Journal of Shanghai Jiao Tong University (Medical Science) >

2024 , Vol. 44 >Issue 1: 124 - 130

DOI: https://doi.org/10.3969/j.issn.1674-8115.2024.01.014

Review

Research progress in ceruloplasmin regulation of lipid metabolism homeostasis

  • Quanxin JIANG ,
  • Suzhen CHEN ,
  • Junli LIU
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  • Shanghai Diabetes Institute, Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
CHEN Suzhen, E-mail: cszdream@163.com.
LIU Junli, E-mail: liujunli@sjtu.edu.cn

Received date: 2023-05-30

  Accepted date: 2023-12-25

  Online published: 2024-01-28

Supported by

National Natural Science Foundation of China(81770797);“Two-hundred Talents” Program of Shanghai Jiao Tong University School of Medicine(20220009)

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Abstract

Ceruloplasmin (Cp) is a crucial protein secreted by the liver and plays a vital role in regulating the distribution and transport of copper throughout the body, thereby maintaining copper homeostasis. Additionally, Cp functions as a significant enzyme known as ferroxidase, which is involved in iron metabolism within the body. Numerous studies have suggested a close relationship between Cp and metabolic disorders, such as diabetes and cardiovascular diseases. Recent research has also shed light on the involvement of Cp in the regulation of lipid metabolism. The various activities associated with lipid metabolism, including lipid synthesis, adipose hydrolysis, fatty acid oxidation, lipid transport, and absorption, collectively contribute to maintaining lipid homeostasis. Dysregulation of lipid metabolism can lead to metabolic disorders and cardiovascular complications. Cp regulates lipid metabolism through two main mechanisms. Firstly, Cp participates in the regulation of oxidative stress by modulating iron metabolism through its ferroxidase activity and involvement in redox reaction. Secondly, copper along with copper-dependent enzymes directly participates in the processes such as cholesterol metabolism, lipoprotein metabolism, and fatty acid synthesis. As a result, the role of Cp in maintaining the homeostasis of copper and iron allows it to regulate lipid metabolism by influencing copper or iron-dependent enzymes and related pathways. Although the correlation between Cp and lipid metabolism has been identified, an in-depth exploration of the precise mechanisms by which Cp governs lipid metabolism is warranted. This article provides an overview of the role of Cp in lipid metabolism and highlights the progress in related research, with the aim of providing new insights for the development and treatment of disorders related to lipid metabolism.

Key words： ceruloplasmin; copper homeostasis; iron homeostasis; lipid metabolism; metabolic disease

Cite this article

Quanxin JIANG , Suzhen CHEN , Junli LIU . Research progress in ceruloplasmin regulation of lipid metabolism homeostasis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024 , 44(1) : 124 -130 . DOI: 10.3969/j.issn.1674-8115.2024.01.014

References

1 BIAN X L, LIU R, MENG Y, et al. Lipid metabolism and cancer[J]. J Exp Med, 2021, 218(1): e20201606.
2 LU Y, WEI X, CHEN M L, et al. Non-ceruloplasmin-bound copper and copper speciation in serum with extraction using functionalized dendritic silica spheres followed by ICP-MS detection[J]. Anal Chim Acta, 2023, 1251: 340993.
3 CHEN M, ZHENG J S, LIU G H, et al. Ceruloplasmin and hephaestin jointly protect the exocrine pancreas against oxidative damage by facilitating iron efflux[J]. Redox Biol, 2018, 17: 432-439.
4 WANG P W, WU T H, PAN T L, et al. Integrated proteome and cytokine profiles reveal ceruloplasmin eliciting liver allograft tolerance via antioxidant cascades[J]. Front Immunol, 2018, 9: 2216.
5 WANG B, WANG X P. Does ceruloplasmin defend against neurodegenerative diseases?[J]. Curr Neuropharmacol, 2019, 17(6): 539-549.
6 GUPTA M N, UVERSKY V N. Moonlighting enzymes: when cellular context defines specificity[J]. Cell Mol Life Sci, 2023, 80(5): 130.
7 TIAN S L, JONES S M, SOLOMON E I. Role of a tyrosine radical in human ceruloplasmin catalysis[J]. ACS Cent Sci, 2020, 6(10): 1835-1843.
8 CURNOCK R, CULLEN P J. Mammalian copper homeostasis requires retromer-dependent recycling of the high-affinity copper transporter 1[J]. J Cell Sci, 2020, 133(16): jcs249201.
9 DAS S, SAHOO P K. Ceruloplasmin, a moonlighting protein in fish[J]. Fish Shellfish Immunol, 2018, 82: 460-468.
10 LUTSENKO S. Dynamic and cell-specific transport networks for intracellular copper ions[J]. J Cell Sci, 2021, 134(21): jcs240523.
11 CHEN J, JIANG Y H, SHI H, et al. The molecular mechanisms of copper metabolism and its roles in human diseases[J]. Pflugers Arch, 2020, 472(10): 1415-1429.
12 NE?ELIO?LU S, O?UZ E F, EREL ?. Development of a new colorimetric, kinetic and automated ceruloplasmin ferroxidase activity measurement method[J]. Antioxidants (Basel), 2022, 11(11): 2187.
13 VASILYEV V B. Looking for a partner: ceruloplasmin in protein-protein interactions[J]. Biometals, 2019, 32(2): 195-210.
14 SHANG Y X, LUO M Y, YAO F P, et al. Ceruloplasmin suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma cells[J]. Cell Signal, 2020, 72: 109633.
15 DOGUER C, HA J H, COLLINS J F. Intersection of iron and copper metabolism in the mammalian intestine and liver[J]. Compr Physiol, 2018, 8(4): 1433-1461.
16 MARCHI G, BUSTI F, LIRA ZIDANES A, et al. Aceruloplasminemia: a severe neurodegenerative disorder deserving an early diagnosis[J]. Front Neurosci, 2019, 13: 325.
17 DIXON S J, LEMBERG K M, LAMPRECHT M R, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072.
18 HEALY J, TIPTON K. Ceruloplasmin and what it might do[J]. J Neural Transm, 2007, 114(6): 777-781.
19 VASILYEV V B. Interactions of caeruloplasmin with other proteins participating in inflammation[J]. Biochem Soc Trans, 2010, 38(4): 947-951.
20 KO C W, QU J, BLACK D D, et al. Regulation of intestinal lipid metabolism: current concepts and relevance to disease[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(3): 169-183.
21 YKI-J?RVINEN H, LUUKKONEN P K, HODSON L, et al. Dietary carbohydrates and fats in nonalcoholic fatty liver disease[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(11): 770-786.
22 SEEBACHER F, ZEIGERER A, KORY N, et al. Hepatic lipid droplet homeostasis and fatty liver disease[J]. Semin Cell Dev Biol, 2020, 108: 72-81.
23 SONG Z Y, XIAOLI A, YANG F J. Regulation and metabolic significance of de novo lipogenesis in adipose tissues[J]. Nutrients, 2018, 10(10): 1383.
24 LEE E, KORF H, VIDAL-PUIG A. An adipocentric perspective on the development and progression of non-alcoholic fatty liver disease[J]. J Hepatol, 2023, 78(5): 1048-1062.
25 MA Y B, TEMKIN S M, HAWKRIDGE A M, et al. Fatty acid oxidation: an emerging facet of metabolic transformation in cancer[J]. Cancer Lett, 2018, 435: 92-100.
26 ZHONG S S, LI L X, SHEN X, et al. An update on lipid oxidation and inflammation in cardiovascular diseases[J]. Free Radic Biol Med, 2019, 144: 266-278.
27 KIM C H, PARK J Y, KIM J Y, et al. Elevated serum ceruloplasmin levels in subjects with metabolic syndrome: a population-based study[J]. Metabolism, 2002, 51(7): 838-842.
28 ENGSTR?M G, STAVENOW L, HEDBLAD B, et al. Inflammation-sensitive plasma proteins, diabetes, and mortality and incidence of myocardial infarction and stroke: a population-based study[J]. Diabetes, 2003, 52(2): 442-447.
29 XIE L P, YUAN Y M, XU S M, et al. Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex[J]. Cell Rep, 2022, 41(3): 111498.
30 GUTHRIE L M, SOMA S, YUAN S, et al. Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice[J]. Science, 2020, 368(6491): 620-625.
31 AIGNER E, STRASSER M, HAUFE H, et al. A role for low hepatic copper concentrations in nonalcoholic fatty liver disease[J]. Am J Gastroenterol, 2010, 105(9): 1978-1985.
32 HEFFERN M C, PARK H M, AU-YEUNG H Y, et al. In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease[J]. Proc Natl Acad Sci USA, 2016, 113(50): 14219-14224.
33 TANG Z, GASPERKOVA D, XU J, et al. Copper deficiency induces hepatic fatty acid synthase gene transcription in rats by increasing the nuclear content of mature sterol regulatory element binding protein 1[J]. J Nutr, 2000, 130(12): 2915-2921.
34 HERZIG S, SHAW R J. AMPK: guardian of metabolism and mitochondrial homeostasis[J]. Nat Rev Mol Cell Biol, 2018, 19(2): 121-135.
35 TREFTS E, SHAW R J. AMPK: restoring metabolic homeostasis over space and time[J]. Mol Cell, 2021, 81(18): 3677-3690.
36 LIN S C, HARDIE D G. AMPK: sensing glucose as well as cellular energy status[J]. Cell Metab, 2018, 27(2): 299-313.
37 CUSI K, ALKHOURI N, HARRISON S A, et al. Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study[J]. Lancet Gastroenterol Hepatol, 2021, 6(11): 889-902.
38 YANG H J, RALLE M, WOLFGANG M J, et al. Copper-dependent amino oxidase 3 governs selection of metabolic fuels in adipocytes[J]. PLoS Biol, 2018, 16(9): e2006519.
39 BOUR S, CASPAR-BAUGUIL S, IFFIú-SOLTéSZ Z, et al. Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 deficiency reduces leukocyte infiltration into adipose tissue and favors fat deposition[J]. Am J Pathol, 2009, 174(3): 1075-1083.
40 KRISHNAMOORTHY L, COTRUVO J A Jr, CHAN J, et al. Copper regulates cyclic-AMP-dependent lipolysis[J]. Nat Chem Biol, 2016, 12(8): 586-592.
41 RAIA S, CONTI A, ZANARDI A, et al. Ceruloplasmin-deficient mice show dysregulation of lipid metabolism in liver and adipose tissue reduced by a protein replacement[J]. Int J Mol Sci, 2023, 24(2): 1150.
42 MANNELLA V, CHAABANE L, CANU T, et al. Lipid dysmetabolism in ceruloplasmin-deficient mice revealed both in vivo and ex vivo by MRI, MRS and NMR analyses[J]. FEBS Open Bio, 2023. DOI: 10.1002/2211-5463.13740.
43 KONO S. Aceruloplasminemia[M]//BHATIA K P, SCHNEIDER S A. International review of neurobiology. Amsterdam: Elsevier, 2013: 125-151.
44 LIU Z D, WANG M, ZHANG C B, et al. Molecular functions of ceruloplasmin in metabolic disease pathology[J]. Diabetes Metab Syndr Obes, 2022, 15: 695-711.
45 CORRADINI E, BUZZETTI E, DONGIOVANNI P, et al. Ceruloplasmin gene variants are associated with hyperferritinemia and increased liver iron in patients with NAFLD[J]. J Hepatol, 2021, 75(3): 506-513.
46 THEPSUWAN P, BHATTACHARYA A, SONG Z F, et al. Hepatic SEL1L-HRD1 ER-associated degradation regulates systemic iron homeostasis via ceruloplasmin[J]. Proc Natl Acad Sci USA, 2023, 120(2): e2212644120.
47 PATEL B N, DUNN R J, JEONG S Y, et al. Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury[J]. J Neurosci, 2002, 22(15): 6578-6586.
48 CZ?ONKOWSKA A, LITWIN T, DUSEK P, et al. Wilson disease[J]. Nat Rev Dis Primers, 2018, 4(1): 21.
49 YURKOVA I L, ARNHOLD J, FITZL G, et al. Fragmentation of mitochondrial cardiolipin by copper ions in the Atp7b -/- mouse model of Wilson′s disease[J]. Chem Phys Lipids, 2011, 164(5): 393-400.
50 ARENAS DE LARRIVA A P, LIMIA-PéREZ L, ALCALá-DíAZ J F, et al. Ceruloplasmin and coronary heart disease: a systematic review[J]. Nutrients, 2020, 12(10): 3219.
51 FOX P L, MAZUMDER B, EHRENWALD E, et al. Ceruloplasmin and cardiovascular disease[J]. Free Radic Biol Med, 2000, 28(12): 1735-1744.
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