Copper and liver fibrosis in MASLD: the two-edged sword of copper deficiency and toxicity

Abstract

Copper is a trace metal whose absence or deficiency can cause structural and functional alterations that can be corrected by copper administration. Copper excess is associated with significant liver toxicity, such as that seen in Wilson’s disease, which often exhibits liver steatosis and can be managed by copper sequestrants. Copper, due to its ability to either accept or donate electrons, is a cofactor in many physiological redox reactions, playing an essential role in cell energy homeostasis, detoxification of reactive oxygen species, and hepatic immunometabolism. Given these facts, it is reasonable to speculate that copper might be involved in the pathogenesis of liver fibrosis in the setting of metabolic dysfunction-associated fatty liver disease (MASLD). To address this research question, a narrative review of published studies was conducted, spanning from the needs, sources, and toxicity of copper to Menkes and Wilson’s disease. Most epidemiological studies have demonstrated that MASLD is associated with copper deficiency. However, several studies show that MASLD is associated with copper excess and very few conclude that copper is not associated with MASLD. Therefore, the putative pathomechanisms associating both copper excess and deficiency with MASLD development and progression are reviewed. In conclusion, epidemiological and pathogenic data support the notion that well-balanced copper homeostasis is a prerequisite for liver health. Accordingly, both copper excess and deficiency may potentially predispose to liver fibrosis via the development of MASLD. Therefore, studies aimed at restoring normal bodily stores of copper should be tailored according to precision medicine approaches based on the specific features of copper metabolism in individual MASLD patients.

Keywords

Copper / epidemiology / fructose / iron / liver histology / pathomechanisms / sex differences / steatohepatitis

References

[1] Neuschwander-Tetri BA. Trace elements and the liver. In: Rodes J, Benhamou JP, Rizzetto M, Reichen J, Blei A, editors. Textbook in hepatology: from basic science to clinical practice, 3rd edition, 2007 Oxford: Blackwell. pp. 233-240. Available from: https://books.google.com/books?hl=zh-CN&lr=&id=xfpS5XMb9mgC&oi=fnd&pg=PP2&dq=Textbook+in+hepatology:+from+basic+science+to+clinical+practice,+3rd+edition,+2007+Oxford:+Blackwell&ots=DlMU6WA1eH&sig=xhvwuv-BfPRCEE9RxmNHGoaz_5Y#v=onepage&q=Textbook%20in%20hepatology%3A%20from%20basic%20science%20to%20clinical%20practice%2C%203rd%20edition%2C%202007%20Oxford%3A%20Blackwell&f=false

[2] Susnea I.Trace metal imaging in diagnostic of hepatic metal disease.Mass Spectrom Rev2016;35:666-86

[3] Anderson GJ.Revisiting hemochromatosis: genetic vs. phenotypic manifestations.Ann Transl Med2021;9:731 PMCID:PMC8106074

[4] Yang J,Iida K.Integrated-gut-liver-on-a-chip platform as an in vitro human model of non-alcoholic fatty liver disease.Commun Biol2023;6:310 PMCID:PMC10036655

[5] Witt B,Schwerdtle T.Subcellular localization of copper-cellular bioimaging with focus on neurological disorders.Int J Mol Sci2020;21:2341 PMCID:PMC7178132

[6] He P,Liu C.U-shaped association between dietary copper intake and new-onset hypertension.Clin Nutr2022;41:536-42

[7] Shi Y,Wu Z.Associations between dietary copper intake and hypertriglyceridemia among children and adolescents in the US.Nutr Metab Cardiovasc Dis2023;33:809-16

[8] Liu Y,Kuang Y.A national cross-sectional analysis of dietary copper intake and abdominal aortic calcification in the US adults: NHANES 2013-2014.Nutr Metab Cardiovasc Dis2023;33:1941-50

[9] Yang L,Cheng H.Dietary copper intake and risk of stroke in adults: a case-control study based on national health and nutrition examination survey 2013-2018.Nutrients2022;14:409 PMCID:PMC8839334

[10] Stefan N,Targher G.Role of steatotic liver disease in prediction and prevention of cardiometabolic diseases.Nat Rev Gastroenterol Hepatol2024;21:136-7

[11] Loria P,Leonardi F.Non-organ-specific autoantibodies in nonalcoholic fatty liver disease: prevalence and correlates.Dig Dis Sci2003;48:2173-81

[12] Song M,Chen T,McClain CJ.Copper deficiency exacerbates bile duct ligation-induced liver injury and fibrosis in rats.J Pharmacol Exp Ther2011;339:298-306 PMCID:PMC3186282

[13] Dhanraj P,Bester MJ.Induction of hepatic portal fibrosis, mitochondria damage, and extracellular vesicle formation in Sprague-Dawley rats exposed to copper, manganese, and mercury, alone and in combination.Ultrastruct Pathol2020;44:182-92

[14] Altarelli M,Schneider A.Copper deficiency: causes, manifestations, and treatment.Nutr Clin Pract2019;34:504-13

[15] Morrell A,Yu L.The role of insufficient copper in lipid synthesis and fatty-liver disease.IUBMB Life2017;69:263-70 PMCID:PMC5619695

[16] Członkowska A,Dusek P.Wilson disease.Nat Rev Dis Primers2018;4:21 PMCID:PMC6416051

[17] Roberts EA.Current and Emerging Issues in Wilson’s Disease.N Engl J Med2023;389:922-38

[18] Ovchinnikova EV,Ovchinnikova AA.Epidemiology of wilson’s disease and pathogenic variants of the ATP7B gene leading to diversified protein disfunctions.Int J Mol Sci2024;25:2402 PMCID:PMC10889319

[19] Stremmel W.Therapeutic strategies in Wilson disease: pathophysiology and mode of action.Ann Transl Med2021;9:732 PMCID:PMC8106045

[20] Dang J,Letavernier E.Kidney involvement in Wilson’s disease: a review of the literature.Clin Kidney J2024;17:sfae058 PMCID:PMC11040517

[21] Stremmel W,Weiskirchen R.Clinical features of Wilson disease.Ann Transl Med2019;7:S61 PMCID:PMC6531660

[22] Choudhury N,Atiqullah A,Al Mahtab M.High prevalence of wilson’s diseases with low prevalence of kayser-fleischer rings among patients with cryptogenic chronic liver diseases in bangladesh.Euroasian J Hepatogastroenterol2019;9:67-70 PMCID:PMC7047311

[23] Mak CM,Tam S.Diagnostic accuracy of serum ceruloplasmin in Wilson disease: determination of sensitivity and specificity by ROC curve analysis among ATP7B-genotyped subjects.Clin Chem2008;54:1356-62

[24] García-Villarreal L,Sánchez-Monteagudo A.Wilson disease: revision of diagnostic criteria in a clinical series with great genetic homogeneity.J Gastroenterol2021;56:78-89

[25] Fanni D,Gerosa C.Liver changes in Wilson’s disease: the full spectrum. A report of 127 biopsies from 43 patients.Eur Rev Med Pharmacol Sci2021;25:4336-44

[26] Mahmood S,Izumi A,Kobashi H.Wilson’s disease masquerading as nonalcoholic steatohepatitis.N Am J Med Sci2009;1:74-6. PMCID:PMC3364654

[27] Liggi M,Civolani A,Sorbello O.The relationship between copper and steatosis in Wilson’s disease.Clin Res Hepatol Gastroenterol2013;37:36-40

[28] Alqahtani SA,Abuquteish D.Hepatic ultrastructural features distinguish paediatric Wilson disease from NAFLD and autoimmune hepatitis.Liver Int2022;42:2482-91

[29] Sobesky R,Bouzbib C.Non-invasive diagnosis and follow-up of rare genetic liver diseases.Clin Res Hepatol Gastroenterol2022;46:101768

[30] Litwin T,Antos A.Liver transplantation as a treatment for Wilson's disease with neurological presentation: a systematic literature review.Acta Neurol Belg2022;122:505-18 PMCID:PMC8986686

[31] Cave V, Di Dato F, Iorio R. Wilson’s disease with acute hepatic onset: how to diagnose and treat it.Children (Basel)2024;11:68 PMCID:PMC10814100

[32] Antos A,Smolinski L.Early neurological deterioration in Wilson's disease: a systematic literature review and meta-analysis.Neurol Sci2023;44:3443-55 PMCID:PMC10495500

[33] Litwin T,Bembenek J.Copper deficiency as wilson’s disease overtreatment: a systematic review.Diagnostics (Basel)2023;13:2424 PMCID:PMC10377829

[34] Kumar P,Madhok B.Copper deficiency after gastric bypass for morbid obesity: a systematic review.Obes Surg2016;26:1335-42

[35] Ramani PK. Menkes disease. Available from: https://europepmc.org/books/n/statpearls/article-24982/?extid=29262003&src=med

[36] Duncan A,McMillan DC,O’Reilly DS.Quantitative data on the magnitude of the systemic inflammatory response and its effect on micronutrient status based on plasma measurements.Am J Clin Nutr2012;95:64-71

[37] Kharel Z,Phatak PD.Diagnosing aceruloplasminemia: navigating through red herrings.Ann Hematol2024;103:2173-6

[38] Corradini E,Dongiovanni P.Ceruloplasmin gene variants are associated with hyperferritinemia and increased liver iron in patients with NAFLD.J Hepatol2021;75:506-13

[39] King D,Senthil L,Cooper SC.Copper deficiency myelopathy after upper gastrointestinal surgery.Nutr Clin Pract2018;33:515-9

[40] Griffith DP,Ziegler TR,Winton EF.Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery.Obesity (Silver Spring)2009;17:827-31. PMCID:PMC2712481

[41] Kiela PR.Physiology of intestinal absorption and secretion.Best Pract Res Clin Gastroenterol2016;30:145-59 PMCID:PMC4956471

[42] Wang Y,Yang K,Li Y.Copper in colorectal cancer: from copper-related mechanisms to clinical cancer therapies.Clin Transl Med2024;14:e1724 PMCID:PMC11131360

[43] Horn D.Mitochondrial copper metabolism and delivery to cytochrome c oxidase.IUBMB Life2008;60:421-9 PMCID:PMC2864105

[44] Antonucci L,Iannucci G,Barbaro B.Non-alcoholic fatty liver disease and nutritional implications: special focus on copper.Nutrients2017;9:1137 PMCID:PMC5691753

[45] Gale J.The physiological and pathophysiological roles of copper in the nervous system.Eur J Neurosci2024;60:3505-43

[46] Cheng F,Lu Y.Relationship between copper and immunity: the potential role of copper in tumor immunity.Front Oncol2022;12:1019153 PMCID:PMC9676660

[47] Xue Q,Klionsky DJ,Liu J.Copper metabolism in cell death and autophagy.Autophagy2023;19:2175-95 PMCID:PMC10351475

[48] Guo CH,Ko WS.Status of essential trace minerals and oxidative stress in viral hepatitis C patients with nonalcoholic fatty liver disease.Int J Med Sci2013;10:730-7 PMCID:PMC3638296

[49] Porcu C,Barbaro B.Copper/MYC/CTR1 interplay: a dangerous relationship in hepatocellular carcinoma.Oncotarget2018;9:9325-43 PMCID:PMC5823635

[50] Chen C,Yang R.Copper exposure association with prevalence of non-alcoholic fatty liver disease and insulin resistance among US adults (NHANES 2011-2014).Ecotoxicol Environ Saf2021;218:112295

[51] Zhang D,Lan Y.Essential metal mixtures exposure and NAFLD: A cohort-based case-control study in northern Chinese male adults.Chemosphere2023;339:139598

[52] Hou JZ,Zhang L.Association between micronutrients intake and metabolic-associated fatty liver disease: a cross-sectional study based on the National Health and Nutrition Examination Survey.J Nutr Sci2023;12:e117 PMCID:PMC10685258

[53] Li L,Shu X,Kang H.The correlation between serum copper and non-alcoholic fatty liver disease in american adults: an analysis based on NHANES 2011 to 2016.Biol Trace Elem Res2024;202:4398-409

[54] Aigner E,Haufe H.Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease.Gastroenterology2008;135:680-8

[55] Aigner E,Haufe H.A role for low hepatic copper concentrations in nonalcoholic Fatty liver disease.Am J Gastroenterol2010;105:1978-85

[56] Nobili V,Bedogni G.Levels of serum ceruloplasmin associate with pediatric nonalcoholic fatty liver disease.J Pediatr Gastroenterol Nutr2013;56:370-5

[57] Church SJ,Kureishy N.Deficient copper concentrations in dried-defatted hepatic tissue from ob/ob mice: a potential model for study of defective copper regulation in metabolic liver disease.Biochem Biophys Res Commun2015;460:549-54 PMCID:PMC4427106

[58] Stättermayer AF,Aigner E.Low hepatic copper content and PNPLA3 polymorphism in non-alcoholic fatty liver disease in patients without metabolic syndrome.J Trace Elem Med Biol2017;39:100-7

[59] Mendoza M,Song M.Low hepatic tissue copper in pediatric nonalcoholic fatty liver disease.J Pediatr Gastroenterol Nutr2017;65:89-92 PMCID:PMC5492896

[60] Fujii Y,Hiyoshi M,Yano K.Risk factors for development of nonalcoholic fatty liver disease after pancreatoduodenectomy.Ann Gastroenterol Surg2017;1:226-31 PMCID:PMC5881353

[61] El-Rayah EA,Wallace EM.Both α-1-antitrypsin Z phenotypes and low caeruloplasmin levels are over-represented in alcohol and nonalcoholic fatty liver disease cirrhotic patients undergoing liver transplant in Ireland.Eur J Gastroenterol Hepatol2018;30:364-7

[62] Lee SH,Kim YS.Low hair copper concentration is related to a high risk of nonalcoholic fatty liver disease in adults.J Trace Elem Med Biol2018;50:28-33

[63] Nasr P,Lundberg P,Ekstedt M.Low hepatic manganese concentrations in patients with hepatic steatosis - a cohort study of copper, iron and manganese in liver biopsies.J Trace Elem Med Biol2021;67:126772

[64] Lan Y,Wang Y.Association between blood copper and nonalcoholic fatty liver disease according to sex.Clin Nutr2021;40:2045-52

[65] Zhang H,Zhu PW.Lower serum copper concentrations are associated with higher prevalence of nonalcoholic steatohepatitis: a matched case-control study.Eur J Gastroenterol Hepatol2022;34:838-43

[66] Kamada Y,Ogawa Y.Japan study group of NAFLD (JSG-NAFLD)characterization of nutrient intake in biopsy-confirmed NAFLD patients.Nutrients2022;14:3453 PMCID:PMC9460347

[67] Xie L,Xu S.Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex.Cell Rep2022;41:111498 PMCID:PMC10153649

[68] Chen Y,Li G,Tang S.Comparison of copper concentration between non-alcoholic fatty liver disease patients and normal individuals: a meta-analysis.Front Public Health2023;11:1095916 PMCID:PMC9929538

[69] Tinkov AA,Morozova GD.Association between serum trace element, mineral, and amino acid levels with non-alcoholic fatty liver disease (NAFLD) in adult women.J Trace Elem Med Biol2024;83:127397

[70] Jiang Q,Lu S.Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism.J Mol Cell Biol2024;15 PMCID:PMC10993722

[71] Arefhosseini S,Tutunchi H.Serum copper, ceruloplasmin, and their relations to metabolic factors in nonalcoholic fatty liver disease: a cross-sectional study.Eur J Gastroenterol Hepatol2022;34:443-8

[72] Liu K,Chen J.Genetically determined circulating micronutrients and the risk of nonalcoholic fatty liver disease.Sci Rep2024;14:1105 PMCID:PMC10784479

[73] Wei Y,Thyfault JP.Nonalcoholic fatty liver disease and mitochondrial dysfunction.World J Gastroenterol2008;14:193-9 PMCID:PMC2675113

[74] Ma Y,Heo SY.Oxidative stress is a key modulator in the development of nonalcoholic fatty liver disease.Antioxidants (Basel)2021;11:91 PMCID:PMC8772974

[75] Aigner E,Datz C.Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver.World J Hepatol2015;7:177-88 PMCID:PMC4342600

[76] Harder NHO,Stanhope KL.Effects of dietary glucose and fructose on copper, iron, and zinc metabolism parameters in humans.Nutrients2020;12:2581 PMCID:PMC7551875

[77] Song M,Zhou Z.High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver.J Hepatol2012;56:433-40 PMCID:PMC3261305

[78] Troost FJ,Dainty JR,Bull VJ.Iron supplements inhibit zinc but not copper absorption in vivo in ileostomy subjects.Am J Clin Nutr2003;78:1018-23

[79] Wei X,Yin X.Effects of dietary different doses of copper and high fructose feeding on rat fecal metabolome.J Proteome Res2015;14:4050-8 PMCID:PMC6545594

[80] Tallino S,Ralle M,Latorre M.Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease.J Nutr Biochem2015;26:996-1006 PMCID:PMC4578989

[81] Weiskirchen R.Targeting copper to combat macrophage-driven inflammation: a potential advanced therapeutic strategy.Signal Transduct Target Ther2023;8:339 PMCID:PMC10493218

[82] Ballestri S,Girolamo MD,Capitelli M.Liver fibrosis in nonalcoholic fatty liver disease patients: noninvasive evaluation and correlation with cardiovascular disease and mortality.Metab Target Organ Damage2023;3:1

[83] Tsvetkov P,Petrova B.Copper induces cell death by targeting lipoylated TCA cycle proteins.Science2022;375:1254-61 PMCID:PMC9273333

[84] Li SR,Cai L.Cuproptosis: lipoylated TCA cycle proteins-mediated novel cell death pathway.Signal Transduct Target Ther2022;7:158 PMCID:PMC9106713

[85] Xiong C,Hao Q.Cuproptosis: p53-regulated metabolic cell death?.Cell Death Differ2023;30:876-84 PMCID:PMC10070433

[86] Li J,Ma X,Xu C,Dong M.Identification and validation of cuproptosis-related genes for diagnosis and therapy in nonalcoholic fatty liver disease.Mol Cell Biochem2024;

[87] Li Y,Song SY.Elucidating cuproptosis in metabolic dysfunction-associated steatotic liver disease.Biomed Pharmacother2024;174:116585

[88] Qu J,Wang Q.Cuproptosis: potential new direction in diabetes research and treatment.Front Endocrinol (Lausanne)2024;15:1344729 PMCID:PMC11188452

[89] Liu N.Crosstalk between ferroptosis and cuproptosis: From mechanism to potential clinical application.Biomed Pharmacother2024;171:116115

[90] Wang R,Ni Z.Intermittent hypoxia exacerbates metabolic dysfunction-associated fatty liver disease by aggravating hepatic copper deficiency-induced ferroptosis.FASEB J2024;38:e23788

[91] Feng S,Wang Y.The mechanism of ferroptosis and its related diseases.Mol Biomed2023;4:33 PMCID:PMC10577123

[92] Chen Y,Wang S,Zhong J.Targeting iron metabolism and ferroptosis as novel therapeutic approaches in cardiovascular diseases.Nutrients2023;15:591 PMCID:PMC9921472

[93] Zechner R,Eichmann TO.FAT SIGNALS--lipases and lipolysis in lipid metabolism and signaling.Cell Metab2012;15:279-91 PMCID:PMC3314979

[94] Homma T,Kobayashi S,Fujii J.d-Cysteine supplementation partially protects against ferroptosis induced by xCT dysfunction via increasing the availability of glutathione.J Clin Biochem Nutr2022;71:48-54 PMCID:PMC9309085

[95] Wooton-Kee CR,Wagner M.Elevated copper impairs hepatic nuclear receptor function in Wilson’s disease.J Clin Invest2015;125:3449-60 PMCID:PMC4588285

[96] Ballestri S,Romagnoli D,Lonardo A.The role of nuclear receptors in the pathophysiology, natural course, and drug treatment of NAFLD in humans.Adv Ther2016;33:291-319

[97] Lonardo A.Association of NAFLD/NASH, and MAFLD/MASLD with chronic kidney disease: an updated narrative review.Metab Target Organ Damage2024;4:16

[98] Hordyjewska A,Kocot J.The many “faces” of copper in medicine and treatment.Biometals2014;27:611-21 PMCID:PMC4113679

[99] Ma C,Zhu Z,Pan G.Mineral metabolism and ferroptosis in non-alcoholic fatty liver diseases.Biochem Pharmacol2022;205:115242

[100] Song M,Zhang X.Dietary copper-fructose interactions alter gut microbial activity in male rats.Am J Physiol Gastrointest Liver Physiol2018;314:G119-30 PMCID:PMC5866377

[101] Song M,McClain CJ.Copper-fructose interactions: a novel mechanism in the pathogenesis of NAFLD.Nutrients2018;10:1815 PMCID:PMC6266129

[102] Song M,Li X.Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis.Biol Sex Differ2021;12:3 PMCID:PMC7789350