Lipotoxicity, the role in the process of atherosclerosis

Jiayao Li; Xiao  Zhang; Zixuan  Xing; Yixin  Sun; Shengyan  Cui; Xintao  Lv; Shuaiwei  Guo; Liqun  Jiao; Wenjing  Li; Tao  Wang

doi:10.37819/hb.2.2016

Lipotoxicity, the role in the process of atherosclerosis

Jiayao Li

Xiao Zhang

Zixuan Xing

Yixin Sun

Shengyan Cui

Xintao Lv

Shuaiwei Guo

Liqun Jiao

Wenjing Li

Tao Wang

Table of Contents

Article
References

Metrics
Related Content

Abstract

Background: Atherosclerosis (AS) is a growing problem in the elderly population causing a variety of diseases with high mortality and disability rates. Lipotoxicity plays an important role in the process of AS. Aim: This review aims to summarize the characteristics of glucose and lipid metabolism, local pathological changes of arteries and functional changes or death of perivascular cells in the process of lipotoxicity. Result: From the perspective of lipotoxicity and aging, we review the current understanding of the relationship between lipid metabolism and the development of atherosclerosis, and discuss the corresponding pharmacological treatment options. Conclusion: Various metabolic factors can lead to lipotoxicity, which in turn affects the vascular wall and various cells within the blood vessels, leading to the development of atherosclerosis. Clarifying the role of lipotoxicity in atherosclerosis provides a new perspective for the prevention and treatment of atherosclerosis.

Keywords: Lipotoxicity Atherosclerosis Aging Inflammation

Section

References

1. Thakur M, Tupe RS. Lipoxin and glycation in SREBP signaling: Insight into diabetic cardiomyopathy and associated lipotoxicity. Prostaglandins Other Lipid Mediat. 2023 Feb;164:106698.
2. Kageyama A, Matsui H, Ohta M, Sambuichi K, Kawano H, Notsu T, et al. Palmitic acid induces osteoblastic differentiation in vascular smooth muscle cells through ACSL3 and NF-κB, novel targets of eicosapentaenoic acid. PloS One. 2013;8(6):e68197.
3. Bir SC, Kelley RE. Carotid atherosclerotic disease: A systematic review of pathogenesis and management. Brain Circ. 2022 Sep 21;8(3):127–36.
4. Al Kasab S, Hess DC, Chimowitz MI. Rationale for ischemic conditioning to prevent stroke in patients with intracranial arterial stenosis. Brain Circ. 2016;2(2):67–71.
5. Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nat Rev Dis Primer. 2019 Aug 16;5(1):56.
6. Lim S, Meigs JB. Ectopic fat and cardiometabolic and vascular risk. Int J Cardiol. 2013 Nov 5;169(3):166–76.
7. Schönfeld P, Wojtczak L. Fatty acids as modulators of the cellular production of reactive oxygen species. Free Radic Biol Med. 2008 Aug 1;45(3):231–41.
8. De Keulenaer GW, Alexander RW, Ushio-Fukai M, Ishizaka N, Griendling KK. Tumour necrosis factor alpha activates a p22phox-based NADH oxidase in vascular smooth muscle. Biochem J. 1998 Feb 1;329 ( Pt 3)(Pt 3):653–7.
9. Srivastava S, Chan C. Hydrogen peroxide and hydroxyl radicals mediate palmitate-induced cytotoxicity to hepatoma cells: relation to mitochondrial permeability transition. Free Radic Res. 2007 Jan;41(1):38–49.
10. Dymkowska D, Szczepanowska J, Wieckowski MR, Wojtczak L. Short-term and long-term effects of fatty acids in rat hepatoma AS-30D cells: the way to apoptosis. Biochim Biophys Acta. 2006 Feb;1763(2):152–63.
11. Fauconnier J, Andersson DC, Zhang SJ, Lanner JT, Wibom R, Katz A, et al. Effects of palmitate on Ca(2+) handling in adult control and ob/ob cardiomyocytes: impact of mitochondrial reactive oxygen species. Diabetes. 2007 Apr;56(4):1136–42.
12. Rachek LI, Musiyenko SI, LeDoux SP, Wilson GL. Palmitate induced mitochondrial deoxyribonucleic acid damage and apoptosis in l6 rat skeletal muscle cells. Endocrinology. 2007 Jan;148(1):293–9.
13. Chang MK, Binder CJ, Torzewski M, Witztum JL. C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: Phosphorylcholine of oxidized phospholipids. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13043–8.
14. Chang MK, Bergmark C, Laurila A, Hörkkö S, Han KH, Friedman P, et al. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6353–8.
15. Kagan VE, Gleiss B, Tyurina YY, Tyurin VA, Elenström-Magnusson C, Liu SX, et al. A role for oxidative stress in apoptosis: oxidation and externalization of phosphatidylserine is required for macrophage clearance of cells undergoing Fas-mediated apoptosis. J Immunol Baltim Md 1950. 2002 Jul 1;169(1):487–99.
16. Berliner JA, Subbanagounder G, Leitinger N, Watson AD, Vora D. Evidence for a role of phospholipid oxidation products in atherogenesis. Trends Cardiovasc Med. 2001;11(3–4):142–7.
17. Berliner J. Introduction. Lipid oxidation products and atherosclerosis. Vascul Pharmacol. 2002 Apr;38(4):187–91.
18. Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res. 2016 Nov;57(11):1953–75.
19. Hörkkö S, Bird DA, Miller E, Itabe H, Leitinger N, Subbanagounder G, et al. Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. J Clin Invest. 1999 Jan;103(1):117–28.
20. Karman RJ, Gupta MP, Garcia JG, Hart CM. Exogenous fatty acids modulate the functional and cytotoxic responses of cultured pulmonary artery endothelial cells to oxidant stress. J Lab Clin Med. 1997 May;129(5):548–56.
21. Kim F, Tysseling KA, Rice J, Pham M, Haji L, Gallis BM, et al. Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol. 2005 May;25(5):989–94.
22. Maloney E, Sweet IR, Hockenbery DM, Pham M, Rizzo NO, Tateya S, et al. Activation of NF-kappaB by palmitate in endothelial cells: a key role for NADPH oxidase-derived superoxide in response to TLR4 activation. Arterioscler Thromb Vasc Biol. 2009 Sep;29(9):1370–5.
23. Symons JD, McMillin SL, Riehle C, Tanner J, Palionyte M, Hillas E, et al. Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase in the regulation of endothelial function and blood pressure. Circ Res. 2009 May 8;104(9):1085–94.
24. Artwohl M, Lindenmair A, Roden M, Waldhäusl WK, Freudenthaler A, Klosner G, et al. Fatty acids induce apoptosis in human smooth muscle cells depending on chain length, saturation, and duration of exposure. Atherosclerosis. 2009 Feb 1;202(2):351–62.
25. Mesenchymal stem cells alleviate palmitic acid-induced endothelial-to-mesenchymal transition by suppressing endoplasmic reticulum stress | American Journal of Physiology-Endocrinology and Metabolism [Internet]. [cited 2023 Aug 3]. Available from: https://journals.physiology.org/doi/full/10.1152/ajpendo.00155.2020?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org
26. Imrie H, Abbas A, Kearney M. Insulin resistance, lipotoxicity and endothelial dysfunction. Biochim Biophys Acta. 2010 Mar;1801(3):320–6.
27. Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res. 2016 Feb 19;118(4):692–702.
28. Regan CP, Adam PJ, Madsen CS, Owens GK. Molecular mechanisms of decreased smooth muscle differentiation marker expression after vascular injury. J Clin Invest. 2000 Nov;106(9):1139–47.
29. Salmon M, Gomez D, Greene E, Shankman L, Owens GK. Cooperative binding of KLF4, pELK-1, and HDAC2 to a G/C repressor element in the SM22α promoter mediates transcriptional silencing during SMC phenotypic switching in vivo. Circ Res. 2012 Aug 31;111(6):685–96.
30. Wamhoff BR, Hoofnagle MH, Burns A, Sinha S, McDonald OG, Owens GK. A G/C element mediates repression of the SM22alpha promoter within phenotypically modulated smooth muscle cells in experimental atherosclerosis. Circ Res. 2004 Nov 12;95(10):981–8.
31. Shankman LS, Gomez D, Cherepanova OA, Salmon M, Alencar GF, Haskins RM, et al. KLF4 Dependent Phenotypic Modulation of SMCs Plays a Key Role in Atherosclerotic Plaque Pathogenesis. Nat Med. 2015 Jun;21(6):628–37.
32. Aqel NM, Ball RY, Waldmann H, Mitchinson MJ. Monocytic origin of foam cells in human atherosclerotic plaques. Atherosclerosis. 1984 Dec;53(3):265–71.
33. Hotamisligil GS, Erbay E. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol. 2008 Dec;8(12):923–34.
34. Gregor MF, Hotamisligil GS. Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res. 2007 Sep;48(9):1905–14.
35. Tabas I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2255–64.
36. Myoishi M, Hao H, Minamino T, Watanabe K, Nishihira K, Hatakeyama K, et al. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation. 2007 Sep 11;116(11):1226–33.
37. Erbay E, Babaev VR, Mayers JR, Makowski L, Charles KN, Snitow M, et al. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat Med. 2009 Dec;15(12):1383–91.
38. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006 Aug 25;313(5790):1137–40.
39. Vora DK, Fang ZT, Liva SM, Tyner TR, Parhami F, Watson AD, et al. Induction of P-selectin by oxidized lipoproteins. Separate effects on synthesis and surface expression. Circ Res. 1997 Jun;80(6):810–8.
40. Leitinger N, Tyner TR, Oslund L, Rizza C, Subbanagounder G, Lee H, et al. Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12010–5.
41. Cole AL, Subbanagounder G, Mukhopadhyay S, Berliner JA, Vora DK. Oxidized phospholipid-induced endothelial cell/monocyte interaction is mediated by a cAMP-dependent R-Ras/PI3-kinase pathway. Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1384–90.
42. Eguchi K, Manabe I. Toll-Like Receptor, Lipotoxicity and Chronic inflammation: The Pathological Link Between Obesity and Cardiometabolic Disease. J Atheroscler Thromb. 2014;21(7):629–39.
43. de Kreutzenberg SV, Crepaldi C, Marchetto S, Calò L, Tiengo A, Del Prato S, et al. Plasma free fatty acids and endothelium-dependent vasodilation: effect of chain-length and cyclooxygenase inhibition. J Clin Endocrinol Metab. 2000 Feb;85(2):793–8.
44. de Man FH, Weverling-Rijnsburger AW, van der Laarse A, Smelt AH, Jukema JW, Blauw GJ. Not acute but chronic hypertriglyceridemia is associated with impaired endothelium-dependent vasodilation: reversal after lipid-lowering therapy by atorvastatin. Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):744–50.
45. Ying R, Wang XQ, Yang Y, Gu ZJ, Mai JT, Qiu Q, et al. Hydrogen sulfide suppresses endoplasmic reticulum stress-induced endothelial-to-mesenchymal transition through Src pathway. Life Sci. 2016 Jan 1;144:208–17.
46. Castaño D, Rattanasopa C, Monteiro-Cardoso VF, Corlianò M, Liu Y, Zhong S, et al. Lipid efflux mechanisms, relation to disease and potential therapeutic aspects. Adv Drug Deliv Rev. 2020;159:54–93.
47. Phillips MC. Molecular Mechanisms of Cellular Cholesterol Efflux *. J Biol Chem. 2014 Aug 1;289(35):24020–9.
48. Favari E, Chroni A, Tietge UJF, Zanotti I, Escolà-Gil JC, Bernini F. Cholesterol Efflux and Reverse Cholesterol Transport. In: von Eckardstein A, Kardassis D, editors. High Density Lipoproteins: From Biological Understanding to Clinical Exploitation [Internet]. Cham: Springer International Publishing; 2015 [cited 2023 Sep 25]. p. 181–206. (Handbook of Experimental Pharmacology). Available from: https://doi.org/10.1007/978-3-319-09665-0_4
49. Anastasius M, Kockx M, Jessup W, Sullivan D, Rye KA, Kritharides L. Cholesterol efflux capacity: An introduction for clinicians. Am Heart J. 2016 Oct 1;180:54–63.
50. Adorni MP, Zimetti F, Billheimer JT, Wang N, Rader DJ, Phillips MC, et al. The roles of different pathways in the release of cholesterol from macrophages. J Lipid Res. 2007 Nov 1;48(11):2453–62.
51. Rodríguez-Carrio J, Salazar N, Margolles A, González S, Gueimonde M, de Los Reyes-Gavilán CG, et al. Free Fatty Acids Profiles Are Related to Gut Microbiota Signatures and Short-Chain Fatty Acids. Front Immunol. 2017;8:823.
52. Hidalgo MA, Carretta MD, Burgos RA. Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors. Front Physiol. 2021;12:668330.
53. Lemos G de O, Torrinhas RS, Waitzberg DL. Nutrients, Physical Activity, and Mitochondrial Dysfunction in the Setting of Metabolic Syndrome. Nutrients. 2023 Feb 28;15(5):1217.
54. Jensen MD. Is visceral fat involved in the pathogenesis of the metabolic syndrome? Human model. Obes Silver Spring Md. 2006 Feb;14 Suppl 1:20S-24S.
55. Carobbio S, Rodriguez-Cuenca S, Vidal-Puig A. Origins of metabolic complications in obesity: ectopic fat accumulation. The importance of the qualitative aspect of lipotoxicity. Curr Opin Clin Nutr Metab Care. 2011 Nov;14(6):520–6.
56. Hao JW, Wang J, Guo H, Zhao YY, Sun HH, Li YF, et al. CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis. Nat Commun. 2020 Sep 21;11(1):4765.
57. Febbraio M, Podrez EA, Smith JD, Hajjar DP, Hazen SL, Hoff HF, et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest. 2000 Apr;105(8):1049–56.
58. Zeng Y, Tao N, Chung KN, Heuser JE, Lublin DM. Endocytosis of oxidized low density lipoprotein through scavenger receptor CD36 utilizes a lipid raft pathway that does not require caveolin-1. J Biol Chem. 2003 Nov 14;278(46):45931–6.
59. Yazgan B, Sozen E, Karademir B, Ustunsoy S, Ince U, Zarkovic N, et al. CD36 expression in peripheral blood mononuclear cells reflects the onset of atherosclerosis. BioFactors Oxf Engl. 2018 Nov;44(6):588–96.
60. Chistiakov DA, Bobryshev YV, Orekhov AN. Macrophage-mediated cholesterol handling in atherosclerosis. J Cell Mol Med. 2016 Jan;20(1):17–28.
61. Feng L, Gu C, Li Y, Huang J. High Glucose Promotes CD36 Expression by Upregulating Peroxisome Proliferator-Activated Receptor γ Levels to Exacerbate Lipid Deposition in Renal Tubular Cells. BioMed Res Int. 2017;2017:1414070.
62. Sun X, Li X, Jia H, Wang H, Shui G, Qin Y, et al. Nuclear Factor E2-Related Factor 2 Mediates Oxidative Stress-Induced Lipid Accumulation in Adipocytes by Increasing Adipogenesis and Decreasing Lipolysis. Antioxid Redox Signal. 2020 Jan 20;32(3):173–92.
63. Writing Committee, Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016 Jul 5;68(1):92–125.
64. Dewey FE, Gusarova V, Dunbar RL, O’Dushlaine C, Schurmann C, Gottesman O, et al. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017 Jul 20;377(3):211–21.
65. Sharma RB, Alonso LC. Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well? Curr Diab Rep. 2014 Jun;14(6):492.
66. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998 Nov 10;98(19):2088–93.
67. Jia Z, Sun Y, Yang G, Zhang A, Huang S, Heiney KM, et al. New Insights into the PPAR γ Agonists for the Treatment of Diabetic Nephropathy. PPAR Res. 2014;2014:818530.
68. Choi HM, Doss HM, Kim KS. Multifaceted Physiological Roles of Adiponectin in Inflammation and Diseases. Int J Mol Sci. 2020 Feb 12;21(4):1219.
69. Saxena NK, Anania FA. Adipocytokines and hepatic fibrosis. Trends Endocrinol Metab TEM. 2015 Mar;26(3):153–61.
70. Zha D, Wu X, Gao P. Adiponectin and Its Receptors in Diabetic Kidney Disease: Molecular Mechanisms and Clinical Potential. Endocrinology. 2017 Jul 1;158(7):2022–34.
71. Yamakado S, Cho H, Inada M, Morikawa M, Jiang YH, Saito K, et al. Urinary adiponectin as a new diagnostic index for chronic kidney disease due to diabetic nephropathy. BMJ Open Diabetes Res Care. 2019;7(1):e000661.
72. Lin J, Hu FB, Curhan G. Serum adiponectin and renal dysfunction in men with type 2 diabetes. Diabetes Care. 2007 Feb;30(2):239–44.
73. Saraheimo M, Forsblom C, Fagerudd J, Teppo AM, Pettersson-Fernholm K, Frystyk J, et al. Serum adiponectin is increased in type 1 diabetic patients with nephropathy. Diabetes Care. 2005 Jun;28(6):1410–4.
74. Muoio DM. Metabolism and vascular fatty acid transport. N Engl J Med. 2010 Jul 15;363(3):291–3.
75. Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I, et al. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature. 2010 Apr 8;464(7290):917–21.
76. Hagberg C, Mehlem A, Falkevall A, Muhl L, Eriksson U. Endothelial fatty acid transport: role of vascular endothelial growth factor B. Physiol Bethesda Md. 2013 Mar;28(2):125–34.
77. Hagberg CE, Mehlem A, Falkevall A, Muhl L, Fam BC, Ortsäter H, et al. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature. 2012 Oct 18;490(7420):426–30.

How to Cite

“Lipotoxicity, the Role in the Process of Atherosclerosis”. Human Brain, vol. 3, no. 2, Oct. 2024, https://doi.org/10.37819/hb.2.2016.

How to Cite

“Lipotoxicity, the Role in the Process of Atherosclerosis”. Human Brain, vol. 3, no. 2, Oct. 2024, https://doi.org/10.37819/hb.2.2016.

Download Citation

HTML
24

Total
13

Share

Search Panel

Jiayao Li

Google Scholar
Pubmed
JDMFS Journal

Xiao Zhang

Google Scholar
Pubmed
JDMFS Journal

Zixuan Xing

Google Scholar
Pubmed
JDMFS Journal

Yixin Sun

Google Scholar
Pubmed
JDMFS Journal

Shengyan Cui

Google Scholar
Pubmed
JDMFS Journal

Xintao Lv

Google Scholar
Pubmed
JDMFS Journal

Shuaiwei Guo

Google Scholar
Pubmed
JDMFS Journal

Liqun Jiao

Google Scholar
Pubmed
JDMFS Journal

Wenjing Li

Google Scholar
Pubmed
JDMFS Journal

Tao Wang

Google Scholar
Pubmed
JDMFS Journal

Downloads

PDF

Article Details

Most Read This Month

License

This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License.

[1] 1. Thakur M, Tupe RS. Lipoxin and glycation in SREBP signaling: Insight into diabetic cardiomyopathy and associated lipotoxicity. Prostaglandins Other Lipid Mediat. 2023 Feb;164:106698.

[2] 2. Kageyama A, Matsui H, Ohta M, Sambuichi K, Kawano H, Notsu T, et al. Palmitic acid induces osteoblastic differentiation in vascular smooth muscle cells through ACSL3 and NF-κB, novel targets of eicosapentaenoic acid. PloS One. 2013;8(6):e68197.

[3] 3. Bir SC, Kelley RE. Carotid atherosclerotic disease: A systematic review of pathogenesis and management. Brain Circ. 2022 Sep 21;8(3):127–36.

[4] 4. Al Kasab S, Hess DC, Chimowitz MI. Rationale for ischemic conditioning to prevent stroke in patients with intracranial arterial stenosis. Brain Circ. 2016;2(2):67–71.

[5] 5. Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nat Rev Dis Primer. 2019 Aug 16;5(1):56.

[6] 6. Lim S, Meigs JB. Ectopic fat and cardiometabolic and vascular risk. Int J Cardiol. 2013 Nov 5;169(3):166–76.

[7] 7. Schönfeld P, Wojtczak L. Fatty acids as modulators of the cellular production of reactive oxygen species. Free Radic Biol Med. 2008 Aug 1;45(3):231–41.

[8] 8. De Keulenaer GW, Alexander RW, Ushio-Fukai M, Ishizaka N, Griendling KK. Tumour necrosis factor alpha activates a p22phox-based NADH oxidase in vascular smooth muscle. Biochem J. 1998 Feb 1;329 ( Pt 3)(Pt 3):653–7.

[9] 9. Srivastava S, Chan C. Hydrogen peroxide and hydroxyl radicals mediate palmitate-induced cytotoxicity to hepatoma cells: relation to mitochondrial permeability transition. Free Radic Res. 2007 Jan;41(1):38–49.

[10] 10. Dymkowska D, Szczepanowska J, Wieckowski MR, Wojtczak L. Short-term and long-term effects of fatty acids in rat hepatoma AS-30D cells: the way to apoptosis. Biochim Biophys Acta. 2006 Feb;1763(2):152–63.

[11] 11. Fauconnier J, Andersson DC, Zhang SJ, Lanner JT, Wibom R, Katz A, et al. Effects of palmitate on Ca(2+) handling in adult control and ob/ob cardiomyocytes: impact of mitochondrial reactive oxygen species. Diabetes. 2007 Apr;56(4):1136–42.

[12] 12. Rachek LI, Musiyenko SI, LeDoux SP, Wilson GL. Palmitate induced mitochondrial deoxyribonucleic acid damage and apoptosis in l6 rat skeletal muscle cells. Endocrinology. 2007 Jan;148(1):293–9.

[13] 13. Chang MK, Binder CJ, Torzewski M, Witztum JL. C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: Phosphorylcholine of oxidized phospholipids. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13043–8.

[14] 14. Chang MK, Bergmark C, Laurila A, Hörkkö S, Han KH, Friedman P, et al. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6353–8.

[15] 15. Kagan VE, Gleiss B, Tyurina YY, Tyurin VA, Elenström-Magnusson C, Liu SX, et al. A role for oxidative stress in apoptosis: oxidation and externalization of phosphatidylserine is required for macrophage clearance of cells undergoing Fas-mediated apoptosis. J Immunol Baltim Md 1950. 2002 Jul 1;169(1):487–99.

[16] 16. Berliner JA, Subbanagounder G, Leitinger N, Watson AD, Vora D. Evidence for a role of phospholipid oxidation products in atherogenesis. Trends Cardiovasc Med. 2001;11(3–4):142–7.

[17] 17. Berliner J. Introduction. Lipid oxidation products and atherosclerosis. Vascul Pharmacol. 2002 Apr;38(4):187–91.

[18] 18. Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res. 2016 Nov;57(11):1953–75.

[19] 19. Hörkkö S, Bird DA, Miller E, Itabe H, Leitinger N, Subbanagounder G, et al. Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. J Clin Invest. 1999 Jan;103(1):117–28.

[20] 20. Karman RJ, Gupta MP, Garcia JG, Hart CM. Exogenous fatty acids modulate the functional and cytotoxic responses of cultured pulmonary artery endothelial cells to oxidant stress. J Lab Clin Med. 1997 May;129(5):548–56.

[21] 21. Kim F, Tysseling KA, Rice J, Pham M, Haji L, Gallis BM, et al. Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol. 2005 May;25(5):989–94.

[22] 22. Maloney E, Sweet IR, Hockenbery DM, Pham M, Rizzo NO, Tateya S, et al. Activation of NF-kappaB by palmitate in endothelial cells: a key role for NADPH oxidase-derived superoxide in response to TLR4 activation. Arterioscler Thromb Vasc Biol. 2009 Sep;29(9):1370–5.

[23] 23. Symons JD, McMillin SL, Riehle C, Tanner J, Palionyte M, Hillas E, et al. Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase in the regulation of endothelial function and blood pressure. Circ Res. 2009 May 8;104(9):1085–94.

[24] 24. Artwohl M, Lindenmair A, Roden M, Waldhäusl WK, Freudenthaler A, Klosner G, et al. Fatty acids induce apoptosis in human smooth muscle cells depending on chain length, saturation, and duration of exposure. Atherosclerosis. 2009 Feb 1;202(2):351–62.

[25] 25. Mesenchymal stem cells alleviate palmitic acid-induced endothelial-to-mesenchymal transition by suppressing endoplasmic reticulum stress | American Journal of Physiology-Endocrinology and Metabolism [Internet]. [cited 2023 Aug 3]. Available from: https://journals.physiology.org/doi/full/10.1152/ajpendo.00155.2020?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org

[26] 26. Imrie H, Abbas A, Kearney M. Insulin resistance, lipotoxicity and endothelial dysfunction. Biochim Biophys Acta. 2010 Mar;1801(3):320–6.

[27] 27. Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res. 2016 Feb 19;118(4):692–702.

[28] 28. Regan CP, Adam PJ, Madsen CS, Owens GK. Molecular mechanisms of decreased smooth muscle differentiation marker expression after vascular injury. J Clin Invest. 2000 Nov;106(9):1139–47.

[29] 29. Salmon M, Gomez D, Greene E, Shankman L, Owens GK. Cooperative binding of KLF4, pELK-1, and HDAC2 to a G/C repressor element in the SM22α promoter mediates transcriptional silencing during SMC phenotypic switching in vivo. Circ Res. 2012 Aug 31;111(6):685–96.

[30] 30. Wamhoff BR, Hoofnagle MH, Burns A, Sinha S, McDonald OG, Owens GK. A G/C element mediates repression of the SM22alpha promoter within phenotypically modulated smooth muscle cells in experimental atherosclerosis. Circ Res. 2004 Nov 12;95(10):981–8.

[31] 31. Shankman LS, Gomez D, Cherepanova OA, Salmon M, Alencar GF, Haskins RM, et al. KLF4 Dependent Phenotypic Modulation of SMCs Plays a Key Role in Atherosclerotic Plaque Pathogenesis. Nat Med. 2015 Jun;21(6):628–37.

[32] 32. Aqel NM, Ball RY, Waldmann H, Mitchinson MJ. Monocytic origin of foam cells in human atherosclerotic plaques. Atherosclerosis. 1984 Dec;53(3):265–71.

[33] 33. Hotamisligil GS, Erbay E. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol. 2008 Dec;8(12):923–34.

[34] 34. Gregor MF, Hotamisligil GS. Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res. 2007 Sep;48(9):1905–14.

[35] 35. Tabas I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2255–64.

[36] 36. Myoishi M, Hao H, Minamino T, Watanabe K, Nishihira K, Hatakeyama K, et al. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation. 2007 Sep 11;116(11):1226–33.

[37] 37. Erbay E, Babaev VR, Mayers JR, Makowski L, Charles KN, Snitow M, et al. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat Med. 2009 Dec;15(12):1383–91.

[38] 38. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006 Aug 25;313(5790):1137–40.

[39] 39. Vora DK, Fang ZT, Liva SM, Tyner TR, Parhami F, Watson AD, et al. Induction of P-selectin by oxidized lipoproteins. Separate effects on synthesis and surface expression. Circ Res. 1997 Jun;80(6):810–8.

[40] 40. Leitinger N, Tyner TR, Oslund L, Rizza C, Subbanagounder G, Lee H, et al. Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12010–5.

[41] 41. Cole AL, Subbanagounder G, Mukhopadhyay S, Berliner JA, Vora DK. Oxidized phospholipid-induced endothelial cell/monocyte interaction is mediated by a cAMP-dependent R-Ras/PI3-kinase pathway. Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1384–90.

[42] 42. Eguchi K, Manabe I. Toll-Like Receptor, Lipotoxicity and Chronic inflammation: The Pathological Link Between Obesity and Cardiometabolic Disease. J Atheroscler Thromb. 2014;21(7):629–39.

[43] 43. de Kreutzenberg SV, Crepaldi C, Marchetto S, Calò L, Tiengo A, Del Prato S, et al. Plasma free fatty acids and endothelium-dependent vasodilation: effect of chain-length and cyclooxygenase inhibition. J Clin Endocrinol Metab. 2000 Feb;85(2):793–8.

[44] 44. de Man FH, Weverling-Rijnsburger AW, van der Laarse A, Smelt AH, Jukema JW, Blauw GJ. Not acute but chronic hypertriglyceridemia is associated with impaired endothelium-dependent vasodilation: reversal after lipid-lowering therapy by atorvastatin. Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):744–50.

[45] 45. Ying R, Wang XQ, Yang Y, Gu ZJ, Mai JT, Qiu Q, et al. Hydrogen sulfide suppresses endoplasmic reticulum stress-induced endothelial-to-mesenchymal transition through Src pathway. Life Sci. 2016 Jan 1;144:208–17.

[46] 46. Castaño D, Rattanasopa C, Monteiro-Cardoso VF, Corlianò M, Liu Y, Zhong S, et al. Lipid efflux mechanisms, relation to disease and potential therapeutic aspects. Adv Drug Deliv Rev. 2020;159:54–93.

[47] 47. Phillips MC. Molecular Mechanisms of Cellular Cholesterol Efflux *. J Biol Chem. 2014 Aug 1;289(35):24020–9.

[48] 48. Favari E, Chroni A, Tietge UJF, Zanotti I, Escolà-Gil JC, Bernini F. Cholesterol Efflux and Reverse Cholesterol Transport. In: von Eckardstein A, Kardassis D, editors. High Density Lipoproteins: From Biological Understanding to Clinical Exploitation [Internet]. Cham: Springer International Publishing; 2015 [cited 2023 Sep 25]. p. 181–206. (Handbook of Experimental Pharmacology). Available from: https://doi.org/10.1007/978-3-319-09665-0_4

[49] 49. Anastasius M, Kockx M, Jessup W, Sullivan D, Rye KA, Kritharides L. Cholesterol efflux capacity: An introduction for clinicians. Am Heart J. 2016 Oct 1;180:54–63.

[50] 50. Adorni MP, Zimetti F, Billheimer JT, Wang N, Rader DJ, Phillips MC, et al. The roles of different pathways in the release of cholesterol from macrophages. J Lipid Res. 2007 Nov 1;48(11):2453–62.

[51] 51. Rodríguez-Carrio J, Salazar N, Margolles A, González S, Gueimonde M, de Los Reyes-Gavilán CG, et al. Free Fatty Acids Profiles Are Related to Gut Microbiota Signatures and Short-Chain Fatty Acids. Front Immunol. 2017;8:823.

[52] 52. Hidalgo MA, Carretta MD, Burgos RA. Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors. Front Physiol. 2021;12:668330.

[53] 53. Lemos G de O, Torrinhas RS, Waitzberg DL. Nutrients, Physical Activity, and Mitochondrial Dysfunction in the Setting of Metabolic Syndrome. Nutrients. 2023 Feb 28;15(5):1217.

[54] 54. Jensen MD. Is visceral fat involved in the pathogenesis of the metabolic syndrome? Human model. Obes Silver Spring Md. 2006 Feb;14 Suppl 1:20S-24S.

[55] 55. Carobbio S, Rodriguez-Cuenca S, Vidal-Puig A. Origins of metabolic complications in obesity: ectopic fat accumulation. The importance of the qualitative aspect of lipotoxicity. Curr Opin Clin Nutr Metab Care. 2011 Nov;14(6):520–6.

[56] 56. Hao JW, Wang J, Guo H, Zhao YY, Sun HH, Li YF, et al. CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis. Nat Commun. 2020 Sep 21;11(1):4765.

[57] 57. Febbraio M, Podrez EA, Smith JD, Hajjar DP, Hazen SL, Hoff HF, et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest. 2000 Apr;105(8):1049–56.

[58] 58. Zeng Y, Tao N, Chung KN, Heuser JE, Lublin DM. Endocytosis of oxidized low density lipoprotein through scavenger receptor CD36 utilizes a lipid raft pathway that does not require caveolin-1. J Biol Chem. 2003 Nov 14;278(46):45931–6.

[59] 59. Yazgan B, Sozen E, Karademir B, Ustunsoy S, Ince U, Zarkovic N, et al. CD36 expression in peripheral blood mononuclear cells reflects the onset of atherosclerosis. BioFactors Oxf Engl. 2018 Nov;44(6):588–96.

[60] 60. Chistiakov DA, Bobryshev YV, Orekhov AN. Macrophage-mediated cholesterol handling in atherosclerosis. J Cell Mol Med. 2016 Jan;20(1):17–28.

[61] 61. Feng L, Gu C, Li Y, Huang J. High Glucose Promotes CD36 Expression by Upregulating Peroxisome Proliferator-Activated Receptor γ Levels to Exacerbate Lipid Deposition in Renal Tubular Cells. BioMed Res Int. 2017;2017:1414070.

[62] 62. Sun X, Li X, Jia H, Wang H, Shui G, Qin Y, et al. Nuclear Factor E2-Related Factor 2 Mediates Oxidative Stress-Induced Lipid Accumulation in Adipocytes by Increasing Adipogenesis and Decreasing Lipolysis. Antioxid Redox Signal. 2020 Jan 20;32(3):173–92.

[63] 63. Writing Committee, Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016 Jul 5;68(1):92–125.

[64] 64. Dewey FE, Gusarova V, Dunbar RL, O’Dushlaine C, Schurmann C, Gottesman O, et al. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. N Engl J Med. 2017 Jul 20;377(3):211–21.

[65] 65. Sharma RB, Alonso LC. Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well? Curr Diab Rep. 2014 Jun;14(6):492.

[66] 66. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998 Nov 10;98(19):2088–93.

[67] 67. Jia Z, Sun Y, Yang G, Zhang A, Huang S, Heiney KM, et al. New Insights into the PPAR γ Agonists for the Treatment of Diabetic Nephropathy. PPAR Res. 2014;2014:818530.

[68] 68. Choi HM, Doss HM, Kim KS. Multifaceted Physiological Roles of Adiponectin in Inflammation and Diseases. Int J Mol Sci. 2020 Feb 12;21(4):1219.

[69] 69. Saxena NK, Anania FA. Adipocytokines and hepatic fibrosis. Trends Endocrinol Metab TEM. 2015 Mar;26(3):153–61.

[70] 70. Zha D, Wu X, Gao P. Adiponectin and Its Receptors in Diabetic Kidney Disease: Molecular Mechanisms and Clinical Potential. Endocrinology. 2017 Jul 1;158(7):2022–34.

[71] 71. Yamakado S, Cho H, Inada M, Morikawa M, Jiang YH, Saito K, et al. Urinary adiponectin as a new diagnostic index for chronic kidney disease due to diabetic nephropathy. BMJ Open Diabetes Res Care. 2019;7(1):e000661.

[72] 72. Lin J, Hu FB, Curhan G. Serum adiponectin and renal dysfunction in men with type 2 diabetes. Diabetes Care. 2007 Feb;30(2):239–44.

[73] 73. Saraheimo M, Forsblom C, Fagerudd J, Teppo AM, Pettersson-Fernholm K, Frystyk J, et al. Serum adiponectin is increased in type 1 diabetic patients with nephropathy. Diabetes Care. 2005 Jun;28(6):1410–4.

[74] 74. Muoio DM. Metabolism and vascular fatty acid transport. N Engl J Med. 2010 Jul 15;363(3):291–3.

[75] 75. Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I, et al. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature. 2010 Apr 8;464(7290):917–21.

[76] 76. Hagberg C, Mehlem A, Falkevall A, Muhl L, Eriksson U. Endothelial fatty acid transport: role of vascular endothelial growth factor B. Physiol Bethesda Md. 2013 Mar;28(2):125–34.

[77] 77. Hagberg CE, Mehlem A, Falkevall A, Muhl L, Fam BC, Ortsäter H, et al. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature. 2012 Oct 18;490(7420):426–30.