The Enigma of Soluble LDLR: Could Inflammation Be the Key?

Overview

Journal Lipids Health Dis

Publisher Biomed Central

Specialties Biochemistry
Endocrinology

Date 2020 Feb 5

PMID 32014013

Citations 8

Authors

Majambu Mbikay

Janice Mayne

Michel Chretien

Affiliations

Soon will be listed here.

Abstract

Soluble low-density lipoprotein receptor (sLDLR) is the circulating ectodomain of transmembrane LDLR. Its blood level strongly correlates with that of triglycerides (TG). This correlation has eluded satisfactory explanation. Hypertriglyceridemia and shedding of the ectodomain of many transmembrane receptors often accompany inflammatory states. The shedding mostly occurs through cleavage by a disintegrin-and-metalloproteinase-17 (ADAM-17), an enzyme activated by inflammation. It reduces the cellular uptake of TG-loaded lipoproteins, causing their accumulation in circulation; hence the correlation between plasma sLDLR and TG. Soluble LDLR could become a new surrogate marker of inflammation.

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References

Han R . Plasma lipoproteins are important components of the immune system. Microbiol Immunol. 2010; 54(4):246-53. DOI: 10.1111/j.1348-0421.2010.00203.x. View

Zagury D, Gallo R . Anti-cytokine Ab immune therapy: present status and perspectives. Drug Discov Today. 2004; 9(2):72-81. DOI: 10.1016/S1359-6446(03)02955-6. View

Fischer D, Tal N, Novick D, Barak S, Rubinstein M . An antiviral soluble form of the LDL receptor induced by interferon. Science. 1993; 262(5131):250-3. DOI: 10.1126/science.8211145. View

Girona J, Rodriguez-Borjabad C, Ibarretxe D, Heras M, Amigo N, Feliu A . Plasma inducible degrader of the LDLR, soluble low-density lipoprotein receptor, and proprotein convertase subtilisin/kexin type 9 levels as potential biomarkers of familial hypercholesterolemia in children. J Clin Lipidol. 2017; 12(1):211-218. DOI: 10.1016/j.jacl.2017.10.003. View

Novick D, Rubinstein M . The tale of soluble receptors and binding proteins: from bench to bedside. Cytokine Growth Factor Rev. 2007; 18(5-6):525-33. DOI: 10.1016/j.cytogfr.2007.06.024. View

Krenkel O, Tacke F . Macrophages in Nonalcoholic Fatty Liver Disease: A Role Model of Pathogenic Immunometabolism. Semin Liver Dis. 2017; 37(3):189-197. DOI: 10.1055/s-0037-1604480. View

Yuan G, Al-Shali K, Hegele R . Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007; 176(8):1113-20. PMC: 1839776. DOI: 10.1503/cmaj.060963. View

Hansen S, Madsen C, Varbo A, Nordestgaard B . Low-Grade Inflammation in the Association between Mild-to-Moderate Hypertriglyceridemia and Risk of Acute Pancreatitis: A Study of More Than 115000 Individuals from the General Population. Clin Chem. 2018; 65(2):321-332. DOI: 10.1373/clinchem.2018.294926. View

Scheller J, Chalaris A, Garbers C, Rose-John S . ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol. 2011; 32(8):380-7. DOI: 10.1016/j.it.2011.05.005. View

10.

Mayne J, Ooi T, Tepliakova L, Seebun D, Walker K, Mohottalage D . Associations Between Soluble LDLR and Lipoproteins in a White Cohort and the Effect of PCSK9 Loss-of-Function. J Clin Endocrinol Metab. 2018; 103(9):3486-3495. DOI: 10.1210/jc.2018-00777. View

11.

Gooz M . ADAM-17: the enzyme that does it all. Crit Rev Biochem Mol Biol. 2010; 45(2):146-69. PMC: 2841225. DOI: 10.3109/10409231003628015. View

12.

Heilbronn L, Campbell L . Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des. 2008; 14(12):1225-30. DOI: 10.2174/138161208784246153. View

13.

Stanford K, Bishop J, Foley E, Gonzales J, Niesman I, Witztum J . Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice. J Clin Invest. 2009; 119(11):3236-45. PMC: 2769193. DOI: 10.1172/JCI38251. View

14.

Horiuchi K, Kimura T, Miyamoto T, Takaishi H, Okada Y, Toyama Y . Cutting edge: TNF-alpha-converting enzyme (TACE/ADAM17) inactivation in mouse myeloid cells prevents lethality from endotoxin shock. J Immunol. 2007; 179(5):2686-9. DOI: 10.4049/jimmunol.179.5.2686. View

15.

Gallin J, Kaye D, Oleary W . Serum lipids in infection. N Engl J Med. 1969; 281(20):1081-6. DOI: 10.1056/NEJM196911132812001. View

16.

Berneis K, Krauss R . Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res. 2002; 43(9):1363-79. DOI: 10.1194/jlr.r200004-jlr200. View

17.

Medzhitov R . Origin and physiological roles of inflammation. Nature. 2008; 454(7203):428-35. DOI: 10.1038/nature07201. View

18.

Ma K, Ruan X, Powis S, Chen Y, Moorhead J, Varghese Z . Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatology. 2008; 48(3):770-81. DOI: 10.1002/hep.22423. View

19.

Shimohiro H, Taniguchi S, Koda M, Sakai C, Yamada S . Association between serum soluble low-density lipoprotein receptor levels and metabolic factors in healthy Japanese individuals. J Clin Lab Anal. 2014; 29(1):52-6. PMC: 6807053. DOI: 10.1002/jcla.21727. View

20.

Deng Y, Foley E, Gonzales J, Gordts P, Li Y, Esko J . Shedding of syndecan-1 from human hepatocytes alters very low density lipoprotein clearance. Hepatology. 2011; 55(1):277-86. PMC: 3245353. DOI: 10.1002/hep.24626. View