinez-Botas J., Wooten E.C., Sharma S., O’Connell P., Taegtmeyer H., Chan L. Coordinated upregulation of oxidative pathways and downregulation of lipid biosynthesis underlie obesity resistance in perilipin knockout mice: A microarray gene expression profile. Diabetes. 2003;52:2666–2674. doi: 10.2337/diabetes.52.11.2666. PubMed DOI

Schweiger M., Schreiber R., Haemmerle G., Lass A., Fledelius C., Jacobsen P., Tornqvist H., Zechner R., Zimmermann R. Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J. Biol. Chem. 2006;281:40236–40241. doi: 10.1074/jbc.M608048200. PubMed DOI

Zimmermann R., Strauss J.G., Haemmerle G., Schoiswohl G., Birner-Gruenberger R., Riederer M., Lass A., Neuberger G., Eisenhaber F., Hermetter A. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004;306:1383–1386. doi: 10.1126/science.1100747. PubMed DOI

Zechner R., Kienesberger P.C., Haemmerle G., Zimmermann R., Lass A. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. J. Lipid Res. 2009;50:3–21. doi: 10.1194/jlr.R800031-JLR200. PubMed DOI

Subramanian V., Rothenberg A., Gomez C., Cohen A.W., Garcia A., Bhattacharyya S., Shapiro L., Dolios G., Wang R., Lisanti M.P. Perilipin A mediates the reversible binding of CGI-58 to lipid droplets in 3T3-L1 adipocytes. J. Biol. Chem. 2004;279:42062–42071. doi: 10.1074/jbc.M407462200. PubMed DOI

Brasaemle D.L., Barber T., Wolins N.E., Serrero G., Blanchette-Mackie E.J., Londos C. Adipose differentiation-related protein is an ubiquitously expressed lipid storage droplet-associated protein. J. Lipid Res. 1997;38:2249–2263. PubMed

Listenberger L.L., Ostermeyer-Fay A.G., Goldberg E.B., Brown W.J., Brown D.A. Adipocyte differentiation-related protein reduces the lipid droplet association of adipose triglyceride lipase and slows triacylglycerol turnover. J. Lipid Res. 2007;48:2751–2761. doi: 10.1194/jlr.M700359-JLR200. PubMed DOI

Yang X., Lu X., Lombes M., Rha G.B., Chi Y.I., Guerin T.M., Smart E.J., Liu J. The G0/G1 switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab. 2010;11:194–205. doi: 10.1016/j.cmet.2010.02.003. PubMed DOI PMC

Lu X., Yang X., Liu J. Differential control of ATGL-mediated lipid droplet degradation by CGI-58 and G0S2. Cell Cycle. 2010;9:2719–2725. PubMed PMC

Storey S.M., McIntosh A.L., Senthivinayagam S., Moon K.C., Atshaves B.P. The phospholipid monolayer associated with perilipin-enriched lipid droplets is a highly organized rigid membrane structure. Am. J. Physiol. Endocrinol. Metab. 2011;301:E991–E1003. doi: 10.1152/ajpendo.00109.2011. PubMed DOI PMC

Mehrpour M., Esclatine A., Beau I., Codogno P. Autophagy in health and disease. 1. Regulation and significance of autophagy: An overview. Am. J. Physiol. Cell Physiol. 2010;298:C776–C785. doi: 10.1152/ajpcell.00507.2009. PubMed DOI

Mizushima N., Levine B. Autophagy in mammalian development and differentiation. Nat. Cell Biol. 2010;12:823–830. doi: 10.1038/ncb0910-823. PubMed DOI PMC

Ohsaki Y., Cheng J., Suzuki M., Shinohara Y., Fujita A., Fujimoto T. Biogenesis of cytoplasmic lipid droplets: From the lipid ester globule in the membrane to the visible structure. BBA. 2009;1791:399–407. PubMed

Papáčková Z., Cahová M. Important role of autophagy in regulation of metabolic processes in health, disease and aging. Physiol. Res. 2014;63:409–420. PubMed

Cohen D.E. New players on the metabolic stage: How do you like Them Acots? Adipocyte. 2013;2:3–6. doi: 10.4161/adip.21853. PubMed DOI PMC

Kirkby B., Roman N., Kobe B., Kellie S., Forwood J.K. Functional and structural properties of mammalian acyl-coenzyme A thioesterases. Prog. Lipid Res. 2010;49:366–377. doi: 10.1016/j.plipres.2010.04.001. PubMed DOI

Hunt M.C., Alexson S.E. The role Acyl-CoA thioesterases play in mediating intracellular lipid metabolism. Prog. Lipid Res. 2002;41:99–130. doi: 10.1016/S0163-7827(01)00017-0. PubMed DOI

Zhang Y., Li Y., Niepel M.W., Kawano Y., Han S., Liu S., Marsili A., Larsen P.R., Lee C.H., Cohen D.E. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance. Proc. Natl. Acad. Sci. USA. 2012;109:5417–5422. doi: 10.1073/pnas.1116011109. PubMed DOI PMC

Kang H.W., Niepel M.W., Han S., Kawano Y., Cohen D.E. Thioesterase superfamily member 2/acyl-CoA thioesterase 13 (Them2/Acot13) regulates hepatic lipid and glucose metabolism. FASEB J. 2012;26:2209–2221. doi: 10.1096/fj.11-202853. PubMed DOI PMC

Maira S.M., Galetic I., Brazil D.P., Kaech S., Ingley E., Thelen M. Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science. 2001;294:374–380. doi: 10.1126/science.1062030. PubMed DOI

Parcellier A., Tintignac L.A., Zhuravleva E., Cron P., Schenk S., Bozulic L. Carboxy-Terminal Modulator Protein (CTMP) is a mitochondrial protein that sensitizes cells to apoptosis. Cell. Signal. 2009;21:639–650. doi: 10.1016/j.cellsig.2009.01.016. PubMed DOI

Zhao H., Martin B.M., Bisoffi M., Dunaway-Mariano D. The Akt C-terminal modulator protein is an acyl-CoA thioesterase of the Hotdog-Fold family. Biochemistry. 2009;48:5507–5509. doi: 10.1021/bi900710w. PubMed DOI PMC

Zhuravleva E., Gut H., Hynx D., Marcellin D., Bleck C.K., Genoud C. Acyl coenzyme a thioesterase them5/ acot15 is involved in cardiolipin remodeling and fatty liver development. Mol. Cell. Biol. 2012;32:2685–2697. doi: 10.1128/MCB.00312-12. PubMed DOI PMC

Clarke S.D. The multi-dimensional regulation of gene expression by fatty acids: Polyunsaturated fats as nutrient sensors. Curr. Opin. Lipidol. 2004;15:13–18. doi: 10.1097/00041433-200402000-00004. PubMed DOI

Chakravarthy M.V., Pan Z., Zhu Y., Tordjman K., Schneider J.G., Coleman T., Turk J., Semenkovich C.F. New hepatic fat activates PPARα to maintain glucose, lipid, and cholesterol homeostasis. Cell. Metab. 2005;1:309–322. doi: 10.1016/j.cmet.2005.04.002. PubMed DOI

Ong K.T., Mashek M.T., Bu S.Y., Greenberg A.S., Mashek D.G. Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning. Hepatology. 2011;53:116–126. doi: 10.1002/hep.24006. PubMed DOI PMC

Jha P., Claudel T., Baghdasaryan A., Mueller M., Halilbasic E., Das S.K., Lass A., Zimmermann R., Zechner R., Hoefler G., et al. Role of adipose triglyceride lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia. Hepatology. 2014;59:858–869. doi: 10.1002/hep.26732. PubMed DOI

Amri E.Z., Ailhaud G., Grimaldi P. Regulation of adipose cell differentiation. II. Kinetics of induction of the aP2 gene by fatty acids and modulation by dexamethasone. J. Lipid Res. 1991;32:1457–14563. PubMed

Duplus E., Glorian M., Forest C. Transcription fatty acid regulation of gene. J. Biol. Chem. 2000;275:30749–30752. doi: 10.1074/jbc.R000015200. PubMed DOI

Amri E.Z., Bertrand B., Ailhaud G., Grimaldi P. Regulation of adipose cell differentiation. I. Fatty acids are inducers of the aP2 gene expression. J. Lipid Res. 1991;32:1449–1456. PubMed

Forest C., Franckhauser S., Glorian M., Antras-Ferry J., Robin D., Robin P. Regulation of gene transcription by fatty acids, fibrates and prostaglandins: The phosphoenolpyruvate carboxykinase gene as a model. Prostaglandins Leukot. Essent. Fatty Acids. 1997;57:47–56. doi: 10.1016/S0952-3278(97)90492-0. PubMed DOI

Flachs P., Rühl R., Hensler M., Janovska P., Zouhar P., Kus V., Macek Jilkova Z., Papp E., Kuda O., Svobodova M., et al. Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and N-3 fatty acids. Diabetologia. 2011;54:2626–2638. doi: 10.1007/s00125-011-2233-2. PubMed DOI

Sessler A.M., Kaur N., Palta J.P., Ntambi J.M. Regulation of stearoyl-CoA desaturase 1 mRNA stability by polyunsaturated fatty acids in 3T3-L1 adipocytes. J. Biol. Chem. 1996;271:29854–29858. doi: 10.1074/jbc.271.47.29854. PubMed DOI

Ahmadian M., Abbott M.J., Tang T., Hudak C.S., Kim Y., Bruss M., Hellerstein M.K., Lee H.Y., Samuel V.T., Shulman G.I., et al. Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab. 2011;13:739–748. doi: 10.1016/j.cmet.2011.05.002. PubMed DOI PMC

Mottillo E.P., Bloch A.E., Leff T., Granneman J.G. Lipolytic products activate peroxisome proliferator-activated receptor (PPAR) α and δ in brown adipocytes to match fatty acid oxidation with supply. J. Biol. Chem. 2012;287:25038–25048. doi: 10.1074/jbc.M112.374041. PubMed DOI PMC

Mottillo E.P., Granneman J.G. Intracellular fatty acids suppress β-adrenergic induction of PKA-targeted gene expression in white adipocytes. Am. J. Physiol. Endocrinol. Metab. 2011;301:E122–E131. doi: 10.1152/ajpendo.00039.2011. PubMed DOI PMC

Mottillo E.P., Shen X.J., Granneman J.G. Role of hormone-sensitive lipase in β-adrenergic remodeling of white adipose tissue. Am. J. Physiol. Endocrinol. Metab. 2007;293:E1188–E1197. doi: 10.1152/ajpendo.00051.2007. PubMed DOI

Haemmerle G., Moustafa T., Woelkart G., Büttner S., Schmidt A., van de Weijer T., Hesselink M., Jaeger D., Kienesberger P.C., Zierler K., et al. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1. Nat. Med. 2011;17:1076–1085. doi: 10.1038/nm.2439. PubMed DOI PMC

Kienesberger P.C., Pulinilkunnil T., Nagendran J., Dyck J.R. Myocardial triacylglycerol metabolism. J. Mol. Cell. Cardiol. 2013;55:101–110. doi: 10.1016/j.yjmcc.2012.06.018. PubMed DOI

Ueno M., Suzuki J., Zenimaru Y., Takahashi S., Koizumi T., Noriki S., Yamaguchi O., Otsu K., Shen W.J., Kraemer F.B., et al. Cardiac overexpression of hormone-sensitive lipase inhibits myocardial steatosis and fibrosis in streptozotocin diabetic mice. Am. J. Physiol. Endocrinol. Metab. 2008;294:E1109–E1118. doi: 10.1152/ajpendo.00016.2008. PubMed DOI

Suzuki J., Shen W.J., Nelson B.D., Patel S., Veerkamp J.H., Selwood S.P., Murphy G.M., Reaven E., Kraemer F.B. Absence of cardiac lipid accumulation in transgenic mice with heart-specific HSL overexpression. Am. J. Physiol. Endocrinol. Metab. 2001;281:E857–E866. PubMed

Chandak P.G., Radovic B., Aflaki E., Kolb D., Buchebner M., Fröhlich E., Magnes C., Sinner F., Haemmerle G., Zechner R., et al. Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase. J. Biol. Chem. 2010;285:20192–20201. doi: 10.1074/jbc.M110.107854. PubMed DOI PMC

Lammers B., Chandak P.G., Aflaki E., van Puijvelde G.H., Radovic B., Hildebrand R.B., Meurs I., Out R., Kuiper J., van Berkel T.J., et al. Macrophage adipose triglyceride lipase deficiency attenuates atherosclerotic lesion development in low-density lipoprotein receptor knockout mice. Arterioscler. Thromb. Vasc. Biol. 2011;31:67–73. doi: 10.1161/ATVBAHA.110.215814. PubMed DOI PMC

Aflaki E., Radovic B., Chandak P.G., Kolb D., Eisenberg T., Ring J., Fertschai I., Uellen A., Wolinski H., Kohlwein S.D., et al. Triacylglycerol accumulation activates the mitochondrial apoptosis pathway in macrophages. J. Biol. Chem. 2011;286:7418–7428. doi: 10.1074/jbc.M110.175703. PubMed DOI PMC

Varela L.M., Ortega-Gomez A., Lopez S., Abia R., Muriana J.G., Bermudez B. The effects of dietary fatty acids on the postprandial triglyceride-rich lipoprotein/apoB48 receptor axis in human monocyte/macrophage cells. J. Nutr. Biochem. 2013;24:2031–2039. doi: 10.1016/j.jnutbio.2013.07.004. PubMed DOI

Xu H.E., Lambert M.H., Montana V.G., Parks D.J., Blanchard S.G., Brown P.J. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell. 1999;3:397–403. doi: 10.1016/S1097-2765(00)80467-0. PubMed DOI

Lin Y., Chiba S., Suzuki A., Yamaguchi S., Nakanishi T., Matsumoto H., Ikeda Y., Ishibashi-Ueda H., Hirano K., Kato S. Vascular smooth muscle cells isolated from adipose triglyceride lipase-deficient mice exhibit distinct phenotype and phenotypic plasticity. Biochem. Biophys. Res. Commun. 2013;434:534–540. doi: 10.1016/j.bbrc.2013.03.109. PubMed DOI

Inoue T., Kobayashi K., Inoguchi T., Sonoda N., Fujii M., Maeda Y., Fujimura Y., Miura D., Hirano K., Takayanagi R. Reduced expression of adipose triglyceride lipase enhances tumor necrosis factor α-induced intercellular adhesion molecule-1 expression in human aortic endothelial cells via protein kinase C-dependent activation of nuclear factor-κB. J. Biol. Chem. 2011;286:32045–32053. doi: 10.1074/jbc.M111.285650. PubMed DOI PMC

Kaushik S., Rodriguez-Navarro J.A., Arias E., Kiffin R., Sahu S., Schwartz G.J., Cuervo A.M., Singh R. Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab. 2011;14:173–183. doi: 10.1016/j.cmet.2011.06.008. PubMed DOI PMC