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Acta Diabetologica

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22-02-2024 | Original Article

Elevated serum levels of leukocyte cell-derived chemotaxin 2 are associated with the prevalence of metabolic syndrome

Authors: Xialei Zheng, Junmi Lu, Shaojun Xiang, Pu Zou, Hao Chen, Jing Liu, Cheng Zeng, Yuhu He

Published in: Acta Diabetologica | Issue 5/2024

Abstract

Aims

Inflammation is central to the pathogenesis of metabolic syndrome (MetS). Leukocyte cell-derived chemotaxin 2 (LECT2) is constitutively secreted in response to inflammatory stimuli and oxidative stress contributing to tissue or systemic inflammation. We explored the relationship between LECT2 levels and MetS severity in humans and mice.

Methods

Serum LECT2 levels were measured in 210 participants with MetS and 114 without MetS (non-MetS). LECT2 expression in the liver and adipose tissue was also examined in mice fed a high-fat diet (HFD) and genetically obese (ob/ob) mice.

Results

Serum LECT2 levels were significantly higher in MetS participants than in non-MetS participants (7.47[3.36–17.14] vs. 3.74[2.61–5.82], P < 0.001). Particularly, serum LECT2 levels were significantly elevated in participants with hypertension, central obesity, diabetes mellitus (DM), hyperglycaemia, elevated triglyceride (TG) levels, and reduced high-density lipoprotein cholesterol (HDL-C) levels compared to those in participants without these conditions. Pearson’s correlation analysis showed that serum LECT2 levels were positively associated with conventional risk factors in all patients. Moreover, LECT2 was positively associated with the number of MetS components (r = 0.355, P < 0.001), indicating that higher serum LECT2 levels reflected MetS severity. Multivariate regression analysis revealed that a one standard deviation increase in LECT2 was associated with an odds ratio of 1.52 (1.01–2.29, P = 0.044) for MetS prevalence after adjusting for age, sex, body mass index, waist circumference, smoking status, white blood cell count, fasting blood glucose, TG, total cholesterol, HDL-C, blood urea nitrogen, and alanine aminotransferase. Receiver operating characteristic curve analysis confirmed the strong predictive ability of serum LECT2 levels for MetS. The optimum serum LECT2 cut-off value was 9.05. The area under the curve was 0.73 (95% confidence interval 0.68–0.78, P < 0.001), with a sensitivity and specificity of 45.71% and 95.61%, respectively. Additionally, LECT2 expression levels were higher at baseline and dramatically enhanced in metabolic organs (e.g. the liver) and adipose tissue in HFD-induced obese mice and ob/ob mice.

Conclusions

Increased LECT2 levels were significantly and independently associated with the presence and severity of MetS, indicating that LECT2 could be used as a novel biomarker and clinical predictor of MetS.

Graphical abstract

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Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC, Spertus JA, Costa F (2005) American heart association, national heart, lung, and blood institute, diagnosis and management of the metabolic syndrome: an American heart association/national heart, lung, and blood institute scientific statement. Circulation 112:2735–2752. https://doi.org/10.1161/CIRCULATIONAHA.105.169404CrossRefPubMed

Wu XY, Lin L, Qi HY, Du R, Hu CY, Ma LN, Peng K, Li M, Xu Y, Xu M, Chen YH, Lu JL, Bi YF, Wang WQ, Ning G (2019) Association between lipoprotein (a) levels and metabolic syndrome in a middle-aged and elderly chinese cohort. Biomed Environ Sci 32:477–485. https://doi.org/10.3967/bes2019.065CrossRefPubMed

Zhong L, Liu J, Liu S, Tan G (2023) Correlation between pancreatic cancer and metabolic syndrome: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 14:1116582. https://doi.org/10.3389/fendo.2023.1116582CrossRefPubMed

Kim J, Han K, Kim MK, Baek K-H, Song K-H, Kwon H-S (2023) Cumulative exposure to metabolic syndrome increases thyroid cancer risk in young adults: a population-based cohort study. Korean J Intern Med. https://doi.org/10.3904/kjim.2022.405CrossRefPubMedPubMedCentral

Yin L, Li S, He Y, Yang L, Wang L, Li C, Wang Y, Wang J, Yang P, Wang J, Chen Z, Li Y (2023) Impact of urinary sodium excretion on the prevalence and incidence of metabolic syndrome: a population-based study. BMJ Open 13:e065402. https://doi.org/10.1136/bmjopen-2022-065402CrossRefPubMedPubMedCentral

Hirode G, Wong RJ (2020) Trends in the prevalence of metabolic syndrome in the United States, 2011–2016. JAMA 323:2526–2528. https://doi.org/10.1001/jama.2020.4501CrossRefPubMedPubMedCentral

Saklayen MG (2018) The global epidemic of the metabolic syndrome. Curr Hypertens Rep 20:12. https://doi.org/10.1007/s11906-018-0812-zCrossRefPubMedPubMedCentral

O’Neill S, O’Driscoll L (2015) Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev 16:1–12. https://doi.org/10.1111/obr.12229CrossRefPubMed

Do Vale Moreira NC, Hussain A, Bhowmik B, Mdala I, Siddiquee T, Fernandes VO, Júnior RM, Meyer HE (2020) Prevalence of Metabolic Syndrome by different definitions, and its association with type 2 diabetes, pre-diabetes, and cardiovascular disease risk in Brazil. Diabetes Metab Syndr 14:1217–1224. https://doi.org/10.1016/j.dsx.2020.05.043CrossRefPubMed

10.

Ranasinghe P, Mathangasinghe Y, Jayawardena R, Hills AP, Misra A (2017) Prevalence and trends of metabolic syndrome among adults in the asia-pacific region: a systematic review. BMC Public Health 17:101. https://doi.org/10.1186/s12889-017-4041-1CrossRefPubMedPubMedCentral

11.

Fatima SS, Jamil Z, Abidi SH, Nadeem D, Bashir Z, Ansari A (2017) Interleukin-18 polymorphism as an inflammatory index in metabolic syndrome: a preliminary study, World. J Diabetes 8:304–310. https://doi.org/10.4239/wjd.v8.i6.304CrossRef

12.

Matsubayashi Y, Fujihara K, Yamada-Harada M, Mitsuma Y, Sato T, Yaguchi Y, Osawa T, Yamamoto M, Kitazawa M, Yamada T, Kodama S, Sone H (2022) Impact of metabolic syndrome and metabolic dysfunction-associated fatty liver disease on cardiovascular risk by the presence or absence of type 2 diabetes and according to sex. Cardiovasc Diabetol 21:90. https://doi.org/10.1186/s12933-022-01518-4CrossRefPubMedPubMedCentral

13.

Yoo HJ, Hwang SY, Choi J-H, Lee HJ, Chung HS, Seo J-A, Kim SG, Kim NH, Baik SH, Choi DS, Choi KM (2017) Association of leukocyte cell-derived chemotaxin 2 (LECT2) with NAFLD, metabolic syndrome, and atherosclerosis. PLoS ONE 12:e0174717. https://doi.org/10.1371/journal.pone.0174717CrossRefPubMedPubMedCentral

14.

Yamagoe S, Yamakawa Y, Matsuo Y, Minowada J, Mizuno S, Suzuki K (1996) Purification and primary amino acid sequence of a novel neutrophil chemotactic factor LECT2. Immunol Lett 52:9–13. https://doi.org/10.1016/0165-2478(96)02572-2CrossRefPubMed

15.

Hiraki Y, Inoue H, Kondo J, Kamizono A, Yoshitake Y, Shukunami C, Suzuki F (1996) A novel growth-promoting factor derived from fetal bovine cartilage, chondromodulin II. Purification and amino acid sequence. J Biol Chem 271:22657–22662. https://doi.org/10.1074/jbc.271.37.22657CrossRefPubMed

16.

Xu M, Xu H-H, Lin Y, Sun X, Wang L-J, Fang Z-P, Su X-H, Liang X-J, Hu Y, Liu Z-M, Cheng Y, Wei Y, Li J, Li L, Liu H-J, Cheng Z, Tang N, Peng C, Li T, Liu T, Qiao L, Wu D, Ding Y-Q, Zhou W-J (2019) LECT2, a Ligand for Tie1, plays a crucial role in liver fibrogenesis. Cell 178:1478-1492.e20. https://doi.org/10.1016/j.cell.2019.07.021CrossRefPubMed

17.

Lu X-J, Chen J, Yu C-H, Shi Y-H, He Y-Q, Zhang R-C, Huang Z-A, Lv J-N, Zhang S, Xu L (2013) LECT2 protects mice against bacterial sepsis by activating macrophages via the CD209a receptor. J Exp Med 210:5–13. https://doi.org/10.1084/jem.20121466CrossRefPubMedPubMedCentral

18.

Takata N, Ishii K-A, Takayama H, Nagashimada M, Kamoshita K, Tanaka T, Kikuchi A, Takeshita Y, Matsumoto Y, Ota T, Yamamoto Y, Yamagoe S, Seki A, Sakai Y, Kaneko S, Takamura T (2021) LECT2 as a hepatokine links liver steatosis to inflammation via activating tissue macrophages in NASH. Sci Rep 11:555. https://doi.org/10.1038/s41598-020-80689-0CrossRefPubMedPubMedCentral

19.

Xie Y, Zhong K-B, Hu Y, Xi Y-L, Guan S-X, Xu M, Lin Y, Liu F-Y, Zhou W-J, Gao Y (2022) Liver infiltration of multiple immune cells during the process of acute liver injury and repair. World J Gastroenterol 28:6537–6550. https://doi.org/10.3748/wjg.v28.i46.6537CrossRefPubMedPubMedCentral

20.

Xie Y, Fan K-W, Guan S-X, Hu Y, Gao Y, Zhou W-J (2022) LECT2: A pleiotropic and promising hepatokine, from bench to bedside. J Cell Mol Med 26:3598–3607. https://doi.org/10.1111/jcmm.17407CrossRefPubMedPubMedCentral

21.

He W-M, Dai T, Chen J, Wang J-A (2019) Leukocyte cell-derived chemotaxin 2 inhibits development of atherosclerosis in mice. Zool Res 40:317–323. https://doi.org/10.24272/j.issn.2095-8137.2019.030CrossRefPubMedPubMedCentral

22.

Zhang Z, Zeng H, Lin J, Hu Y, Yang R, Sun J, Chen R, Chen H (2018) Circulating LECT2 levels in newly diagnosed type 2 diabetes mellitus and their association with metabolic parameters. Medicine (Baltimore) 97:e0354. https://doi.org/10.1097/MD.0000000000010354CrossRefPubMed

23.

Kim J, Lee SK, Kim D, Lee E, Park CY, Choe H, Kang M-J, Kim HJ, Kim J-H, Hong JP, Lee YJ, Park HS, Heo Y, Jang YJ (2022) Adipose tissue LECT2 expression is associated with obesity and insulin resistance in Korean women. Obesity (Silver Spring) 30:1430–1441. https://doi.org/10.1002/oby.23445CrossRefPubMed

24.

Lan F, Misu H, Chikamoto K, Takayama H, Kikuchi A, Mohri K, Takata N, Hayashi H, Matsuzawa-Nagata N, Takeshita Y, Noda H, Matsumoto Y, Ota T, Nagano T, Nakagen M, Miyamoto K, Takatsuki K, Seo T, Iwayama K, Tokuyama K, Matsugo S, Tang H, Saito Y, Yamagoe S, Kaneko S, Takamura T (2014) LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance. Diabetes 63:1649–1664. https://doi.org/10.2337/db13-0728CrossRefPubMed

25.

Greenow KR, Zverev M, May S, Kendrick H, Williams GT, Phesse T, Parry L (2018) Lect2 deficiency is characterised by altered cytokine levels and promotion of intestinal tumourigenesis. Oncotarget 9:36430–36443. https://doi.org/10.18632/oncotarget.26335CrossRefPubMedPubMedCentral

26.

Sangaraju SL, Yepez D, Grandes XA, Talanki Manjunatha R, Habib S (2022) Cardio-metabolic disease and polycystic ovarian syndrome (PCOS): a narrative review. Cureus 14:e25076. https://doi.org/10.7759/cureus.25076CrossRefPubMedPubMedCentral

27.

Yang L, Cao C, Kantor ED, Nguyen LH, Zheng X, Park Y, Giovannucci EL, Matthews CE, Colditz GA, Cao Y (2019) Trends in sedentary behavior among the US population, 2001–2016. JAMA 321:1587–1597. https://doi.org/10.1001/jama.2019.3636CrossRefPubMedPubMedCentral

28.

Ahmed M, Kumari N, Mirgani Z, Saeed A, Ramadan A, Ahmed MH, Almobarak AO (2022) Metabolic syndrome definition, pathogenesis, elements, and the effects of medicinal plants on it’s elements. J Diabetes Metab Disord 21:1011–1022. https://doi.org/10.1007/s40200-021-00965-2CrossRefPubMedPubMedCentral

29.

Kuzan A, Maksymowicz K, Królewicz E, Lindner-Pawłowicz K, Zatyka P, Wojnicz P, Nowaczyński M, Słomczyński A, Sobieszczańska M (2023) Association between leukocyte cell-derived chemotaxin 2 and metabolic and renal diseases in a geriatric population: a pilot study. J Clin Med 12:7544. https://doi.org/10.3390/jcm12247544CrossRefPubMedPubMedCentral

30.

Kameoka Y, Yamagoe S, Hatano Y, Kasama T, Suzuki K (2000) Val58Ile polymorphism of the neutrophil chemoattractant LECT2 and rheumatoid arthritis in the Japanese population. Arthritis Rheum 43:1419–1420. https://doi.org/10.1002/1529-0131(200006)43:6%3c1419::AID-ANR28%3e3.0.CO;2-ICrossRefPubMed

31.

Wang Q, Xu F, Chen J, Xie Y-Q, Xu S-L, He W-M (2023) Serum Leukocyte cell-derived chemotaxin 2 (LECT2) level is associated with osteoporosis. Lab Med 54:106–111. https://doi.org/10.1093/labmed/lmac080CrossRefPubMed

32.

Qin J, Sun W, Zhang H, Wu Z, Shen J, Wang W, Wei Y, Liu Y, Gao Y, Xu H (2022) Prognostic value of LECT2 and relevance to immune infiltration in hepatocellular carcinoma. Front Genet 13:951077. https://doi.org/10.3389/fgene.2022.951077CrossRefPubMedPubMedCentral

33.

Lin Y, Dong M-Q, Liu Z-M, Xu M, Huang Z-H, Liu H-J, Gao Y, Zhou W-J (2022) A strategy of vascular-targeted therapy for liver fibrosis. Hepatology 76:660–675. https://doi.org/10.1002/hep.32299CrossRefPubMed

34.

de la Cruz Jasso MA, Mejía-Vilet JM, Del Toro-Cisneros N, Aguilar-León DE, Morales-Buenrostro LE, Herrera G, Uribe-Uribe NO (2023) Leukocyte chemotactic factor 2 amyloidosis (ALECT2) distribution in a mexican population. Am J Clin Pathol 159:89–97. https://doi.org/10.1093/ajcp/aqac138CrossRefPubMed

35.

Spahis S, Borys J-M, Levy E (2017) Metabolic syndrome as a multifaceted risk factor for oxidative stress. Antioxid Redox Signal 26:445–461. https://doi.org/10.1089/ars.2016.6756CrossRefPubMed

36.

Vona R, Gambardella L, Cittadini C, Straface E, Pietraforte D (2019) Biomarkers of oxidative stress in metabolic syndrome and associated diseases. Oxid Med Cell Longev 2019:8267234. https://doi.org/10.1155/2019/8267234CrossRefPubMedPubMedCentral

37.

Rezzani R, Franco C (2021) Liver, oxidative stress and metabolic syndromes. Nutrients 13:301. https://doi.org/10.3390/nu13020301CrossRefPubMedPubMedCentral

38.

Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N (2014) Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 105:141–150. https://doi.org/10.1016/j.diabres.2014.04.006CrossRefPubMed

39.

Després J-P (2006) Is visceral obesity the cause of the metabolic syndrome? Ann Med 38:52–63. https://doi.org/10.1080/07853890500383895CrossRefPubMed

40.

Kong Q, Zou J, Zhang Z, Pan R, Zhang ZY, Han S, Xu Y, Gao Y, Meng Z-X (2022) BAF60a deficiency in macrophage promotes diet-induced obesity and metabolic inflammation. Diabetes 71:2136–2152. https://doi.org/10.2337/db22-0114CrossRefPubMed

41.

Blüher M, Bashan N, Shai I, Harman-Boehm I, Tarnovscki T, Avinaoch E, Stumvoll M, Dietrich A, Klöting N, Rudich A (2009) Activated Ask1-MKK4-p38MAPK/JNK stress signaling pathway in human omental fat tissue may link macrophage infiltration to whole-body Insulin sensitivity. J Clin Endocrinol Metab 94:2507–2515. https://doi.org/10.1210/jc.2009-0002CrossRefPubMed

42.

Shen HX, Li L, Chen Q, He YQ, Yu CH, Chu CQ, Lu XJ, Chen J (2016) LECT2 association with macrophage-mediated killing of Helicobacter pylori by activating NF-κB and nitric oxide production. Genet Mol Res 15:gmr15048889. https://doi.org/10.4238/gmr15048889CrossRef

43.

Jung TW, Chung YH, Kim H-C, Abd El-Aty AM, Jeong JH (2018) LECT2 promotes inflammation and insulin resistance in adipocytes via P38 pathways. J Mol Endocrinol 61:37–45. https://doi.org/10.1530/JME-17-0267CrossRefPubMed

44.

Rao K-R, Bao R-Y, Ming H, Liu J-W, Dong Y-F (2023) The correlation between aldosterone and leukocyte-related inflammation: a comparison between patients with primary aldosteronism and essential hypertension. J Inflamm Res 16:2401–2413. https://doi.org/10.2147/JIR.S409146CrossRefPubMedPubMedCentral

45.

Zhang X, Sun K, Tang C, Cen L, Li S, Zhu W, Liu P, Chen Y, Yu C, Li L (2023) LECT2 modulates dendritic cell function after Helicobacter pylori infection via the CD209a receptor. J Gastroenterol Hepatol 38:625–633. https://doi.org/10.1111/jgh.16138CrossRefPubMed

46.

Hwang H-J, Jung TW, Hong HC, Seo JA, Kim SG, Kim NH, Choi KM, Choi DS, Baik SH, Yoo HJ (2015) LECT2 induces atherosclerotic inflammatory reaction via CD209 receptor-mediated JNK phosphorylation in human endothelial cells. Metabolism 64:1175–1182. https://doi.org/10.1016/j.metabol.2015.06.001CrossRefPubMed

47.

Inhibition of VEGF165/VEGFR2-dependent signaling by LECT2 suppresses hepatocellular carcinoma angiogenesis - PMC, (n.d.). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979047/ (accessed May 27, 2023)

48.

Okumura A, Unoki-Kubota H, Matsushita Y, Shiga T, Moriyoshi Y, Yamagoe S, Kaburagi Y (2013) Increased serum leukocyte cell-derived chemotaxin 2 (LECT2) levels in obesity and fatty liver. Biosci Trends 7:276–283PubMed

49.

Li L, Xiong Y-L, Tu B, Liu S-Y, Zhang Z-H, Hu Z, Yao Y (2023) Effect of renal denervation for patients with isolated systolic hypertension: a systematic review and meta-analysis. J Geriatr Cardiol 20:121–129. https://doi.org/10.26599/1671-5411.2023.02.003CrossRefPubMedPubMedCentral

50.

Gao L-W, Huang Y-W, Cheng H, Wang X, Dong H-B, Xiao P, Yan Y-K, Shan X-Y, Zhao X-Y, Mi J (2023) Prevalence of hypertension and its associations with body composition across Chinese and American children and adolescents. World J Pediatr. https://doi.org/10.1007/s12519-023-00740-8CrossRefPubMedPubMedCentral

51.

Tsai T-Y, Cheng H-M, Chuang S-Y, Chia Y-C, Soenarta AA, Minh HV, Siddique S, Turana Y, Tay JC, Kario K, Chen C-H (2021) Isolated systolic hypertension in Asia. J Clin Hypertens (Greenwich) 23:467–474. https://doi.org/10.1111/jch.14111CrossRefPubMed

52.

Grebla RC, Rodriguez CJ, Borrell LN, Pickering TG (2010) Prevalence and determinants of isolated systolic hypertension among young adults: the 1999–2004 US National Health And Nutrition Examination Survey. J Hypertens 28:15–23. https://doi.org/10.1097/HJH.0b013e328331b7ffCrossRefPubMedPubMedCentral

Title: Elevated serum levels of leukocyte cell-derived chemotaxin 2 are associated with the prevalence of metabolic syndrome
Authors: Xialei Zheng
Junmi Lu
Shaojun Xiang
Pu Zou
Hao Chen
Jing Liu
Cheng Zeng
Yuhu He
Publication date: 22-02-2024
Publisher: Springer Milan
Published in: Acta Diabetologica / Issue 5/2024
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-024-02242-z

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