CoChat
Sign Up
Cited by 12

The DOI matches its Crossref record.

LY86 facilitates ox-LDL-induced lipid accumulation in macrophages by upregulating SREBP2/HMGCR expression

Jiang, Guangwei, Li, Jikuan, Niu, Shuai, Dong, Ruoyu, Chen, Yuyan, Bi, Wei·2024·BMC Cardiovascular Disorders
DOI 10.1186/s12872-024-03957-1PMC PMC11140969
Open this paper in CoChat — free account

Abstract

LY86, also known as MD1, has been implicated in various pathophysiological processes including inflammation, obesity, insulin resistance, and immunoregulation. However, the role of LY86 in cholesterol metabolism remains incompletely understood. Several studies have reported significant up-regulation of LY86 mRNA in atherosclerosis; nevertheless, the regulatory mechanism by which LY86 is involved in this disease remains unclear. In this study, we aimed to investigate whether LY86 affects ox-LDL-induced lipid accumulation in macrophages. Firstly, we confirmed that LY86 is indeed involved in the process of atherosclerosis and found high expression levels of LY86 in human atherosclerotic plaque tissue. Furthermore, our findings suggest that LY86 may mediate intracellular lipid accumulation induced by ox-LDL through the SREBP2/HMGCR pathway. This mechanism could be associated with increased cholesterol synthesis resulting from enhanced endoplasmic reticulum stress response.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s12872-024-03957-1

Cites

Statistics

Figures

Fig. 1 LY86 exhibits significantly elevated expression in human atherosclerotic tissues. (A,B) HE staining and statistical analysis of human carotid plaque tissue (×10) (n = 4). (C, D) Immunohistochemical staining and statistical analysis demonstrate the increased presence of LY86 in human carotid plaque tissue (×10) (n = 4). (E) Quantification of LY86 mRNA levels in human carotid plaque and adjacent normal intimal tissues (n = 6). (F, G) The cropped blot and quantification of LY86 protein in human carotid plaque and adjacent normal intimal (n = 3). The data are presented as mean ± SD; *P<0.05, **P<0.01, ***P<0.001. the cropped
Fig. 1 LY86 exhibits significantly elevated expression in human atherosclerotic tissues. (A,B) HE staining and statistical analysis of human carotid plaque tissue (×10) (n = 4). (C, D) Immunohistochemical staining and statistical analysis demonstrate the increased presence of LY86 in human carotid plaque tissue (×10) (n = 4). (E) Quantification of LY86 mRNA levels in human carotid plaque and adjacent normal intimal tissues (n = 6). (F, G) The cropped blot and quantification of LY86 protein in human carotid plaque and adjacent normal intimal (n = 3). The data are presented as mean ± SD; *P<0.05, **P<0.01, ***P<0.001. the croppedCC BY · PubMed Central
Fig. 2 Ly86 expression is up-regulated in high-fat-induced atherosclerotic plaques in ApoE-/- mice. (A) Body weight statistics of mice at 0–12 weeks. (B,C) Mice thoracic and abdominal aortic tissue stained with oil red O. (D-G) Mouse Lipid Panel (T-CHO, TG, HDL-C, LDL-C). (H,I) Immunofluorescence staining of partial aortic arch in mice (LY86 and HMCGR). (J) The immunofluorescence co-localization of LY86 and CD68 in partial aortic arch of mice. The findings were presented as mean ± SD (n = 3); *P<0.05, ***P<0.001
Fig. 2 Ly86 expression is up-regulated in high-fat-induced atherosclerotic plaques in ApoE-/- mice. (A) Body weight statistics of mice at 0–12 weeks. (B,C) Mice thoracic and abdominal aortic tissue stained with oil red O. (D-G) Mouse Lipid Panel (T-CHO, TG, HDL-C, LDL-C). (H,I) Immunofluorescence staining of partial aortic arch in mice (LY86 and HMCGR). (J) The immunofluorescence co-localization of LY86 and CD68 in partial aortic arch of mice. The findings were presented as mean ± SD (n = 3); *P<0.05, ***P<0.001CC BY · PubMed Central
Fig. 3 Construction of a THP-1 lipid-loaded model and screening of the LY86 knockdown sequence were performed. THP-1 cells were treated with 50 µg/ml ox-LDL for 24 h, and the cropped blot and quantification of LY86 protein. (Figures A and C). The expression level of LY86 was also evaluated by Western blotting and qRT-PCR after transfection of THP-1 cells with si-LY86-01 sequence for 24 h (Figures B, D, E). The results are presented as mean ± SD (n = 3); *P<0.05, **P<0.01, ***P<0.001
Fig. 3 Construction of a THP-1 lipid-loaded model and screening of the LY86 knockdown sequence were performed. THP-1 cells were treated with 50 µg/ml ox-LDL for 24 h, and the cropped blot and quantification of LY86 protein. (Figures A and C). The expression level of LY86 was also evaluated by Western blotting and qRT-PCR after transfection of THP-1 cells with si-LY86-01 sequence for 24 h (Figures B, D, E). The results are presented as mean ± SD (n = 3); *P<0.05, **P<0.01, ***P<0.001CC BY · PubMed Central
Fig. 4 LY86 effectively attenuates ox-LDL-induced lipid accumulation in THP-1 macrophages. (A) Representative images of oil red O staining in THP-1 cells (×40 magnification). (B, C) The cropped blot and quantification of intracellular HMGCR, SREBP2, GRP78, and LY86 after 24-hour knockdown treatment with si-LY86 followed by 24-hour stimulation with ox-LDL; groups 1–4 represent the following conditions: 1 si-NC; 2 si-NC + ox-LDL; 3 si-LY86; and 4 si-LY86 + ox-LDL. Data are presented as mean ± SD (n = 3); *P<0.05, **P<0.01, ***P<0.001
Fig. 4 LY86 effectively attenuates ox-LDL-induced lipid accumulation in THP-1 macrophages. (A) Representative images of oil red O staining in THP-1 cells (×40 magnification). (B, C) The cropped blot and quantification of intracellular HMGCR, SREBP2, GRP78, and LY86 after 24-hour knockdown treatment with si-LY86 followed by 24-hour stimulation with ox-LDL; groups 1–4 represent the following conditions: 1 si-NC; 2 si-NC + ox-LDL; 3 si-LY86; and 4 si-LY86 + ox-LDL. Data are presented as mean ± SD (n = 3); *P<0.05, **P<0.01, ***P<0.001CC BY · PubMed Central
Fig. 5 The effect of endoplasmic reticulum stress inhibitor 4-PBA on the expression of SREBP2 and HMGCR protein in THP-1 macrophages induced by ox-LDL. (A-B) Immunofluorescence staining of partial aortic arch in mice (GRP78). (C-G) The cropped blot and quantification of SREBP2, HMGCR, GRP78, and LY86 protein in THP-1 macrophages under the effect of 4-PBA on LY86 knockdown and ox-LDL. (H) THP-1 cells stained with oil red O (× 40). (I) Statistical analysis of Oil Red O staining results; a-f represent groupings, a si-NC, b si-NC + ox-LDL, c si-NC + ox-LDL + 4-PBA; d si-LY86, e si-LY86 + ox-LDL, f si-LY86 + ox-LDL + 4-PBA. The findings were presented as mean ± SD (n = 3); *P<0.05, **P<0.01, ***P<0.001
Fig. 5 The effect of endoplasmic reticulum stress inhibitor 4-PBA on the expression of SREBP2 and HMGCR protein in THP-1 macrophages induced by ox-LDL. (A-B) Immunofluorescence staining of partial aortic arch in mice (GRP78). (C-G) The cropped blot and quantification of SREBP2, HMGCR, GRP78, and LY86 protein in THP-1 macrophages under the effect of 4-PBA on LY86 knockdown and ox-LDL. (H) THP-1 cells stained with oil red O (× 40). (I) Statistical analysis of Oil Red O staining results; a-f represent groupings, a si-NC, b si-NC + ox-LDL, c si-NC + ox-LDL + 4-PBA; d si-LY86, e si-LY86 + ox-LDL, f si-LY86 + ox-LDL + 4-PBA. The findings were presented as mean ± SD (n = 3); *P<0.05, **P<0.01, ***P<0.001CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

No references could be resolved yet.

Research works printed but not linked: 41

  1. Feng LA, Shi J, Guo JY, Wang SF. Recent strategies for improving hemocompatibility and endothelialization of cardiovascular devices and inhibition of intimal hyperplasia. J Mater Chem B. 2022;10(20):3781–92. · DOI
  2. Fan J, Watanabe T. Atherosclerosis: known and unknown. PATHOL INT. 2022;72(3):151–60. · DOI
  3. Zhu Y, Xian X, Wang Z, Bi Y, Chen Q, Han X, Tang D, Chen R. Research Progress on the relationship between atherosclerosis and inflammation. Biomolecules. 2018;23(3):80. · DOI
  4. Liu YX, Liu XW, Yang YJ, Li SH, Bai LX, Ge WB, Xu X, Li C, Li JY, Qin Z. AEE alleviates ox-LDL-induced lipid accumulation and inflammation in macrophages. Biomed Pharmacother. 2023;167:115486. · DOI
  5. Chen JH, Tsai CW, Wang CP, Lin HH. Anti-atherosclerotic potential of gossypetin via inhibiting LDL oxidation and foam cell formation. Toxicol Appl Pharmacol. 2013;272(2):313–24. · DOI
  6. Vozenilek AE, Navratil AR, Green JM, Coleman DT, Blackburn CMR, Finney AC, Pearson BH, Chrast R, Finck BN, Klein RL, Orr AW, Woolard MD. Macrophage-Associated Lipin-1 enzymatic activity contributes to Modified Low-Density Lipoprotein-Induced Proinflammatory Signaling and Atherosclerosis. Arterioscler Thromb Vasc Biol. 2018;38(2):324–34. · DOI
  7. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362(6423):801–9. · DOI
  8. Razmkhah F, Ghasemi S, Soleimani M, Amini Kafi-Abad S. LY86, LRG1 and PDE9A genes overexpression in umbilical cord blood hematopoietic stem progenitor cells by acute myeloid leukemia (M3) microvesicles. Exp Hematol Oncol. 2019;18:8:23. · DOI
  9. Xiong X, Liu Y, Mei Y, Peng J, Wang Z, Kong B, Zhong P, Xiong L, Quan D, Li Q, Wang G, Huang H. Novel protective role of myeloid differentiation 1 in pathological cardiac remodelling. Sci Rep. 2017;7:41857. · DOI
  10. Peng J, Liu Y, Xiong X, Huang C, Mei Y, Wang Z, Tang Y, Ye J, Kong B, Liu W, Wang T, Huang H. Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling. Sci Rep. 2017;7(1):5116. · DOI
  11. Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL. Inhibition of TLR-4/MD-2 signaling by RP105/MD-1. J Endotoxin Res. 2005;11(6):363–8. · DOI
  12. Shuai W, Kong B, Fu H, Shen C, Jiang X, Huang H. MD1 Deficiency promotes inflammatory Atrial Remodelling Induced by High-Fat diets. Can J Cardiol. 2019;35(2):208–16. · DOI
  13. Xu J, Chen C, Yang Y. Identification and validation of candidate Gene Module along with Immune cells infiltration patterns in atherosclerosis progression to Plaque rupture via Transcriptome Analysis. Front Cardiovasc Med. 2022;9:894879. · DOI
  14. Zhang L, Gu J, Wang S, He F, Gong K. Identification of key differential genes in intimal hyperplasia induced by left carotid artery ligation. PeerJ. 2022;10:e13436. · DOI
  15. Tian L, Luo N, Klein RL, Chung BH, Garvey WT, Fu Y. Adiponectin reduces lipid accumulation in macrophage foam cells. Atherosclerosis. 2009;202(1):152–61. · DOI
  16. Xu L, Wang YR, Li PC, 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. 2016;15(1):161. · DOI
  17. Sozen E, Ozer NK. Impact of high cholesterol and endoplasmic reticulum stress on metabolic diseases: an updated mini-review. Redox Biol. 2017;12:456–61. · DOI
  18. Kamtchum-Tatuene J. Epidemiology of carotid atherosclerosis in Africa: a blind spot. Lancet Glob Health. 2020;8:e996. · DOI
  19. Libby P. The changing landscape of atherosclerosis. Nature. 2021;592:524–33. · DOI · Paper page
  20. Chen FH, Liu T, Xu L, Zhang L, Zhou XB. Association of serum vitamin D level and carotid atherosclerosis: a systematic review and meta-analysis. J Ultrasound Med. 2018;37:1293–303. · DOI
  21. Zhao M, Liu A, Mo L, Wan G, Lu F, Chen L, Fu S, Chen H, Fu T, Deng H. Higher expression of PLEK and LY86 as the potential biomarker of carotid atherosclerosis. Med (Baltim). 2023;102(42):e34445. · DOI
  22. Luo J, Yang H, Song BL. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol. 2020;21(4):225–45. · DOI · Paper page
  23. Cardoso D, Perucha E. Cholesterol metabolism: a new molecular switch to control inflammation. Clin Sci (Lond). 2021;135(11):1389–408. · DOI
  24. Goldstein JL, Brown MS. The LDL receptor Arterioscler. Thromb Vasc Biol. 2009;29(4):431–8. · DOI · Paper page
  25. Mineo C. Lipoprotein receptor signalling in atherosclerosis. Cardiovasc Res. 2020;116(7):1254–74. · DOI
  26. Bah SY, Dickinson P, Forster T, Kampmann B, Ghazal P. Immune oxysterols: role in mycobacterial infection and inflammation. J Steroid Biochem Mol Biol. 2017;169:152–63. · DOI
  27. Kang MH, Singaraja R, Hayden MR. Adenosine-triphosphate-binding cassette transporter-1 trafficking and function. Trends Cardiovasc Med. 2010;20(2):41–9. · DOI
  28. Phillips MC. Molecular mechanisms of cellular cholesterol efflux. J Biol Chem. 2014;289(35):24020–9. · DOI
  29. Chang TY, Li BL, Chang CC, Urano Y. Acyl-coenzyme A: cholesterol acyltransferases. Am J Physiol Endocrinol Metab. 2009;297:E1–9. · DOI · Paper page
  30. Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature. 2008;454(7203):470–7. · DOI
  31. Wang D, Yang Y, Lei Y, Tzvetkov NT, Liu X, Yeung AWK, Xu S, Atanasov AG. Targeting foam cell formation in atherosclerosis: therapeutic potential of natural products. Pharmacol Rev. 2019;71(4):596–670. · DOI
  32. Luo G, Xiang L, Yao P, Xiao L. Quercetin attenuates atherosclerosis in ApoE KO mice by regulating macrophage cholesterol homeostasis. Chin Pharmacol Bull. 2022;38(9):1395–400.
  33. Lebeaupin C, Vallée D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018;69(4):927–47. · DOI
  34. Mota M, Banini BA, Cazanave SC, Sanyal AJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism. 2016;65(8):1049–61. · DOI · Paper page
  35. Nasiri-Ansari N, Nikolopoulou C, Papoutsi K, Kyrou I, Mantzoros CS, Kyriakopoulos G, Chatzigeorgiou A, Kalotychou V, Randeva MS, Chatha K, Kontzoglou K, Kaltsas G, Papavassiliou AG, Randeva HS, Kassi E. Empagliflozin attenuates non-alcoholic fatty liver Disease (NAFLD) in High Fat Diet Fed ApoE(-/-) mice by activating Autophagy and reducing ER stress and apoptosis. Int J Mol Sci. 2021;22(2):818. · DOI
  36. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306(5695):457–61. · DOI · Paper page
  37. Myoishi M, Hao H, Minamino T, Watanabe K, Nishihira K, Hatakeyama K, Asada Y, Okada K, Ishibashi-Ueda H, Gabbiani G, Bochaton-Piallat ML, Mochizuki N, Kitakaze M. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation. 2007;116(11):1226–33. · DOI
  38. Kolb PS, Ayaub EA, Zhou W, Yum V, Dickhout JG, Ask K. The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis. Int J Biochem Cell Biol. 2015;61:45–52. · DOI
  39. Yang HJ, Kong B, Shuai W, Zhang JJ, Huang H. MD1 deletion exaggerates cardiomyocyte autophagy induced by heart failure with preserved ejection fraction through ROS/MAPK signalling pathway. J Cell Mol Med. 2020;24(16):9300–12. · DOI
  40. Strandberg TE. Role of statin therapy in primary Prevention of Cardiovascular Disease in Elderly patients. Curr Atheroscler Rep. 2019;21(8):28. · DOI
  41. Averna M, Banach M, Bruckert E, Drexel H, Farnier M, Gaita D, Magni P, März W, Masana L, Mello E, Silva A, Reiner Z, Ros E, Vrablik M, Zambon A, Zamorano JL, Stock JK, Tokgözoğlu LS, Catapano AL. Practical guidance for combination lipid-modifying therapy in high- and very-high-risk patients: a statement from a European Atherosclerosis Society Task Force. Atherosclerosis. 2021;325:99–109. · DOI

Cited by

Sorted by citations

Metadata

Authors
Jiang, G., Li, J., Niu, S., Dong, R., Chen, Y., & Bi, W.
Venue
BMC Cardiovascular Disorders
Publisher
Springer Science and Business Media LLC
Published
2024-05-31
Volume
24
Issue
1
ISSN
1471-2261
DOI
10.1186/s12872-024-03957-1
PMC
PMC11140969
Cited by
12
References
0
Language
en
Licence
Funders
Hebei Medical Science Research Project (20190383)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review