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CD36 in chronic kidney disease: novel insights and therapeutic opportunities

Nature Reviews Nephrology volume 13, pages 769–781 (2017)Cite this article

Subjects

Key Points

  • CD36 is a multifunctional receptor for long-chain fatty acids, oxidized lipids, advanced oxidation protein products, thrombospondin and advanced glycation end products

  • CD36 is expressed in a wide variety of kidney cells such as proximal tubular epithelial cells, mesangial cells, podocytes, monocytes and macrophages

  • The expression and intracellular location of CD36 are regulated by multiple ligands with roles in gene transcription and post-translational modifications

  • CD36 is involved in lipid accumulation, inflammation, energy reprograming, apoptosis and kidney fibrosis through activation of Toll-like receptors, Na+/K+ATPase, the NLRP3 inflammasome, PKC-NAPDH oxidase, Scr/Lyn/Fyn and mitogen-activated protein kinases, and TGF-β signalling pathways

  • The levels of circulating soluble CD36 correlate with tissue CD36 expression and could be a biomarker for progression of chronic kidney disease

  • Experimental studies have demonstrated that blockade or knockout of CD36 can prevent kidney injury, suggesting that CD36 could be a novel therapeutic target for the prevention of kidney fibrosis

Abstract

CD36 (also known as scavenger receptor B2) is a multifunctional receptor that mediates the binding and cellular uptake of long-chain fatty acids, oxidized lipids and phospholipids, advanced oxidation protein products, thrombospondin and advanced glycation end products, and has roles in lipid accumulation, inflammatory signalling, energy reprogramming, apoptosis and kidney fibrosis. Renal CD36 is mainly expressed in tubular epithelial cells, podocytes and mesangial cells, and is markedly upregulated in the setting of chronic kidney disease (CKD). As fatty acids are the preferred energy source for proximal tubule cells, a reduction in fatty acid oxidation in CKD affects kidney lipid metabolism by disrupting the balance between fatty acid synthesis, uptake and consumption. The outcome is intracellular lipid accumulation, which has an important role in the pathogenesis of kidney fibrosis. In experimental models, antagonist blockade or genetic knockout of CD36 prevents kidney injury, suggesting that CD36 could be a novel target for therapy. Here, we discuss the regulation and post-translational modification of CD36, its role in renal pathophysiology and its potential as a biomarker and as a therapeutic target for the prevention of kidney fibrosis.

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Figure 1: CD36 structure and post-translational modifications.
Figure 2: CD36 ligand and signal transduction pathways with roles in progression of chronic kidney disease.
Figure 3: Post-translational modifications regulate CD36 distribution and function.

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References

  1. Nicholson, A. C., Febbraio, M., Han, J., Silverstein, R. L. & Hajjar, D. P. CD36 in atherosclerosis. The role of a class B macrophage scavenger receptor. Ann. N. Y. Acad. Sci. 902, 128–133 (2000).

    CAS  PubMed  Google Scholar 

  2. Miquilena-Colina, M. E. et al. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut 60, 1394–1402 (2011).

    CAS  PubMed  Google Scholar 

  3. Handberg, A. et al. Soluble CD36 (sCD36) clusters with markers of insulin resistance, and high sCD36 is associated with increased type 2 diabetes risk. J. Clin. Endocrinol. Metab. 95, 1939–1946 (2010).

    CAS  PubMed  Google Scholar 

  4. Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41–45 (2017).

    CAS  PubMed  Google Scholar 

  5. Jiang, Y. et al. Dyslipidemia in human kidney transplant recipients receiving cyclosporine and tacrolimus is associated with different expression of CD36 on peripheral blood monocytes. Transplant. Proc. 43, 1612–1615 (2011).

    CAS  PubMed  Google Scholar 

  6. Ohgami, N. et al. Cd36, a member of the class b scavenger receptor family, as a receptor for advanced glycation end products. J. Biol. Chem. 276, 3195–3202 (2001).

    CAS  PubMed  Google Scholar 

  7. Qiao, L. et al. Transcriptional regulation of fatty acid translocase/CD36 expression by CCAAT/enhancer-binding protein alpha. J. Biol. Chem. 283, 8788–8795 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bodart, V. et al. CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ. Res. 90, 844–849 (2002).

    CAS  PubMed  Google Scholar 

  9. Hsieh, J. et al. Glucagon-like peptide-2 increases intestinal lipid absorption and chylomicron production via CD36. Gastroenterology 137, 997–1005 (2009).

    CAS  PubMed  Google Scholar 

  10. Susztak, K., Ciccone, E., McCue, P., Sharma, K. & Bottinger, E. P. Multiple metabolic hits converge on CD36 as novel mediator of tubular epithelial apoptosis in diabetic nephropathy. PLoS Med 2, e45 (2005).

    PubMed  PubMed Central  Google Scholar 

  11. Okamura, D. M., Lopez-Guisa, J. M., Koelsch, K., Collins, S. & Eddy, A. A. Atherogenic scavenger receptor modulation in the tubulointerstitium in response to chronic renal injury. Am. J. Physiol. Renal Physiol. 293, F575–F585 (2007).

    CAS  PubMed  Google Scholar 

  12. Hua, W. et al. CD36 mediated fatty acid-induced podocyte apoptosis via oxidative stress. PLoS ONE 10, e0127507 (2015).

    PubMed  PubMed Central  Google Scholar 

  13. Ruan, X. Z., Varghese, Z., Powis, S. H. & Moorhead, J. F. Human mesangial cells express inducible macrophage scavenger receptor. Kidney Int. 56, 440–451 (1999).

    CAS  PubMed  Google Scholar 

  14. Hughes, J., Liu, Y., Van Damme, J. & Savill, J. Human glomerular mesangial cell phagocytosis of apoptotic neutrophils: mediation by a novel CD36-independent vitronectin receptor/thrombospondin recognition mechanism that is uncoupled from chemokine secretion. J. Immunol. 158, 4389–4397 (1997).

    CAS  PubMed  Google Scholar 

  15. Kennedy, D. J. et al. CD36 and Na/K-ATPase-alpha1 form a proinflammatory signaling loop in kidney. Hypertension 61, 216–224 (2013).

    CAS  PubMed  Google Scholar 

  16. Bezaire, V. et al. Identification of fatty acid translocase on human skeletal muscle mitochondrial membranes: essential role in fatty acid oxidation. Am. J. Physiol. Endocrinol. Metab. 290, E509–E515 (2006).

    CAS  PubMed  Google Scholar 

  17. Herman-Edelstein, M., Scherzer, P., Tobar, A., Levi, M. & Gafter, U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J. Lipid Res. 55, 561–572 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Tanaka, T. et al. Defect in human myocardial long-chain fatty acid uptake is caused by FAT/CD36 mutations. J. Lipid Res. 42, 751–759 (2001).

    CAS  PubMed  Google Scholar 

  19. Wintergerst, E. S., Jelk, J., Rahner, C. & Asmis, R. Apoptosis induced by oxidized low density lipoprotein in human monocyte-derived macrophages involves CD36 and activation of caspase-3. Eur. J. Biochem. 267, 6050–6059 (2000).

    CAS  PubMed  Google Scholar 

  20. Liu, W., Yin, Y., Zhou, Z., He, M. & Dai, Y. OxLDL-induced IL-1 beta secretion promoting foam cells formation was mainly via CD36 mediated ROS production leading to NLRP3 inflammasome activation. Inflamm. Res. 63, 33–43 (2014).

    PubMed  Google Scholar 

  21. Seimon, T. A. et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab. 12, 467–482 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Iwao, Y. et al. CD36 is one of important receptors promoting renal tubular injury by advanced oxidation protein products. Am. J. Physiol. Renal Physiol. 295, F1871–F1880 (2008).

    CAS  PubMed  Google Scholar 

  23. Zhu, W., Li, W. & Silverstein, R. L. Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36. Blood 119, 6136–6144 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Daviet, L., Malvoisin, E., Wild, T. F. & McGregor, J. L. Thrombospondin induces dimerization of membrane-bound, but not soluble CD36. Thromb. Haemost. 78, 897–901 (1997).

    CAS  PubMed  Google Scholar 

  25. Simantov, R., Febbraio, M. & Silverstein, R. L. The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and modulated by histidine-rich glycoprotein. Matrix Biol. 24, 27–34 (2005).

    CAS  PubMed  Google Scholar 

  26. Kerkhoff, C., Sorg, C., Tandon, N. N. & Nacken, W. Interaction of S100A8/S100A9-arachidonic acid complexes with the scavenger receptor CD36 may facilitate fatty acid uptake by endothelial cells. Biochemistry 40, 241–248 (2001).

    CAS  PubMed  Google Scholar 

  27. Tondera, C., Laube, M. & Pietzsch, J. Insights into binding of S100 proteins to scavenger receptors: class B scavenger receptor CD36 binds S100A12 with high affinity. Amino Acids 49, 183–191 (2017).

    CAS  PubMed  Google Scholar 

  28. Baranova, I. N. et al. Serum amyloid A binding to CLA-1 (CD36 and LIMPII analogous-1) mediates serum amyloid A protein-induced activation of ERK1/2 and p38 mitogen-activated protein kinases. J. Biol. Chem. 280, 8031–8040 (2005).

    CAS  PubMed  Google Scholar 

  29. Baranova, I. N. et al. CD36 is a novel serum amyloid A (SAA) receptor mediating SAA binding and SAA-induced signaling in human and rodent cells. J. Biol. Chem. 285, 8492–8506 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Demers, A. et al. Identification of the growth hormone-releasing peptide binding site in CD36: a photoaffinity cross-linking study. Biochem. J. 382, 417–424 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Marleau, S. et al. EP 80317, a ligand of the CD36 scavenger receptor, protects apolipoprotein E-deficient mice from developing atherosclerotic lesions. FASEB J. 19, 1869–1871 (2005).

    CAS  PubMed  Google Scholar 

  32. Albert, M. L. et al. Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J. Exp. Med. 188, 1359–1368 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhou, J. et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 134, 556–567 (2008).

    CAS  PubMed  Google Scholar 

  34. Kim, T. T. & Dyck, J. R. The role of CD36 in the regulation of myocardial lipid metabolism. Biochim. Biophys. Acta 1860, 1450–1460 (2016).

    Google Scholar 

  35. Kumar, S., Gowda, N. M., Wu, X., Gowda, R. N. & Gowda, D. C. CD36 modulates proinflammatory cytokine responses to Plasmodium falciparum glycosylphosphatidylinositols and merozoites by dendritic cells. Parasite Immunol. 34, 372–382 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Samovski, D. et al. Regulation of AMPK activation by CD36 links fatty acid uptake to beta-oxidation. Diabetes 64, 353–359 (2015).

    CAS  PubMed  Google Scholar 

  37. Nagendran, J. et al. Cardiomyocyte-specific ablation of CD36 improves post-ischemic functional recovery. J. Mol. Cell. Cardiol. 63, 180–188 (2013).

    CAS  PubMed  Google Scholar 

  38. Silverstein, R. L. & Febbraio, M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior. Sci. Signal. 2, re3 (2009).

    PubMed  PubMed Central  Google Scholar 

  39. Meyer, C., Nadkarni, V., Stumvoll, M. & Gerich, J. Human kidney free fatty acid and glucose uptake: evidence for a renal glucose-fatty acid cycle. Am. J. Physiol. 273, E650–E654 (1997).

    CAS  PubMed  Google Scholar 

  40. Kang, H. M. et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nature Med. 21, 37–46 (2015).

    CAS  PubMed  Google Scholar 

  41. Souza, A. C. et al. Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation. Kidney Int. 89, 809–822 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Armesilla, A. L. & Vega, M. A. Structural organization of the gene for human CD36 glycoprotein. J. Biol. Chem. 269, 18985–18991 (1994).

    CAS  PubMed  Google Scholar 

  43. Ma, X. et al. A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians. Hum. Mol. Genet. 13, 2197–2205 (2004).

    CAS  PubMed  Google Scholar 

  44. Jedidi, I. et al. Cholesteryl ester hydroperoxides increase macrophage CD36 gene expression via PPARalpha. Biochem. Biophys. Res. Commun. 351, 733–738 (2006).

    CAS  PubMed  Google Scholar 

  45. Goto, K. et al. Peroxisome proliferator-activated receptor-gamma in capillary endothelia promotes fatty acid uptake by heart during long-term fasting. J. Am. Heart Associ. 2, e004861 (2013).

    Google Scholar 

  46. Feng, L., Gu, C., Li, Y. & Huang, J. High glucose promotes CD36 expression by upregulating peroxisome proliferator-activated receptor gamma levels to exacerbate lipid deposition in renal tubular cells. Biomed. Res. Int. 2017, 1414070 (2017).

    PubMed  PubMed Central  Google Scholar 

  47. Li, H. et al. EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent mechanism. Kidney Int. 67, 867–874 (2005).

    CAS  PubMed  Google Scholar 

  48. Patel, M. et al. Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice. Diabetologia 57, 435–446 (2014).

    CAS  PubMed  Google Scholar 

  49. Tachibana, H. et al. Activation of liver X receptor inhibits osteopontin and ameliorates diabetic nephropathy. J. Am. Soc. Nephrol. 23, 1835–1846 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kiss, E. et al. Lipid droplet accumulation is associated with an increase in hyperglycemia-induced renal damage: prevention by liver X receptors. Am. J. Pathol. 182, 727–741 (2013).

    CAS  PubMed  Google Scholar 

  51. Han, J., Hajjar, D. P., Febbraio, M. & Nicholson, A. C. Native and modified low density lipoproteins increase the functional expression of the macrophage class B scavenger receptor, CD36. J. Biol. Chem. 272, 21654–21659 (1997).

    CAS  PubMed  Google Scholar 

  52. Tontonoz, P., Nagy, L., Alvarez, J. G., Thomazy, V. A. & Evans, R. M. PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93, 241–252 (1998).

    CAS  PubMed  Google Scholar 

  53. Febbraio, M. et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J. Clin. Invest. 105, 1049–1056 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Ren, J., Jin, W. & Chen, H. oxHDL decreases the expression of CD36 on human macrophages through PPARgamma and p38 MAP kinase dependent mechanisms. Mol. Cell. Biochem. 342, 171–181 (2010).

    CAS  PubMed  Google Scholar 

  55. Zhang, C. et al. Lysophosphatidic acid induces neointima formation through PPARgamma activation. J. Exp. Med. 199, 763–774 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ren, B., Hale, J., Srikanthan, S. & Silverstein, R. L. Lysophosphatidic acid suppresses endothelial cell CD36 expression and promotes angiogenesis via a PKD-1-dependent signaling pathway. Blood 117, 6036–6045 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Ren, B. et al. LPA/PKD-1-FoxO1 signaling axis mediates endothelial cell CD36 transcriptional repression and proangiogenic and proarteriogenic reprogramming. Arterioscler. Thromb. Vasc. Biol. 36, 1197–1208 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Song, K. H., Park, J. & Ha, H. High glucose increases mesangial lipid accumulation via impaired cholesterol transporters. Transplant. Proc. 44, 1021–1025 (2012).

    CAS  PubMed  Google Scholar 

  59. Chabowski, A. et al. Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm. Am. J. Physiol. Endocrinol. Metab. 287, E781–E789 (2004).

    CAS  PubMed  Google Scholar 

  60. Yesner, L. M., Huh, H. Y., Pearce, S. F. & Silverstein, R. L. Regulation of monocyte CD36 and thrombospondin-1 expression by soluble mediators. Arterioscler. Thromb. Vasc. Biol. 16, 1019–1025 (1996).

    CAS  PubMed  Google Scholar 

  61. Yamamoto, T. et al. Role of catalase in monocytic differentiation of U937 cells by TPA: hydrogen peroxide as a second messenger. Leukemia 23, 761–769 (2009).

    CAS  PubMed  Google Scholar 

  62. Huh, H. Y., Lo, S. K., Yesner, L. M. & Silverstein, R. L. CD36 induction on human monocytes upon adhesion to tumor necrosis factor-activated endothelial cells. J. Biol. Chem. 270, 6267–6271 (1995).

    CAS  PubMed  Google Scholar 

  63. Feng, J. et al. Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-gamma. J. Lipid Res. 41, 688–696 (2000).

    CAS  PubMed  Google Scholar 

  64. Svensson, L. et al. Fatty acids modulate the effect of darglitazone on macrophage CD36 expression. Eur. J. Clin. Invest. 33, 464–471 (2003).

    CAS  PubMed  Google Scholar 

  65. Hirakata, M., Tozawa, R., Imura, Y. & Sugiyama, Y. Comparison of the effects of pioglitazone and rosiglitazone on macrophage foam cell formation. Biochem. Biophys. Res. Commun. 323, 782–788 (2004).

    CAS  PubMed  Google Scholar 

  66. Liu, F. et al. Effects of Porphyromonas gingivalis lipopolysaccharide on the expression of key genes involved in cholesterol metabolism in macrophages. Arch. Med. Sci. 12, 959–967 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Panousis, C. G. & Zuckerman, S. H. Regulation of cholesterol distribution in macrophage-derived foam cells by interferon-gamma. J. Lipid Res. 41, 75–83 (2000).

    CAS  PubMed  Google Scholar 

  68. Han, J. et al. Transforming growth factor-beta1 (TGF-β1) and TGF-β2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-γ. J. Biol. Chem. 275, 1241–1246 (2000).

    CAS  PubMed  Google Scholar 

  69. Yu, M. et al. Inhibition of macrophage CD36 expression and cellular oxidized low density lipoprotein (oxLDL) accumulation by tamoxifen: a peroxisome proliferator-activated receptor (PPAR)γ-dependent mechanism. J. Biol. Chem. 291, 16977–16989 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Carvalho, M. D. et al. High-density lipoprotein inhibits the uptake of modified low- density lipoprotein and the expression of CD36 and FcγRI. J. Atheroscler. Thromb. 17, 844–857 (2010).

    CAS  PubMed  Google Scholar 

  71. Bruni, F. et al. Different effect of statins on platelet oxidized-LDL receptor (CD36 and LOX-1) expression in hypercholesterolemic subjects. Clin. Appl. Thromb. Hemost. 11, 417–428 (2005).

    CAS  PubMed  Google Scholar 

  72. Abumrad, N. A., el-Maghrabi, M. R., Amri, E. Z., Lopez, E. & Grimaldi, P. A. Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36. J. Biol. Chem. 268, 17665–17668 (1993).

    CAS  PubMed  Google Scholar 

  73. Vega, M. A. et al. Cloning, sequencing, and expression of a cDNA encoding rat LIMP II, a novel 74-kDa lysosomal membrane protein related to the surface adhesion protein CD36. J. Biol. Chem. 266, 16818–16824 (1991).

    CAS  PubMed  Google Scholar 

  74. Neculai, D. et al. Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. Nature 504, 172–176 (2013).

    CAS  PubMed  Google Scholar 

  75. Doi, T. et al. Charged collagen structure mediates the recognition of negatively charged macromolecules by macrophage scavenger receptors. J. Biol. Chem. 268, 2126–2133 (1993).

    CAS  PubMed  Google Scholar 

  76. Klenotic, P. A. et al. Molecular basis of antiangiogenic thrombospondin-1 type 1 repeat domain interactions with CD36. Arterioscler. Thromb. Vasc. Biol. 33, 1655–1662 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Jimenez-Dalmaroni, M. J. et al. Soluble CD36 ectodomain binds negatively charged diacylglycerol ligands and acts as a co-receptor for TLR2. PLoS ONE 4, e7411 (2009).

    PubMed  PubMed Central  Google Scholar 

  78. Wang, L. et al. Discovery of antagonists for human scavenger receptor CD36 via an ELISA-like high-throughput screening assay. J. Biomol. Screen. 15, 239–250 (2010).

    CAS  PubMed  Google Scholar 

  79. Driscoll, W. S., Vaisar, T., Tang, J., Wilson, C. L. & Raines, E. W. Macrophage ADAM17 deficiency augments CD36-dependent apoptotic cell uptake and the linked anti-inflammatory phenotype. Circ. Res. 113, 52–61 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Alkhatatbeh, M. J., Mhaidat, N. M., Enjeti, A. K., Lincz, L. F. & Thorne, R. F. The putative diabetic plasma marker, soluble CD36, is non-cleaved, non-soluble and entirely associated with microparticles. J. Thromb. Haemost. 9, 844–851 (2011).

    CAS  PubMed  Google Scholar 

  81. Luiken, J. J., Chanda, D., Nabben, M., Neumann, D. & Glatz, J. F. Post-translational modifications of CD36 (SR-B2): Implications for regulation of myocellular fatty acid uptake. Biochim. Biophys. Acta 1862, 2253–2258 (2016).

    CAS  PubMed  Google Scholar 

  82. Lundby, A. et al. Proteomic analysis of lysine acetylation sites in rat tissues reveals organ specificity and subcellular patterns. Cell Rep. 2, 419–431 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Kuda, O. et al. Sulfo-N-succinimidyl oleate (SSO) inhibits fatty acid uptake and signaling for intracellular calcium via binding CD36 lysine 164: SSO also inhibits oxidized low density lipoprotein uptake by macrophages. J. Biol. Chem. 288, 15547–15555 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Hatmi, M., Gavaret, J. M., Elalamy, I., Vargaftig, B. B. & Jacquemin, C. Evidence for cAMP-dependent platelet ectoprotein kinase activity that phosphorylates platelet glycoprotein IV (CD36). J. Biol. Chem. 271, 24776–24780 (1996).

    CAS  PubMed  Google Scholar 

  85. Asch, A. S. et al. Analysis of CD36 binding domains: ligand specificity controlled by dephosphorylation of an ectodomain. Science 262, 1436–1440 (1993).

    CAS  PubMed  Google Scholar 

  86. Chu, L. Y. & Silverstein, R. L. CD36 ectodomain phosphorylation blocks thrombospondin-1 binding: structure-function relationships and regulation by protein kinase C. Arterioscler. Thromb. Vasc. Biol. 32, 760–767 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ho, M. et al. Ectophosphorylation of CD36 regulates cytoadherence of Plasmodium falciparum to microvascular endothelium under flow conditions. Infect. Immun. 73, 8179–8187 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Guthmann, F., Maehl, P., Preiss, J., Kolleck, I. & Rustow, B. Ectoprotein kinase-mediated phosphorylation of FAT/CD36 regulates palmitate uptake by human platelets. Cell. Mol. Life Sci. 59, 1999–2003 (2002).

    CAS  PubMed  Google Scholar 

  89. Lynes, M., Narisawa, S., Millan, J. L. & Widmaier, E. P. Interactions between CD36 and global intestinal alkaline phosphatase in mouse small intestine and effects of high-fat diet. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1738–R1747 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Moremen, K. W., Tiemeyer, M. & Nairn, A. V. Vertebrate protein glycosylation: diversity, synthesis and function. Nat. Rev. Mol. Cell Biol. 13, 448–462 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Hoosdally, S. J., Andress, E. J., Wooding, C., Martin, C. A. & Linton, K. J. The human scavenger receptor CD36: glycosylation status and its role in trafficking and function. J. Biol. Chem. 284, 16277–16288 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Lauzier, B. et al. Post-translational modifications, a key process in CD36 function: lessons from the spontaneously hypertensive rat heart. J. Mol. Cell. Cardiol. 51, 99–108 (2011).

    CAS  PubMed  Google Scholar 

  93. Tao, N., Wagner, S. J. & Lublin, D. M. CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails. J. Biol. Chem. 271, 22315–22320 (1996).

    CAS  PubMed  Google Scholar 

  94. Aicart-Ramos, C., Valero, R. A. & Rodriguez-Crespo, I. Protein palmitoylation and subcellular trafficking. Biochim. Biophys. Acta 1808, 2981–2994 (2011).

    CAS  PubMed  Google Scholar 

  95. Thorne, R. F. et al. Palmitoylation of CD36/FAT regulates the rate of its post-transcriptional processing in the endoplasmic reticulum. Biochim. Biophys. Acta 1803, 1298–1307 (2010).

    CAS  PubMed  Google Scholar 

  96. Wang, C. et al. Inflammatory stress increases hepatic CD36 translational efficiency via activation of the mTOR signalling pathway. PLoS ONE 9, e103071 (2014).

    PubMed  PubMed Central  Google Scholar 

  97. Smith, J., Su, X., El-Maghrabi, R., Stahl, P. D. & Abumrad, N. A. Opposite regulation of CD36 ubiquitination by fatty acids and insulin: effects on fatty acid uptake. J. Biol. Chem. 283, 13578–13585 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Srikanthan, S., Li, W., Silverstein, R. L. & McIntyre, T. M. Exosome poly-ubiquitin inhibits platelet activation, downregulates CD36 and inhibits pro-atherothombotic cellular functions. J. Thromb. Haemost. 12, 1906–1917 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Abumrad, N. A. & Moore, D. J. Parkin reinvents itself to regulate fatty acid metabolism by tagging CD36. J. Clin. Invest. 121, 3389–3392 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Kim, K. Y. et al. Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells. J. Clin. Invest. 121, 3701–3712 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Shimura, H. et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet. 25, 302–305 (2000).

    CAS  PubMed  Google Scholar 

  102. Yamaguchi, H. et al. p53 acetylation is crucial for its transcription-independent proapoptotic functions. J. Biol. Chem. 284, 11171–11183 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Starheim, K. K. et al. Knockdown of human N alpha-terminal acetyltransferase complex C leads to p53-dependent apoptosis and aberrant human Arl8b localization. Mol. Cell. Biol. 29, 3569–3581 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Garcia-Aguilar, A., Guillen, C., Nellist, M., Bartolome, A. & Benito, M. TSC2 N-terminal lysine acetylation status affects to its stability modulating mTORC1 signaling and autophagy. Biochim. Biophys. Acta 1863, 2658–2667 (2016).

    CAS  PubMed  Google Scholar 

  105. Bonen, A., Luiken, J. J., Arumugam, Y., Glatz, J. F. & Tandon, N. N. Acute regulation of fatty acid uptake involves the cellular redistribution of fatty acid translocase. J. Biol. Chem. 275, 14501–14508 (2000).

    CAS  PubMed  Google Scholar 

  106. Luiken, J. J. et al. Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36. Diabetes 51, 3113–3119 (2002).

    CAS  PubMed  Google Scholar 

  107. Lombardi, A. et al. Responses of skeletal muscle lipid metabolism in rat gastrocnemius to hypothyroidism and iodothyronine administration: a putative role for FAT/CD36. Am. J. Physiol. Endocrinol. Metab. 303, E1222–E1233 (2012).

    CAS  PubMed  Google Scholar 

  108. Georgiou, D. K. et al. Ca2+ binding/permeation via calcium channel, CaV1.1, regulates the intracellular distribution of the fatty acid transport protein, CD36, and fatty acid metabolism. J. Biol. Chem. 290, 23751–23765 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Luiken, J. J. et al. Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling. Diabetes 52, 1627–1634 (2003).

    CAS  PubMed  Google Scholar 

  110. Jeppesen, J. et al. Contraction-induced skeletal muscle FAT/CD36 trafficking and FA uptake is AMPK independent. J. Lipid Res. 52, 699–711 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Thorne, R. F. et al. CD36 forms covalently associated dimers and multimers in platelets and transfected COS-7 cells. Biochem. Biophys. Res. Commun. 240, 812–818 (1997).

    CAS  PubMed  Google Scholar 

  112. Wei, P. et al. Critical residues and motifs for homodimerization of the first transmembrane domain of the plasma membrane glycoprotein CD36. J. Biol. Chem. 292, 8683–8693 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Moorhead, J. F., Chan, M. K., El-Nahas, M. & Varghese, Z. Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease. Lancet 2, 1309–1311 (1982).

    CAS  PubMed  Google Scholar 

  114. Ruan, X. Z., Varghese, Z. & Moorhead, J. F. An update on the lipid nephrotoxicity hypothesis. Nat. Rev. Nephrol. 5, 713–721 (2009).

    CAS  PubMed  Google Scholar 

  115. de Vries, A. P. et al. Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease. Lancet Diabetes Endocrinol. 2, 417–426 (2014).

    CAS  PubMed  Google Scholar 

  116. Nieth, H. & Schollmeyer, P. Substrate-utilization of the human kidney. Nature 209, 1244–1245 (1966).

    CAS  PubMed  Google Scholar 

  117. Druilhet, R. E., Overturf, M. L. & Kirkendall, W. M. Structure of neutral glycerides and phosphoglycerides of human kidney. Int. J. Biochem. 6, 893–901 (1975).

    CAS  Google Scholar 

  118. Gold, M. & Spitzer, J. J. Metabolism of free fatty acids by myocardium and kidney. Am. J. Physiol. 206, 153–158 (1964).

    CAS  PubMed  Google Scholar 

  119. Stremmel, W., Pohl, L., Ring, A. & Herrmann, T. A new concept of cellular uptake and intracellular trafficking of long-chain fatty acids. Lipids 36, 981–989 (2001).

    CAS  PubMed  Google Scholar 

  120. Birn, H. & Christensen, E. I. Renal albumin absorption in physiology and pathology. Kidney Int. 69, 440–449 (2006).

    CAS  PubMed  Google Scholar 

  121. Scerbo, D. et al. Kidney triglyceride accumulation in the fasted mouse is dependent upon serum free fatty acids. J. Lipid Res. 58, 1132–1142 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Okamura, D. M. et al. CD36 regulates oxidative stress and inflammation in hypercholesterolemic CKD. J. Am. Soc. Nephrol. 20, 495–505 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Bosmans, J. L. et al. Oxidative modification of low-density lipoproteins and the outcome of renal allografts at 1 1/2 years. Kidney Int. 59, 2346–2356 (2001).

    CAS  PubMed  Google Scholar 

  124. Reddy, S. et al. Interaction of Interceed oxidized regenerated cellulose with macrophages: a potential mechanism by which Interceed may prevent adhesions. Am. J. Obstet. Gynecol. 177, 1315–1321 (1997).

    CAS  PubMed  Google Scholar 

  125. Pennathur, S. et al. The macrophage phagocytic receptor CD36 promotes fibrogenic pathways on removal of apoptotic cells during chronic kidney injury. Am. J. Pathol. 185, 2232–2245 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Sheedy, F. J. et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol. 14, 812–820 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Ferretti, G. et al. Structural modifications of HDL and functional consequences. Atherosclerosis 184, 1–7 (2006).

    CAS  PubMed  Google Scholar 

  128. Yu, R. et al. Proatherogenic high-density lipoprotein, vascular inflammation, and mimetic peptides. Curr. Atheroscler. Rep. 10, 171–176 (2008).

    PubMed  Google Scholar 

  129. Tsumura, M., Kinouchi, T., Ono, S., Nakajima, T. & Komoda, T. Serum lipid metabolism abnormalities and change in lipoprotein contents in patients with advanced-stage renal disease. Clin. Chim. Acta 314, 27–37 (2001).

    CAS  PubMed  Google Scholar 

  130. Gao, X. et al. Oxidized high-density lipoprotein impairs the function of human renal proximal tubule epithelial cells through CD36. Int. J. Mol. Med. 34, 564–572 (2014).

    CAS  PubMed  Google Scholar 

  131. Descamps-Latscha, B. et al. Advanced oxidation protein products as risk factors for atherosclerotic cardiovascular events in nondiabetic predialysis patients. Am. J. Kidney Dis. 45, 39–47 (2005).

    CAS  PubMed  Google Scholar 

  132. Zhou, Q. et al. Accumulation of circulating advanced oxidation protein products is an independent risk factor for ischaemic heart disease in maintenance haemodialysis patients. Nephrology (Carlton) 17, 642–649 (2012).

    CAS  Google Scholar 

  133. Cao, W. et al. Advanced oxidation protein products activate intrarenal renin-angiotensin system via a CD36-mediated, redox-dependent pathway. Antioxid. Redox Signal. 18, 19–35 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Bige, N. et al. Thrombospondin-1 plays a profibrotic and pro-inflammatory role during ureteric obstruction. Kidney Int. 81, 1,226–1238 (2017).

    Google Scholar 

  135. Cui, W. et al. Interaction of thrombospondin1 and CD36 contributes to obesity-associated podocytopathy. Biochim. Biophys. Acta 1852, 1323–1333 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Yehualaeshet, T. et al. A CD36 synthetic peptide inhibits bleomycin-induced pulmonary inflammation and connective tissue synthesis in the rat. Am. J. Respir. Cell Mol. Biol. 23, 204–212 (2000).

    CAS  PubMed  Google Scholar 

  137. Thakar, C. V. et al. Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia. J. Clin. Invest. 115, 3451–3459 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Maimaitiyiming, H., Zhou, Q. & Wang, S. Thrombospondin 1 deficiency ameliorates the development of adriamycin-induced proteinuric kidney disease. PLoS ONE 11, e0156144 (2016).

    PubMed  PubMed Central  Google Scholar 

  139. Simantov, R. et al. Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1. J. Clin. Invest. 107, 45–52 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Dawson, D. W. et al. CD36 mediates the In vitro inhibitory effects of thrombospondin-1 on endothelial cells. J. Cell Biol. 138, 707–717 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Xanthis, A. et al. Receptor of advanced glycation end products (RAGE) positively regulates CD36 expression and reactive oxygen species production in human monocytes in diabetes. Angiology 60, 772–779 (2009).

    CAS  PubMed  Google Scholar 

  142. de Oliveira Silva, C. et al. Modulation of CD36 protein expression by AGEs and insulin in aortic VSMCs from diabetic and non-diabetic rats. Nutr. Metab. Cardiovasc. Dis. 18, 23–30 (2008).

    PubMed  Google Scholar 

  143. Xu, L., Wang, Y. R., Li, P. C. & Feng, B. Advanced glycation end products increase lipids accumulation in macrophages through upregulation of receptor of advanced glycation end products: increasing uptake, esterification and decreasing efflux of cholesterol. Lipids Health Dis. 15, 161 (2016).

    PubMed  PubMed Central  Google Scholar 

  144. Hodgkinson, C. P., Laxton, R. C., Patel, K. & Ye, S. Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 28, 2275–2281 (2008).

    CAS  PubMed  Google Scholar 

  145. Kidd, J. & Carl, D. E. Renal amyloidosis. Curr. Probl. Cancer 40, 209–219 (2016).

    PubMed  Google Scholar 

  146. Hou, Y. et al. CD36 is involved in high glucose-induced epithelial to mesenchymal transition in renal tubular epithelial cells. Biochem. Biophys. Res. Commun. 468, 281–286 (2015).

    CAS  PubMed  Google Scholar 

  147. Yang, Y. L. et al. CD36 is a novel and potential anti-fibrogenic target in albumin-induced renal proximal tubule fibrosis. J. Cell. Biochem. 101, 735–744 (2007).

    CAS  PubMed  Google Scholar 

  148. Brown, P. M., Kennedy, D. J., Morton, R. E. & Febbraio, M. CD36/SR-B2-TLR2 dependent pathways enhance Porphyromonas gingivalis mediated atherosclerosis in the Ldlr KO mouse model. PLoS ONE 10, e0125126 (2015).

    PubMed  PubMed Central  Google Scholar 

  149. Li, Y., Qi, X., Tong, X. & Wang, S. Thrombospondin 1 activates the macrophage Toll-like receptor 4 pathway. Cell. Mol. Immunol. 10, 506–512 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Stewart, C. R. et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat. Immunol. 11, 155–161 (2010).

    CAS  PubMed  Google Scholar 

  151. Huang, W., Febbraio, M. & Silverstein, R. L. CD9 tetraspanin interacts with CD36 on the surface of macrophages: a possible regulatory influence on uptake of oxidized low density lipoprotein. PLoS ONE 6, e29092 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Yakubenko, V. P., Bhattacharjee, A., Pluskota, E. & Cathcart, M. K. alphaMbeta(2) integrin activation prevents alternative activation of human and murine macrophages and impedes foam cell formation. Circ. Res. 108, 544–554 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Antonov, A. S., Kolodgie, F. D., Munn, D. H. & Gerrity, R. G. Regulation of macrophage foam cell formation by alphaVbeta3 integrin: potential role in human atherosclerosis. Am. J. Pathol. 165, 247–258 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Zhang, M. et al. Oxidized high-density lipoprotein enhances inflammatory activity in rat mesangial cells. Diabetes Metab. Res. Rev. 26, 455–463 (2010).

    CAS  PubMed  Google Scholar 

  155. Thomas, M. E., Harris, K. P., Walls, J., Furness, P. N. & Brunskill, N. J. Fatty acids exacerbate tubulointerstitial injury in protein-overload proteinuria. Am. J. Physiol. Renal Physiol. 283, F640–F647 (2002).

    PubMed  Google Scholar 

  156. Chmielewski, M. et al. Expression of scavenger receptor CD36 in chronic renal failure patients. Artif. Organs 29, 608–614 (2005).

    CAS  PubMed  Google Scholar 

  157. Wu, C. C. et al. Aberrant activation of the TNF-alpha system and production of Fas and scavenger receptors on monocytes in patients with end-stage renal disease. Artif. Organs 29, 701–707 (2005).

    CAS  PubMed  Google Scholar 

  158. Murakoshi, M. et al. Pleiotropic effect of pyridoxamine on diabetic complications via CD36 expression in KK-Ay/Ta mice. Diabetes Res. Clin. Pract. 83, 183–189 (2009).

    CAS  PubMed  Google Scholar 

  159. Sas, K. M. et al. Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications. JCI Insight 1, e86976 (2016).

    PubMed  PubMed Central  Google Scholar 

  160. Ruggiero, C. et al. Albumin-bound fatty acids but not albumin itself alter redox balance in tubular epithelial cells and induce a peroxide-mediated redox-sensitive apoptosis. Am. J. Physiol. Renal Physiol. 306, F 896–F906 (2014).

    CAS  Google Scholar 

  161. Campbell, S. E. et al. A novel function for fatty acid translocase (FAT)/CD36: involvement in long chain fatty acid transfer into the mitochondria. J. Biol. Chem. 279, 36235–36241 (2004).

    CAS  PubMed  Google Scholar 

  162. Muoio, D. M. et al. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab. 15, 764–777 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Stadler, K., Goldberg, I. J. & Susztak, K. The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease. Curr. Diabetes Rep. 15, 40 (2015).

    Google Scholar 

  164. Markwell, M. A., McGroarty, E. J., Bieber, L. L. & Tolbert, N. E. The subcellular distribution of carnitine acyltransferases in mammalian liver and kidney. A new peroxisomal enzyme. J. Biol. Chem. 248, 3426–3432 (1973).

    CAS  PubMed  Google Scholar 

  165. Haynie, K. R., Vandanmagsar, B., Wicks, S. E., Zhang, J. & Mynatt, R. L. Inhibition of carnitine palymitoyltransferase1b induces cardiac hypertrophy and mortality in mice. Diabetes Obes. Metab. 16, 757–760 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Vickers, A. E. Characterization of hepatic mitochondrial injury induced by fatty acid oxidation inhibitors. Toxicol. Pathol. 37, 78–88 (2009).

    CAS  PubMed  Google Scholar 

  167. Hardie, D. G. AMP-activated protein kinase: the guardian of cardiac energy status. J. Clin. Invest. 114, 465–468 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Hardie, D. G., Schaffer, B. E. & Brunet, A. AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol. 26, 190–201 (2016).

    CAS  PubMed  Google Scholar 

  169. Glatz, J. F., Luiken, J. J. & Bonen, A. Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol. Rev. 90, 367–417 (2010).

    CAS  PubMed  Google Scholar 

  170. Angin, Y. et al. Calcium signaling recruits substrate transporters GLUT4 and CD36 to the sarcolemma without increasing cardiac substrate uptake. Am. J. Physiol. Endocrinol. Metab. 307, E225–E236 (2014).

    CAS  PubMed  Google Scholar 

  171. Ruderman, N. B., Carling, D., Prentki, M. & Cacicedo, J. M. AMPK, insulin resistance, and the metabolic syndrome. J. Clin. Invest. 123, 2764–2772 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Pietka, T. A. et al. CD36 protein influences myocardial Ca2+ homeostasis and phospholipid metabolism: conduction anomalies in CD36-deficient mice during fasting. J. Biol. Chem. 287, 38901–38912 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Han, S. H. et al. Deletion of Lkb1 in renal tubular epithelial cells leads to CKD by altering metabolism. J. Am. Soc. Nephrol. 27, 439–453 (2016).

    CAS  PubMed  Google Scholar 

  174. Handberg, A., Levin, K., Hojlund, K. & Beck-Nielsen, H. Identification of the oxidized low-density lipoprotein scavenger receptor CD36 in plasma: a novel marker of insulin resistance. Circulation 114, 1169–1176 (2006).

    CAS  PubMed  Google Scholar 

  175. Chmielewski, M., Bragfors-Helin, A. C., Stenvinkel, P., Lindholm, B. & Anderstam, B. Serum soluble CD36, assessed by a novel monoclonal antibody-based sandwich ELISA, predicts cardiovascular mortality in dialysis patients. Clin. Chim. Acta 411, 2079–2082 (2010).

    CAS  PubMed  Google Scholar 

  176. Liani, R. et al. Plasma levels of soluble CD36, platelet activation, inflammation, and oxidative stress are increased in type 2 diabetic patients. Free Radic. Biol. Med. 52, 1318–1324 (2012).

    CAS  PubMed  Google Scholar 

  177. Handberg, A. et al. Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population. J. Intern. Med. 271, 294–304 (2012).

    CAS  PubMed  Google Scholar 

  178. Handberg, A. et al. Soluble CD36 in plasma is increased in patients with symptomatic atherosclerotic carotid plaques and is related to plaque instability. Stroke 39, 3092–3095 (2008).

    CAS  PubMed  Google Scholar 

  179. Shiju, T. M., Mohan, V., Balasubramanyam, M. & Viswanathan, P. Soluble CD36 in plasma and urine: a plausible prognostic marker for diabetic nephropathy. J. Diabetes Complications 29, 400–406 (2015).

    PubMed  Google Scholar 

  180. Garcia-Monzon, C. et al. Increased soluble CD36 is linked to advanced steatosis in nonalcoholic fatty liver disease. Eur. J. Clin. Invest. 44, 65–73 (2014).

    CAS  PubMed  Google Scholar 

  181. Knosgaard, L., Thomsen, S. B., Stockel, M., Vestergaard, H. & Handberg, A. Circulating sCD36 is associated with unhealthy fat distribution and elevated circulating triglycerides in morbidly obese individuals. Nutr. Diabetes 4, e114 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Ramos-Arellano, L. E. et al. Circulating CD36 and oxLDL levels are associated with cardiovascular risk factors in young subjects. BMC Cardiovasc. Disord. 14, 54 (2014).

    PubMed  PubMed Central  Google Scholar 

  183. Alkhatatbeh, M. J., Ayoub, N. M., Mhaidat, N. M., Saadeh, N. A. & Lincz, L. F. Soluble cluster of differentiation 36 concentrations are not associated with cardiovascular risk factors in middle-aged subjects. Biomed. Rep. 4, 642–648 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Krzystolik, A. et al. Is plasma soluble CD36 associated with cardiovascular risk factors in early onset coronary artery disease patients? Scand. J. Clin. Lab. Invest. 75, 398–406 (2015).

    CAS  PubMed  Google Scholar 

  185. Lykkeboe, S., Larsen, A. L. & Handberg, A. Lack of consistency between two commercial ELISAs and against an in-house ELISA for the detection of CD36 in human plasma. Clin. Chem. Lab. Med. 50, 1071–1074 (2012).

    CAS  PubMed  Google Scholar 

  186. Bello, A. K. et al. Effective CKD care in European countries: challenges and opportunities for health policy. Am. J. Kidney Dis. 65, 15–25 (2015).

    PubMed  Google Scholar 

  187. Saran, R. et al. US renal data system 2016 annual data report: epidemiology of kidney disease in the United States. Am. J. Kidney Dis. 69, A7–A8 (2017).

    PubMed  PubMed Central  Google Scholar 

  188. Baines, R. J. et al. CD36 mediates proximal tubular binding and uptake of albumin and is upregulated in proteinuric nephropathies. Am. J. Physiol. Renal Physiol. 303, F1006–F1014 (2012).

    CAS  PubMed  Google Scholar 

  189. Xu, S. et al. Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress. Cell Death Dis. 6, e1976 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Anantharamaiah, G. M. et al. Structural requirements for antioxidative and anti-inflammatory properties of apolipoprotein A-I mimetic peptides. J. Lipid Res. 48, 1915–1923 (2007).

    CAS  PubMed  Google Scholar 

  191. Luo, C. C., Li, W. H., Moore, M. N. & Chan, L. Structure and evolution of the apolipoprotein multigene family. J. Mol. Biol. 187, 325–340 (1986).

    CAS  PubMed  Google Scholar 

  192. Bocharov, A. V. et al. Targeting of scavenger receptor class B type I by synthetic amphipathic alpha-helical-containing peptides blocks lipopolysaccharide (LPS) uptake and LPS-induced pro-inflammatory cytokine responses in THP-1 monocyte cells. J. Biol. Chem. 279, 36072–36082 (2004).

    CAS  PubMed  Google Scholar 

  193. Bocharov, A. V. et al. Synthetic amphipathic helical peptides targeting CD36 attenuate lipopolysaccharide-induced inflammation and acute lung injury. J. Immunol. 197, 611–619 (2016).

    CAS  PubMed  Google Scholar 

  194. Zhang, J., Mulumba, M., Ong, H. & Lubell, W. D. Diversity-oriented synthesis of cyclic azapeptides by A3-macrocyclization provides high-affinity CD36-modulating peptidomimetics. Angew. Chem. Int. Ed Engl. 56, 6284–6288 (2017).

    CAS  PubMed  Google Scholar 

  195. Bessi, V. L. et al. EP 80317, a selective CD36 ligand, shows cardioprotective effects against post-ischaemic myocardial damage in mice. Cardiovasc. Res. 96, 99–108 (2012).

    CAS  PubMed  Google Scholar 

  196. Meiler, S. et al. Selenoprotein K is required for palmitoylation of CD36 in macrophages: implications in foam cell formation and atherogenesis. J. Leukoc. Biol. 93, 771–780 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Simon, N. & Hertig, A. Alteration of fatty acid oxidation in tubular epithelial cells: from acute kidney injury to renal fibrogenesis. Front. Med. (Lausanne) 2, 52 (2015).

    Google Scholar 

  198. Nicholson, A. C., Han, J., Febbraio, M., Silversterin, R. L. & Hajjar, D. P. Role of CD36, the macrophage class B scavenger receptor, in atherosclerosis. Ann. N. Y. Acad. Sci. 947, 224–228 (2001).

    CAS  PubMed  Google Scholar 

  199. Apostolov, E. O. et al. Carbamylated-oxidized LDL: proatherosclerotic effects on endothelial cells and macrophages. J. Atheroscler. Thromb. 20, 878–892 (2013).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors' work is supported in part by grants from the Shenzhen Peacock Plan (KQTD20140630100746562), Shenzhen Research Projects (JCYJ20140509172719310, CXZZ20150601140615135), the National Natural Science Foundation of China (Key Program, No. 81390354, 81270789; Young Scientists Program, No. 31701022), and the National Institutes of Health (5 K08 DK073497 and 5 R03 DK083648 (D.M.O.)).

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  1. Xiaochun Yang and Daryl M. Okamura: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Nephrology & Urology, Shenzhen University Health Science Center, 3688 Nanhai Avenue, Shenzhen, 518060, China

    Xiaochun Yang & Xifeng Lu

  2. Seattle Children's Research Institute, Center for Developmental Biology & Regenerative Medicine, University of Washington, 1900 9th Avenue, C9S-5, Seattle, 98101, Washington, USA

    Daryl M. Okamura

  3. Department of Infectious Diseases, Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400016, China

    Yaxi Chen & Xiong Z. Ruan

  4. John Moorhead Laboratory, Centre for Nephrology, University College London, Rowland Hill Street, London, NW3 2PF, UK

    John Moorhead, Zac Varghese & Xiong Z. Ruan

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  1. Xiaochun Yang
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Contributions

X.Y., D.M.O., X.L. and Y.C. researched the data and wrote the manuscript. X.Z.R. contributed to the writing, reviewing and editing of the manuscript. J.M. and Z.V. critically read and revised the manuscript before submission.

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Metabolic inflammation

Low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy load.

Foam cell

Foam cells are an indicator of plaque build-up or atherosclerosis. They result from excessive influx of modified LDL and accumulation of cholesterol esters in intimal macrophages.

Efferocytosis

The process by which dead or dying cells are removed by phagocytic cells.

Matricellular protein

A dynamically expressed non-structural protein that is present in the extracellular matrix.

Peptidomimetic

A small protein-like chain designed to mimic a peptide.

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Yang, X., Okamura, D., Lu, X. et al. CD36 in chronic kidney disease: novel insights and therapeutic opportunities. Nat Rev Nephrol 13, 769–781 (2017). https://doi.org/10.1038/nrneph.2017.126

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