Lipid Metabolism in Macrophages: Focus on Atherosclerosis
Abstract
:1. Introduction
2. LDL Uptake: Role of Receptors
3. Intracellular Lipid Trafficking and Storage
4. Lipid Biosynthesis
5. Cholesterol Efflux
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Poznyak, A.V.; Wu, W.-K.; Melnichenko, A.A.; Wetzker, R.; Sukhorukov, V.; Markin, A.M.; Khotina, V.A.; Orekhov, A.N. Signaling pathways and key genes involved in regulation of foam cell formation in atherosclerosis. Cells 2020, 9, 584. [Google Scholar] [CrossRef] [Green Version]
- Chistiakov, D.A.; Melnichenko, A.A.; Myasoedova, V.A.; Grechko, A.V.; Orekhov, A.N. Mechanisms of foam cell formation in atherosclerosis. J. Mol. Med. 2017, 95, 1153–1165. [Google Scholar] [CrossRef]
- Bories, G.F.P.; Leitinger, N. Macrophage metabolism in atherosclerosis. FEBS Lett. 2017, 591, 3042–3060. [Google Scholar] [CrossRef] [Green Version]
- Miller, Y.I.; Choi, S.-H.; Fang, L.; Tsimikas, S. Lipoprotein modification and macrophage uptake: Role of pathologic cholesterol transport in atherogenesis. In Cholesterol Binding and Cholesterol Transport Proteins; Springer: Dordrecht, The Netherlands, 2010; pp. 229–251. [Google Scholar]
- PrabhuDas, M.R.; Baldwin, C.L.; Bollyky, P.L.; Bowdish, D.M.E.; Drickamer, K.; Febbraio, M.; Herz, J.; Kobzik, L.; Krieger, M.; Loike, J.; et al. A consensus definitive classification of scavenger receptors and their roles in health and disease. J. Immunol. 2017, 198, 3775–3789. [Google Scholar] [CrossRef] [Green Version]
- Zanoni, P.; Velagapudi, S.; Yalcinkaya, M.; Rohrer, L.; von Eckardstein, A. Endocytosis of lipoproteins. Atherosclerosis 2018, 275, 273–295. [Google Scholar] [CrossRef]
- Deng, S.; Alabi, A.; Gu, H.; Adijiang, A.; Qin, S.; Zhang, D. Identification of amino acid residues in the ligand binding repeats of LDL receptor important for PCSK9 binding. J. Lipid Res. 2019, 60, 516–527. [Google Scholar] [CrossRef] [Green Version]
- Baranowski, M. Biological role of liver X receptors. J. Physiol. Pharmacol. 2008, 59, 31–55. [Google Scholar] [PubMed]
- Rong, S.; Cortés, V.A.; Rashid, S.; Anderson, N.N.; McDonald, J.G.; Liang, G.; Moon, Y.-A.; Hammer, R.E.; Horton, J.D. Expression of SREBP-1c requires SREBP-2-mediated generation of a sterol ligand for LXR in livers of mice. Elife 2017, 6. [Google Scholar] [CrossRef] [PubMed]
- Kruth, H.S.; Huang, W.; Ishii, I.; Zhang, W.Y. Macrophage foam cell formation with native low density lipoprotein. J. Biol. Chem. 2002, 277, 34573–34580. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kruth, H. Fluid-phase pinocytosis of LDL by macrophages: A novel target to reduce macrophage cholesterol accumulation in atherosclerotic lesions. Curr. Pharm. Des. 2013, 19, 5865–5872. [Google Scholar] [CrossRef] [PubMed]
- Benitez-Amaro, A.; Pallara, C.; Nasarre, L.; Rivas-Urbina, A.; Benitez, S.; Vea, A.; Bornachea, O.; de Gonzalo-Calvo, D.; Serra-Mir, G.; Villegas, S.; et al. Molecular basis for the protective effects of low-density lipoprotein receptor-related protein 1 (LRP1)-derived peptides against LDL aggregation. Biochim. Biophys. Acta Biomembr. 2019, 1861, 1302–1316. [Google Scholar] [CrossRef] [PubMed]
- Orekhov, A.N.; Nikiforov, N.G.; Sukhorukov, V.N.; Kubekina, M.V.; Sobenin, I.A.; Wu, W.-K.; Foxx, K.K.; Pintus, S.; Stegmaier, P.; Stelmashenko, D.; et al. Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis. Int. J. Mol. Sci. 2020, 21, 817. [Google Scholar] [CrossRef] [Green Version]
- Singh, R.K.; Haka, A.S.; Asmal, A.; Barbosa-Lorenzi, V.C.; Grosheva, I.; Chin, H.F.; Xiong, Y.; Hla, T.; Maxfield, F.R. TLR4 (toll-like receptor 4)-dependent signaling drives extracellular catabolism of LDL (low-density lipoprotein) aggregates. Arterioscler. Thromb. Vasc. Biol. 2020, 40, 86–102. [Google Scholar] [CrossRef] [PubMed]
- Kelley, J.L.; Ozment, T.R.; Li, C.; Schweitzer, J.B.; Williams, D.L. Scavenger receptor-A (CD204): A two-edged sword in health and disease. Crit. Rev. Immunol. 2014, 34, 241–261. [Google Scholar] [CrossRef] [PubMed]
- Hiltunen, T.P.; Gough, P.J.; Greaves, D.R.; Gordon, S.; Ylä-Herttuala, S. Rabbit atherosclerotic lesions express scavenger receptor AIII mRNA, a naturally occurring splice variant that encodes a non-functional, dominant negative form of the macrophage scavenger receptor. Atherosclerosis 2001, 154, 415–419. [Google Scholar] [CrossRef]
- Nigorikawa, K.; Matsumura, T.; Sakamoto, H.; Morioka, S.; Kofuji, S.; Takasuga, S.; Hazeki, K. Sac1 phosphoinositide phosphatase regulates foam cell formation by modulating SR-A expression in macrophages. Biol. Pharm. Bull. 2019, 42, 923–928. [Google Scholar] [CrossRef]
- Hashizume, M.; Mihara, M. Atherogenic effects of TNF-α and IL-6 via up-regulation of scavenger receptors. Cytokine 2012, 58, 424–430. [Google Scholar] [CrossRef] [PubMed]
- Liu, Z.; Zhu, H.; Dai, X.; Wang, C.; Ding, Y.; Song, P.; Zou, M.H. Macrophage liver kinase B1 inhibits foam cell formation and atherosclerosis. Circ. Res. 2017, 121, 1047–1057. [Google Scholar] [CrossRef]
- Bharadwaj, K.G.; Hiyama, Y.; Hu, Y.; Huggins, L.A.; Ramakrishnan, R.; Abumrad, N.A.; Shulman, G.I.; Blaner, W.S.; Goldberg, I.J. Chylomicron- and VLDL-derived lipids enter the heart through different pathways: In vivo evidence for receptor- and non-receptor-mediated fatty acid uptake. J. Biol. Chem. 2010, 285, 37976–37986. [Google Scholar] [CrossRef] [Green Version]
- Zhao, L.; Varghese, Z.; Moorhead, J.F.; Chen, Y.; Ruan, X.Z. CD36 and lipid metabolism in the evolution of atherosclerosis. Br. Med. Bull. 2018, 126, 101–112. [Google Scholar] [CrossRef] [Green Version]
- Padarti, A.; Zhang, J. Recent advances in cerebral cavernous malformation research. Vessel Plus 2018, 2, 21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Park, Y.M. CD36, a scavenger receptor implicated in atherosclerosis. Exp. Mol. Med. 2014, 46, e99. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Luo, Y.; Duan, H.; Qian, Y.; Feng, L.; Wu, Z.; Wang, F.; Feng, J.; Yang, D.; Qin, Z.; Yan, X. Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis. Cell Res. 2017, 27, 352–372. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ding, Z.; Pothineni, N.V.K.; Goel, A.; Lüscher, T.F.; Mehta, J.L. PCSK9 and inflammation: Role of shear stress, pro-inflammatory cytokines and LOX-1 4. Cardiovasc. Res. 2019. [Google Scholar] [CrossRef]
- Ding, Z.; Liu, S.; Wang, X.; Theus, S.; Deng, X.; Fan, Y.; Zhou, S.; Mehta, J.L. PCSK9 regulates expression of scavenger receptors and ox-LDL uptake in macrophages. Cardiovasc. Res. 2018, 114, 1145–1153. [Google Scholar] [CrossRef]
- Ramprasad, M.P.; Terpstra, V.; Kondratenko, N.; Quehenberger, O.; Steinberg, D. Cell surface expression of mouse macrosialin and human CD68 and their role as macrophage receptors for oxidized low density lipoprotein. Proc. Natl. Acad. Sci. USA 1996, 93, 14833–14838. [Google Scholar] [CrossRef] [Green Version]
- Plüddemann, A.; Neyen, C.; Gordon, S. Macrophage scavenger receptors and host-derived ligands. Methods 2007, 43, 207–217. [Google Scholar] [CrossRef]
- Ramirez-Ortiz, Z.G.; Pendergraft, W.F.; Prasad, A.; Byrne, M.H.; Iram, T.; Blanchette, C.J.; Luster, A.D.; Hacohen, N.; El Khoury, J.; Means, T.K. The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity. Nat. Immunol. 2013, 14, 917–926. [Google Scholar] [CrossRef] [Green Version]
- Shimaoka, T.; Kume, N.; Minami, M.; Hayashida, K.; Kataoka, H.; Kita, T.; Yonehara, S. Molecular cloning of a novel scavenger receptor for oxidized low density lipoprotein, SR-PSOX, on macrophages. J. Biol. Chem. 2000, 275, 40663–40666. [Google Scholar] [CrossRef] [Green Version]
- Yan, Y.; Song, D.; Wu, J.; Wang, J. Long non-coding RNAs link oxidized low-density Lipoprotein with the inflammatory response of macrophages in atherogenesis. Front. Immunol. 2020, 11. [Google Scholar] [CrossRef] [Green Version]
- Simonetti, B.; Cullen, P.J. Endosomal sorting: Architecture of the retromer coat. Curr. Biol. 2018, 28, R1350–R1352. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Perera, R.M.; Zoncu, R. The lysosome as a regulatory hub. Annu. Rev. Cell Dev. Biol. 2016, 32, 223–253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, H. Lysosomal acid lipase and lipid metabolism. Curr. Opin. Lipidol. 2018, 29, 218–223. [Google Scholar] [CrossRef] [PubMed]
- Schlager, S.; Vujic, N.; Korbelius, M.; Duta-Mare, M.; Dorow, J.; Leopold, C.; Rainer, S.; Wegscheider, M.; Reicher, H.; Ceglarek, U.; et al. Lysosomal lipid hydrolysis provides substrates for lipid mediator synthesis in murine macrophages. Oncotarget 2017, 8. [Google Scholar] [CrossRef] [Green Version]
- Emanuel, R.; Sergin, I.; Bhattacharya, S.; Turner, J.N.; Epelman, S.; Settembre, C.; Diwan, A.; Ballabio, A.; Razani, B. Induction of lysosomal biogenesis in atherosclerotic macrophages can rescue lipid-induced lysosomal dysfunction and downstream sequelae. Arter. Thromb. Vasc. Biol. 2014, 34, 1942–1952. [Google Scholar] [CrossRef] [Green Version]
- Kim, K.; Shim, D.; Lee, J.S.; Zaitsev, K.; Williams, J.W.; Kim, K.-W.; Jang, M.-Y.; Seok Jang, H.; Yun, T.J.; Lee, S.H.; et al. Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models. Circ. Res. 2018, 123, 1127–1142. [Google Scholar] [CrossRef]
- Li, F.; Zhang, H. Lysosomal acid lipase in lipid metabolism and beyond. Arter. Thromb. Vasc. Biol. 2019, 39, 850–856. [Google Scholar] [CrossRef]
- Martínez, M.S.; García, A.; Luzardo, E.; Chávez-Castillo, M.; Olivar, L.C.; Salazar, J.; Velasco, M.; Quintero, J.J.R.; Bermúdez, V. Energetic metabolism in cardiomyocytes: Molecular basis of heart ischemia and arrhythmogenesis. Vessel Plus 2017, 1. [Google Scholar] [CrossRef]
- Xu, Y.; Zhang, Q.; Tan, L.; Xie, X.; Zhao, Y. The characteristics and biological significance of NPC2: Mutation and disease. Mutat. Res. Mutat. Res. 2019, 782, 108284. [Google Scholar] [CrossRef]
- Li, J.; Pfeffer, S.R. Lysosomal membrane glycoproteins bind cholesterol and contribute to lysosomal cholesterol export. Elife 2016, 5. [Google Scholar] [CrossRef]
- Gruenberg, J. Life in the lumen: The multivesicular endosome. Traffic 2020, 21, 76–93. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thelen, A.M.; Zoncu, R. Emerging Roles for the Lysosome in Lipid Metabolism. Trends Cell Biol. 2017, 27, 833–850. [Google Scholar] [CrossRef] [PubMed]
- Charman, M.; Kennedy, B.E.; Osborne, N.; Karten, B. MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein. J. Lipid Res. 2010, 51, 1023–1034. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saffi, G.T.; Botelho, R.J. Lysosome Fission: Planning for an Exit. Trends Cell Biol. 2019, 29, 635–646. [Google Scholar] [CrossRef]
- Di Mattia, T.; Tomasetto, C.; Alpy, F. Faraway, so close! Functions of endoplasmic reticulum—Endosome contacts. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2020, 1865, 158490. [Google Scholar] [CrossRef]
- Litvinov, D.Y.; Savushkin, E.V.; Dergunov, A.D. Intracellular and plasma membrane events in cholesterol transport and homeostasis. J. Lipids 2018, 2018, 1–22. [Google Scholar] [CrossRef] [Green Version]
- Calvo, M.J.; Martínez, M.S.; Torres, W.; Chávez-Castillo, M.; Luzardo, E.; Villasmil, N.; Salazar, J.; Velasco, M.; Bermúdez, V. Omega-3 polyunsaturated fatty acids and cardiovascular health: A molecular view into structure and function. Vessel Plus 2017. [Google Scholar] [CrossRef] [Green Version]
- Phillips, M.J.; Voeltz, G.K. Structure and function of ER membrane contact sites with other organelles. Nat. Rev. Mol. Cell Biol. 2016, 17, 69–82. [Google Scholar] [CrossRef] [Green Version]
- Reinisch, K.M.; De Camilli, P. SMP-domain proteins at membrane contact sites: Structure and function. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2016, 1861, 924–927. [Google Scholar] [CrossRef] [Green Version]
- Alpy, F.; Tomasetto, C. START ships lipids across interorganelle space. Biochimie 2014, 96, 85–95. [Google Scholar] [CrossRef]
- Röhrl, C.; Stangl, H. Cholesterol metabolism—Physiological regulation and pathophysiological deregulation by the endoplasmic reticulum. Wiener Medizinische Wochenschrift 2018, 168, 280–285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fu, S.; Watkins, S.M.; Hotamisligil, G.S. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab. 2012, 15, 623–634. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Goldstein, J.L.; DeBose-Boyd, R.A.; Brown, M.S. Protein sensors for membrane sterols. Cell 2006, 124, 35–46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Widenmaier, S.B.; Snyder, N.A.; Nguyen, T.B.; Arduini, A.; Lee, G.Y.; Arruda, A.P.; Saksi, J.; Bartelt, A.; Hotamisligil, G.S. NRF1 is an ER membrane sensor that is central to cholesterol homeostasis. Cell 2017, 171, 1094–1109. [Google Scholar] [CrossRef]
- Ron, D.; Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 2007, 8, 519–529. [Google Scholar] [CrossRef]
- Volmer, R.; van der Ploeg, K.; Ron, D. Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc. Natl. Acad. Sci. USA 2013, 110, 4628–4633. [Google Scholar] [CrossRef] [Green Version]
- Tabas, I.; Seimon, T.; Timmins, J.; Li, G.; Lim, W. Macrophage Apoptosis in Advanced Atherosclerosis. Ann. N. Y. Acad. Sci. 2009, 1173, E40–E45. [Google Scholar] [CrossRef] [Green Version]
- Guo, C.; Ma, R.; Liu, X.; Chen, T.; Li, Y.; Yu, Y.; Duan, J.; Zhou, X.; Li, Y.; Sun, Z. Silica nanoparticles promote oxLDL-induced macrophage lipid accumulation and apoptosis via endoplasmic reticulum stress signaling. Sci. Total Environ. 2018, 631–632, 570–579. [Google Scholar] [CrossRef]
- Li, Y.; Ge, M.; Ciani, L.; Kuriakose, G.; Westover, E.J.; Dura, M.; Covey, D.F.; Freed, J.H.; Maxfield, F.R.; Lytton, J.; et al. Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids: Implications for depletion of endoplasmic reticulum calcium stores and apoptos. J. Biol. Chem. 2004, 279, 37030–37039. [Google Scholar] [CrossRef] [Green Version]
- Zhang, K.; Kaufman, R.J. Unfolding the toxicity of cholesterol. Nat. Cell Biol. 2003, 5, 769–770. [Google Scholar] [CrossRef]
- Suzuki, M.; Ohsaki, Y.; Tatematsu, T.; Shinohara, Y.; Maeda, T.; Cheng, J.; Fujimoto, T. Translation inhibitors induce formation of cholesterol ester-rich lipid droplets. PLoS ONE 2012, 7, e42379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yu, X.H.; Fu, Y.C.; Zhang, D.W.; Yin, K.; Tang, C.K. Foam cells in atherosclerosis. Clin. Chim. Acta 2013, 424, 245–252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Namgaladze, D.; Brüne, B. Macrophage fatty acid oxidation and its roles in macrophage polarization and fatty acid-induced inflammation. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2016, 1861, 1796–1807. [Google Scholar] [CrossRef] [PubMed]
- Harris, C.A.; Haas, J.T.; Streeper, R.S.; Stone, S.J.; Kumari, M.; Yang, K.; Han, X.; Brownell, N.; Gross, R.W.; Zechner, R.; et al. DGAT enzymes are required for triacylglycerol synthesis and lipid droplets in adipocytes. J. Lipid Res. 2011, 52, 657–667. [Google Scholar] [CrossRef] [Green Version]
- Schoiswohl, G.; Schweiger, M.; Schreiber, R.; Gorkiewicz, G.; Preiss-Landl, K.; Taschler, U.; Zierler, K.A.; Radner, F.P.W.; Eichmann, T.O.; Kienesberger, P.C.; et al. Adipose triglyceride lipase plays a key role in the supply of the working muscle with fatty acids. J. Lipid Res. 2010, 51, 490–499. [Google Scholar] [CrossRef] [Green Version]
- Foster, D.W. The role of the carnitine system in human metabolism. Ann. N. Y. Acad. Sci. 2004, 1033, 1–16. [Google Scholar] [CrossRef]
- Qu, Q.; Zeng, F.; Liu, X.; Wang, Q.J.; Deng, F. Fatty acid oxidation and carnitine palmitoyltransferase I: Emerging therapeutic targets in cancer. Cell Death Dis. 2016, 7, e2226. [Google Scholar] [CrossRef]
- Olzmann, J.A.; Carvalho, P. Dynamics and functions of lipid droplets. Nat. Rev. Mol. Cell Biol. 2019, 20, 137–155. [Google Scholar] [CrossRef]
- Jarc, E.; Petan, T. Lipid droplets and the management of cellular stress. Yale J. Biol. Med. 2019, 92, 435–452. [Google Scholar]
- Kadereit, B.; Kumar, P.; Wang, W.J.; Miranda, D.; Snapp, E.L.; Severina, N.; Torregroza, I.; Evans, T.; Silver, D.L. Evolutionarily conserved gene family important for fat storage. Proc. Natl. Acad. Sci. USA 2008, 105, 94–99. [Google Scholar] [CrossRef] [Green Version]
- Szymanski, K.M.; Binns, D.; Bartz, R.; Grishin, N.V.; Li, W.P.; Agarwal, A.K.; Garg, A.; Anderson, R.G.W.; Goodman, J.M. The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc. Natl. Acad. Sci. USA 2007, 104, 20890–20895. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sztalryd, C.; Brasaemle, D.L. The perilipin family of lipid droplet proteins: Gatekeepers of intracellular lipolysis. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2017, 1862, 1221–1232. [Google Scholar] [CrossRef] [PubMed]
- Wilfling, F.; Wang, H.; Haas, J.T.; Krahmer, N.; Gould, T.J.; Uchida, A.; Cheng, J.X.; Graham, M.; Christiano, R.; Fröhlich, F.; et al. Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev. Cell 2013, 24, 384–399. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Krahmer, N.; Guo, Y.; Wilfling, F.; Hilger, M.; Lingrell, S.; Heger, K.; Newman, H.W.; Schmidt-Supprian, M.; Vance, D.E.; Mann, M.; et al. Phosphatidylcholine synthesis for lipid droplet expansion is mediated by localized activation of CTP:Phosphocholine cytidylyltransferase. Cell Metab. 2011, 14, 504–515. [Google Scholar] [CrossRef] [Green Version]
- Petkevicius, K.; Virtue, S.; Bidault, G.; Jenkins, B.; Çubuk, C.; Morgantini, C.; Aouadi, M.; Dopazo, J.; Serlie, M.J.; Koulman, A.; et al. Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity. Elife 2019, 8. [Google Scholar] [CrossRef]
- Wilfling, F.; Thiam, A.R.; Olarte, M.J.; Wang, J.; Beck, R.; Gould, T.J.; Allgeyer, E.S.; Pincet, F.; Bewersdorf, J.; Farese, R.V.; et al. Arf1/COPI machinery acts directly on lipid droplets and enables their connection to the ER for protein targeting. Elife 2014, 2014. [Google Scholar] [CrossRef]
- Moldavski, O.; Amen, T.; Levin-Zaidman, S.; Eisenstein, M.; Rogachev, I.; Brandis, A.; Kaganovich, D.; Schuldiner, M. Lipid droplets are essential for efficient clearance of cytosolic inclusion bodies. Dev. Cell 2015, 33, 603–610. [Google Scholar] [CrossRef] [Green Version]
- Valm, A.M.; Cohen, S.; Legant, W.R.; Melunis, J.; Hershberg, U.; Wait, E.; Cohen, A.R.; Davidson, M.W.; Betzig, E.; Lippincott-Schwartz, J. Applying systems-level spectral imaging and analysis to reveal the organelle interactome. Nature 2017, 546, 162–167. [Google Scholar] [CrossRef]
- Prinz, W.A. Bridging the gap: Membrane contact sites in signaling, metabolism, and organelle dynamics. J. Cell Biol. 2014, 205, 759–769. [Google Scholar] [CrossRef] [Green Version]
- Dirkx, R.; Vanhorebeek, I.; Martens, K.; Schad, A.; Grabenbauer, M.; Fahimi, D.; Declercq, P.; Van Veldhoven, P.P.; Baes, M. Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities. Hepatology 2005, 41, 868–878. [Google Scholar] [CrossRef]
- Stolz, A.; Ernst, A.; Dikic, I. Cargo recognition and trafficking in selective autophagy. Nat. Cell Biol. 2014, 16, 495–501. [Google Scholar] [CrossRef] [PubMed]
- Sakai, K.; Nagashima, S.; Wakabayashi, T.; Tumenbayar, B.; Hayakawa, H.; Hayakawa, M.; Karasawa, T.; Ohashi, K.; Yamazaki, H.; Takei, A.; et al. Myeloid HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase determines atherosclerosis by modulating migration of macrophages. Arter. Thromb. Vasc. Biol. 2018, 38, 2590–2600. [Google Scholar] [CrossRef] [PubMed]
- Batista-Gonzalez, A.; Vidal, R.; Criollo, A.; Carreño, L.J. New insights on the role of lipid metabolism in the metabolic reprogramming of macrophages. Front. Immunol. 2020, 10. [Google Scholar] [CrossRef] [PubMed]
- Shao, W.; Espenshade, P.J. Sterol regulatory element-binding protein (SREBP) cleavage regulates golgi-to-endoplasmic reticulum recycling of SREBP cleavage-activating protein (SCAP). J. Biol. Chem. 2014, 289, 7547–7557. [Google Scholar] [CrossRef] [Green Version]
- Kastaniotis, A.J.; Autio, K.J.; Kerätär, J.M.; Monteuuis, G.; Mäkelä, A.M.; Nair, R.R.; Pietikäinen, L.P.; Shvetsova, A.; Chen, Z.; Hiltunen, J.K. Mitochondrial fatty acid synthesis, fatty acids and mitochondrial physiology. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2017, 1862, 39–48. [Google Scholar] [CrossRef]
- Clarke, S.D.; Nakamura, M.T. Fatty Acid Structure and Synthesis. In Encyclopedia of Biological Chemistry; Elsevier: Amsterdam, The Netherlands, 2013; pp. 285–289. [Google Scholar]
- Orekhov, A.N.; Nikiforov, N.N.; Ivanova, E.A.; Sobenin, I.A. Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis. J. Clin. Med. 2020, 9, 978. [Google Scholar] [CrossRef] [Green Version]
- Volobueva, A.; Grechko, A.; Yet, S.F.; Sobenin, I.; Orekhov, A. Changes in mitochondrial genome associated with predisposition to atherosclerosis and related disease. Biomolecules 2019, 9, 377. [Google Scholar] [CrossRef] [Green Version]
- Orekhov, A.N.; Zhelankin, A.V.; Kolmychkova, K.I.; Mitrofanov, K.; Kubekina, M.V.; Ivanova, E.A.; Sobenin, I.A. Susceptibility of monocytes to activation correlates with atherogenic mitochondrial DNA mutations. Exp. Mol. Pathol. 2015, 99, 672–676. [Google Scholar] [CrossRef]
- Ghosh, S. Early steps in reverse cholesterol transport: Cholesteryl ester hydrolase and other hydrolases. Curr. Opin. Endocrinol. Diabetes Obes. 2012, 19, 136–141. [Google Scholar] [CrossRef]
- Zhao, B.; Song, J.; Chow, W.N.; St. Clair, R.W.; Rudel, L.L.; Ghosh, S. Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr-/- mice. J. Clin. Investig. 2007, 117, 2983–2992. [Google Scholar] [CrossRef] [Green Version]
- Sakai, K.; Igarashi, M.; Yamamuro, D.; Ohshiro, T.; Nagashima, S.; Takahashi, M.; Enkhtuvshin, B.; Sekiya, M.; Okazaki, H.; Osuga, J.I.; et al. Critical role of neutral cholesteryl ester hydrolase 1 in cholesteryl ester hydrolysis in murine macrophages. J. Lipid Res. 2014, 55, 2033–2040. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Phillips, M.C. Molecular mechanisms of cellular cholesterol efflux. J. Biol. Chem. 2014, 289, 24020–24029. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ouimet, M.; Barrett, T.J.; Fisher, E.A. HDL and reverse cholesterol transport: Basic mechanisms and their roles in vascular health and disease. Circ. Res. 2019, 124, 1505–1518. [Google Scholar] [CrossRef] [PubMed]
- Shen, W.-J.; Azhar, S.; Kraemer, F.B. SR-B1: A unique multifunctional receptor for cholesterol influx and efflux. Annu. Rev. Physiol. 2018, 80, 95–116. [Google Scholar] [CrossRef] [PubMed]
- Remmerie, A.; Scott, C.L. Macrophages and lipid metabolism. Cell. Immunol. 2018, 330, 27–42. [Google Scholar] [CrossRef] [PubMed]
- Ren, K.; Li, H.; Zhou, H.; Liang, Y.; Tong, M.; Chen, L.; Zheng, X.; Zhao, G. Mangiferin promotes macrophage cholesterol efflux and protects against atherosclerosis by augmenting the expression of ABCA1 and ABCG1. Aging 2019, 11, 10992–11009. [Google Scholar] [CrossRef]
- Watanabe, T.; Kioka, N.; Ueda, K.; Matsuo, M. Phosphorylation by protein kinase C stabilizes ABCG1 and increases cholesterol efflux. J. Biochem. 2019. [Google Scholar] [CrossRef]
- Adorni, M.P.; Cipollari, E.; Favari, E.; Zanotti, I.; Zimetti, F.; Corsini, A.; Ricci, C.; Bernini, F.; Ferri, N. Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages. Atherosclerosis 2017, 256, 1–6. [Google Scholar] [CrossRef]
- Sun, Y.; Zhang, D.; Liu, X.; Li, X.; Liu, F.; Yu, Y.; Jia, S.; Zhou, Y.; Zhao, Y. Endoplasmic reticulum stress affects lipid metabolism in atherosclerosis via CHOP activation and over-expression of miR-33. Cell. Physiol. Biochem. 2018, 48, 1995–2010. [Google Scholar] [CrossRef]
- Martinet, W.; Coornaert, I.; Puylaert, P.; De Meyer, G.R.Y. Macrophage death as a pharmacological target in atherosclerosis. Front. Pharmacol. 2019, 10, 306. [Google Scholar] [CrossRef]
- Kansanen, E.; Kuosmanen, S.M.; Leinonen, H.; Levonen, A.-L. The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biol. 2013, 1, 45–49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Linton, M.F.; Tao, H.; Linton, E.F.; Yancey, P.G. SR-BI: A multifunctional receptor in cholesterol homeostasis and atherosclerosis. Trends Endocrinol. Metab. 2017, 28, 461–472. [Google Scholar] [CrossRef] [PubMed]
- Galle-Treger, L.; Moreau, M.; Ballaire, R.; Poupel, L.; Huby, T.; Sasso, E.; Troise, F.; Poti, F.; Lesnik, P.; Le Goff, W.; et al. Targeted invalidation of SR-B1 in macrophages reduces macrophage apoptosis and accelerates atherosclerosis. Cardiovasc. Res. 2020, 116, 554–565. [Google Scholar] [CrossRef] [PubMed]
- Ma, X.; Li, S.F.; Qin, Z.S.; Ye, J.; Zhao, Z.L.; Fang, H.H.; Yao, Z.W.; Gu, M.N.; Hu, Y.W. Propofol up-regulates expression of ABCA1, ABCG1, and SR-B1 through the PPARγ/LXRα signaling pathway in THP-1 macrophage-derived foam cells. Cardiovasc. Pathol. 2015, 24, 230–235. [Google Scholar] [CrossRef]
- Tang, S.L.; Chen, W.J.; Yin, K.; Zhao, G.J.; Mo, Z.C.; Lv, Y.C.; Ouyang, X.P.; Yu, X.H.; Kuang, H.J.; Jiang, Z.S.; et al. PAPP-A negatively regulates ABCA1, ABCG1 and SR-B1 expression by inhibiting LXRα through the IGF-I-mediated signaling pathway. Atherosclerosis 2012, 222, 344–354. [Google Scholar] [CrossRef]
- Li, Y.; Shen, S.; Ding, S.; Wang, L. Toll-like receptor 2 downregulates the cholesterol effluxby activating the nuclear factor-κB pathway in macrophagesand may be a potential therapeutic target for the prevention of atherosclerosis. Exp. Ther. Med. 2018, 15, 198–204. [Google Scholar] [CrossRef] [Green Version]
Process | Main Participants of Processes | Regulation | Cell Compartment |
---|---|---|---|
Receptor-mediated LDL uptake | TLR4, MyD88 | SYK/PI3K/Akt signaling pathway | Plasma membrane |
LDLR, LRP1 | AP-2, CCC, WASH, PCSK9, LXR, SREBP1c, SREBP2 | ||
SR-AI, SR-AII | Sac1, Sac3, LKB1 | ||
CD36 | Kinases Src, Jnk, Rac (GTPase) protein, NF-κB, CD146, Nrf1 | ||
LOX-1 | PCSK9 | ||
CD68, SCARF1, SR-PSOX/CXCL16 | |||
Fluid-phase pinocytosis (receptor-independent LDL uptake) | PI3K, LXR, M-CSF receptor, PKC | Plasma membrane | |
LDL lysis | Lysosomal lipoprotein lipase, lysosomal acid lipase (LAL) | Perilipins, Lipases and Rab GTPases | Lysosomes |
Intracellular lipid trafficking | NPC 1 and 2 | LAMP 1 and 2, LBPA | Lysosomes |
ORP, VASt, START | Cytoplasm | ||
Free cholesterol esterification | ACAT1 | Kinase signaling cascade MAP, Jak, Erk, and signaling cascade Jnk, NF-κB | Endoplasmic reticulum |
Fatty acid β-oxidation | Acyl-CoA synthetase, carnitine acyltransferase 1, β-oxidation pathway enzymes | Malonyl-CoA | Cytoplasm, Mitochondria |
Fatty acid synthesis | Acetyl-CoA, ACC, FASN, malonyl-CoA, fatty acyl-CoA | SREBP1, USF1, and USF2 | Mitochondria, Endoplasmic reticulum, Cytoplasm |
Triacylglycerol synthesis | DGAT1, DGAT2, diacylglycerol, fatty acyl-CoA | Endoplasmic reticulum | |
Lipid droplet formation | ACAT1, ACAT2, DGAT1, DGAT2, FIT1, FIT2, seipin, Pln1, CCTα | Endoplasmic reticulum | |
Cholesterol synthesis | HMG-CoA reductase, acetyl-CoA, HMG-CoA, Mevalonate | SREBP2, SCAP, INSIG1 | Endoplasmic reticulum |
Generation of free cholesterol and fatty acids from cholesterol esters | NCEH, Lipe, Ces3 | Endoplasmic reticulum | |
Free cholesterol efflux to HDL | ABCA1, ABCG1, SR-BI | LXRα, LXRβ, RXR, PPARγ, PCSK9, DAPK1, NF-κB, PKA, PKC, JAK2, miRNA-33, mTORC1, Keap1/Nrf2 pathway, IGF-1, PI3, and Akt signaling pathways, TLR2 | Plasma membrane |
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Sukhorukov, V.N.; Khotina, V.A.; Chegodaev, Y.S.; Ivanova, E.; Sobenin, I.A.; Orekhov, A.N. Lipid Metabolism in Macrophages: Focus on Atherosclerosis. Biomedicines 2020, 8, 262. https://doi.org/10.3390/biomedicines8080262
Sukhorukov VN, Khotina VA, Chegodaev YS, Ivanova E, Sobenin IA, Orekhov AN. Lipid Metabolism in Macrophages: Focus on Atherosclerosis. Biomedicines. 2020; 8(8):262. https://doi.org/10.3390/biomedicines8080262
Chicago/Turabian StyleSukhorukov, Vasily N., Victoria A. Khotina, Yegor S. Chegodaev, Ekaterina Ivanova, Igor A. Sobenin, and Alexander N. Orekhov. 2020. "Lipid Metabolism in Macrophages: Focus on Atherosclerosis" Biomedicines 8, no. 8: 262. https://doi.org/10.3390/biomedicines8080262