Palmitic acid induces lipid droplet accumulation and senescence in nucleus pulposus cells via ER-stress pathway.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
07 May 2024
07 May 2024
Historique:
received:
05
09
2023
accepted:
25
04
2024
medline:
8
5
2024
pubmed:
8
5
2024
entrez:
7
5
2024
Statut:
epublish
Résumé
Intervertebral disc degeneration (IDD) is a highly prevalent musculoskeletal disorder affecting millions of adults worldwide, but a poor understanding of its pathogenesis has limited the effectiveness of therapy. In the current study, we integrated untargeted LC/MS metabolomics and magnetic resonance spectroscopy data to investigate metabolic profile alterations during IDD. Combined with validation via a large-cohort analysis, we found excessive lipid droplet accumulation in the nucleus pulposus cells of advanced-stage IDD samples. We also found abnormal palmitic acid (PA) accumulation in IDD nucleus pulposus cells, and PA exposure resulted in lipid droplet accumulation and cell senescence in an endoplasmic reticulum stress-dependent manner. Complementary transcriptome and proteome profiles enabled us to identify solute carrier transporter (SLC) 43A3 involvement in the regulation of the intracellular PA level. SLC43A3 was expressed at low levels and negatively correlated with intracellular lipid content in IDD nucleus pulposus cells. Overexpression of SLC43A3 significantly alleviated PA-induced endoplasmic reticulum stress, lipid droplet accumulation and cell senescence by inhibiting PA uptake. This work provides novel integration analysis-based insight into the metabolic profile alterations in IDD and further reveals new therapeutic targets for IDD treatment.
Identifiants
pubmed: 38714886
doi: 10.1038/s42003-024-06248-9
pii: 10.1038/s42003-024-06248-9
doi:
Substances chimiques
Palmitic Acid
2V16EO95H1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
539Informations de copyright
© 2024. The Author(s).
Références
Knezevic, N. N., Candido, K. D., Vlaeyen, J. W. S., Van Zundert, J. & Cohen, S. P. Low back pain. Lancet 398, 78–92 (2021).
pubmed: 34115979
doi: 10.1016/S0140-6736(21)00733-9
Madhu, V. et al. Hypoxic Regulation Of Mitochondrial Metabolism And Mitophagy In Nucleus Pulposus Cells Is Dependent on HIF-1α-BNIP3 axis. J. Bone Miner. Res. 35, 1504–1524 (2020).
pubmed: 32251541
doi: 10.1002/jbmr.4019
Ji, M. L. et al. Downregulation of microRNA-193a-3p is involved in invertebral disc degeneration by targeting MMP14. J. Mol. Med. 94, 457–468 (2016).
pubmed: 26620678
doi: 10.1007/s00109-015-1371-2
Ji, M. L. et al. Preclinical development of a microRNA-based therapy for intervertebral disc degeneration. Nat. Commun. 9, 5051 (2018).
pubmed: 30487517
pmcid: 6262020
doi: 10.1038/s41467-018-07360-1
Patil, P. et al. Oxidative stress-induced senescence markedly increases disc cell bioenergetics. Mech. Ageing Dev. 180, 97–106 (2019).
pubmed: 31002926
doi: 10.1016/j.mad.2019.04.006
Chen, C. C. et al. Inhibition of the P53/P21 Pathway Attenuates The Effects Of Senescent Nucleus Pulposus Cell-derived Exosomes On The Senescence Of Nucleus Pulposus Cells. Orthop. Surg. 13, 583–591 (2021).
pubmed: 33314719
doi: 10.1111/os.12886
Chen, Q. et al. Endoplasmic reticulum stress induces hepatic steatosis by transcriptional upregulating lipid droplet protein perilipin2. FASEB J. 35, e21900 (2021).
pubmed: 34547130
doi: 10.1096/fj.202100739RR
He, R. et al. HIF1A alleviates compression-induced apoptosis of nucleus pulposus derived stem cells via upregulating autophagy. Autophagy 17, 3338–3360 (2021).
pubmed: 33455530
pmcid: 8632345
doi: 10.1080/15548627.2021.1872227
Wang, B. et al. Mechanosensitive Ion Channel Piezo1 Activated By Matrix Stiffness Regulates Oxidative Stress-induced Senescence And Apoptosis In Human Intervertebral Disc Degeneration. Oxid Med Cell Longev 2021, 8884922 (2021).
pubmed: 33628392
pmcid: 7889339
Novais, E. J., Diekman, B. O., Shapiro, I. M. & Risbud, M. V. p16(Ink4a) deletion in cells of the intervertebral disc affects their matrix homeostasis and senescence associated secretory phenotype without altering onset of senescence. Matrix Biol. 82, 54–70 (2019).
pubmed: 30811968
pmcid: 6708504
doi: 10.1016/j.matbio.2019.02.004
Feng, C. et al. Oxygen-sensing Nox4 generates genotoxic ROS to induce premature senescence of nucleus pulposus cells through MAPK and NF-κB pathways. Oxid. Med. Cell. Longev. 2017, 7426458 (2017).
pubmed: 29147462
pmcid: 5632907
doi: 10.1155/2017/7426458
Han, J. & Kaufman, R. J. The role of ER stress in lipid metabolism and lipotoxicity. J. Lipid Res. 57, 1329–1338 (2016).
pubmed: 27146479
pmcid: 4959874
doi: 10.1194/jlr.R067595
Luo, R. et al. Impaired calcium homeostasis via advanced glycation end products promotes apoptosis through endoplasmic reticulum stress in human nucleus pulposus cells and exacerbates intervertebral disc degeneration in rats. FEBS J. 286, 4356–4373 (2019).
pubmed: 31230413
doi: 10.1111/febs.14972
Kim, H. S. et al. The p38-activated ER stress-ATF6α axis mediates cellular senescence. FASEB J. 33, 2422–2434 (2019).
pubmed: 30260700
doi: 10.1096/fj.201800836R
Xiang, H. et al. Exosomes derived from human urine-derived stem cells inhibit intervertebral disc degeneration by ameliorating endoplasmic reticulum stress. Oxid. Med. Cell. Longev. 2020, 6697577 (2020).
pubmed: 33488928
pmcid: 7787770
doi: 10.1155/2020/6697577
Liao, Z. et al. Exosomes from mesenchymal stem cells modulate endoplasmic reticulum stress to protect against nucleus pulposus cell death and ameliorate intervertebral disc degeneration in vivo. Theranostics 9, 4084–4100 (2019).
pubmed: 31281533
pmcid: 6592170
doi: 10.7150/thno.33638
Ren, S. et al. Integration of metabolomics and transcriptomics reveals major metabolic pathways and potential biomarker involved in prostate cancer. Mol. Cell. Proteom. 15, 154–163 (2016).
doi: 10.1074/mcp.M115.052381
Wigger, L. et al. Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes. Nat. Metab. 3, 1017–1031 (2021).
pubmed: 34183850
doi: 10.1038/s42255-021-00420-9
Ma, P. et al. Integration of metabolomics and transcriptomics reveals ketone body and lipid metabolism disturbance related to ER stress in the liver. J. Proteome Res. 20, 3875–3888 (2021).
pubmed: 34270263
doi: 10.1021/acs.jproteome.1c00167
Yuan, P. et al. Targeted metabolomics reveals that 2,3,7,8-tetrachlorodibenzofuran exposure induces hepatic steatosis in male mice. Environ. Pollut. 259, 113820 (2020).
pubmed: 31918130
doi: 10.1016/j.envpol.2019.113820
Xu, N. et al. Integrative transcriptomics, proteomics, and metabolomics data analysis exploring the injury mechanism of ricin on human lung epithelial cells. Toxicol. In Vitro 60, 160–172 (2019).
pubmed: 31103672
doi: 10.1016/j.tiv.2019.05.012
Rocha, B. et al. Integrative metabolic pathway analysis reveals novel therapeutic targets in osteoarthritis. Mol. Cell. Proteom. 19, 574–588 (2020).
doi: 10.1074/mcp.RA119.001821
Yan, J. et al. Cholesterol induces pyroptosis and matrix degradation via mSREBP1-driven endoplasmic reticulum stress in intervertebral disc degeneration. Front. Cell Dev. Biol. 9, 803132 (2021).
pubmed: 35174163
doi: 10.3389/fcell.2021.803132
Zhang, Z. et al. Orientin downregulating oxidative stress-mediated endoplasmic reticulum stress and mitochondrial dysfunction through AMPK/SIRT1 pathway in rat nucleus pulposus cells in vitro and attenuated intervertebral disc degeneration in vivo. Apoptosis 27, 1031–1048 (2022).
pubmed: 36125665
doi: 10.1007/s10495-022-01770-9
Yao, Y. et al. MIF plays a key role in regulating tissue-specific chondro-osteogenic differentiation fate of human cartilage endplate stem cells under hypoxia. Stem Cell Rep. 7, 249–262 (2016).
doi: 10.1016/j.stemcr.2016.07.003
Gornet, M. G. et al. Magnetic resonance spectroscopy (MRS) can identify painful lumbar discs and may facilitate improved clinical outcomes of lumbar surgeries for discogenic pain. Eur. Spine J. 28, 674–687 (2019).
pubmed: 30610465
doi: 10.1007/s00586-018-05873-3
Smith, L. M. et al. In vivo magnetic resonance spectroscopy of hyperpolarized [1-(13) C]pyruvate and proton density fat fraction in a guinea pig model of non-alcoholic fatty liver disease development after life-long western diet consumption. J. Magn. Reson. Imaging 54, 1404–1414 (2021).
pubmed: 33970520
pmcid: 8516663
doi: 10.1002/jmri.27677
Zuo, J. et al. In vivo intervertebral disc characterization using magnetic resonance spectroscopy and T1ρ imaging: association with discography and Oswestry Disability Index and Short Form-36 Health Survey. Spine 37, 214–221 (2012).
pubmed: 21697767
pmcid: 3633556
doi: 10.1097/BRS.0b013e3182294a63
Keshari, K. R. et al. Lactic acid and proteoglycans as metabolic markers for discogenic back pain. Spine 33, 312–317 (2008).
pubmed: 18303465
doi: 10.1097/BRS.0b013e31816201c3
Cimino, J. et al. Towards lipidomics of low-abundant species for exploring tumor heterogeneity guided by high-resolution mass spectrometry imaging. Int. J. Mol. Sci. 14, 24560–24580 (2013).
pubmed: 24351834
pmcid: 3876128
doi: 10.3390/ijms141224560
Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016).
pubmed: 27789842
pmcid: 5112585
doi: 10.1126/science.aaf6659
Marschallinger, J. et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23, 194–208 (2020).
pubmed: 31959936
pmcid: 7595134
doi: 10.1038/s41593-019-0566-1
Joshi, M. et al. CPT1A over-expression increases reactive oxygen species in the mitochondria and promotes antioxidant defenses in prostate cancer. Cancers 12, 3431 (2020).
Lin, H. et al. Reactive oxygen species regulate endoplasmic reticulum stress and ER-mitochondrial Ca(2+) crosstalk to promote programmed necrosis of rat nucleus pulposus cells under compression. Oxid. Med. Cell. Longev. 2021, 8810698 (2021).
pubmed: 33815661
pmcid: 7987452
doi: 10.1155/2021/8810698
Jo, H. et al. Endoplasmic reticulum stress induces hepatic steatosis via increased expression of the hepatic very low-density lipoprotein receptor. Hepatology 57, 1366–1377 (2013).
pubmed: 23152128
doi: 10.1002/hep.26126
Inoue, C. et al. SMARCD1 regulates senescence-associated lipid accumulation in hepatocytes. NPJ Aging Mech. Dis. 3, 11 (2017).
pubmed: 28868154
pmcid: 5577293
doi: 10.1038/s41514-017-0011-1
Zhang, X. et al. Obesity mediates apoptosis and extracellular matrix metabolic imbalances via MAPK pathway activation in intervertebral disk degeneration. Front. Physiol. 10, 1284 (2019).
pubmed: 31649558
pmcid: 6796795
doi: 10.3389/fphys.2019.01284
Flor, A. C., Wolfgeher, D., Wu, D. & Kron, S. J. A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence. Cell Death Discov. 3, 17075 (2017).
pubmed: 29090099
pmcid: 5661608
doi: 10.1038/cddiscovery.2017.75
Hasbargen, K. B. et al. Slc43a3 is a regulator of free fatty acid flux. J. Lipid Res. 61, 734–745 (2020).
pubmed: 32217606
pmcid: 7193958
doi: 10.1194/jlr.RA119000294
Henkin, A. H. et al. Evidence for protein-mediated fatty acid efflux by adipocytes. Acta Physiol. 204, 562–570 (2012).
doi: 10.1111/j.1748-1716.2011.02367.x
Tarling, E. J., de Aguiar Vallim, T. Q. & Edwards, P. A. Role of ABC transporters in lipid transport and human disease. Trends Endocrinol. Metab. 24, 342–350 (2013).
pubmed: 23415156
pmcid: 3659191
doi: 10.1016/j.tem.2013.01.006
Shishikura, K. et al. Acyl-CoA synthetase 6 regulates long-chain polyunsaturated fatty acid composition of membrane phospholipids in spermatids and supports normal spermatogenic processes in mice. FASEB J. 33, 14194–14203 (2019).
pubmed: 31648559
pmcid: 6894091
doi: 10.1096/fj.201901074R
Stefanyk, L. E., Bonen, A. & Dyck, D. J. Insulin and contraction-induced movement of fatty acid transport proteins to skeletal muscle transverse-tubules is distinctly different than to the sarcolemma. Metabolism 61, 1518–1522 (2012).
pubmed: 22560054
doi: 10.1016/j.metabol.2012.04.002
Han, B. et al. A simple disc degeneration model induced by percutaneous needle puncture in the rat tail. Spine 33, 1925–1934 (2008).
pubmed: 18708924
doi: 10.1097/BRS.0b013e31817c64a9
Yang, X., Sun, Y., Li, X. & Zhang, W. Rac1 regulates nucleus pulposus cell degeneration by activating the Wnt/β-catenin signaling pathway and promotes the progression of intervertebral disc degeneration. Am. J. Physiol. Cell Physiol. 322, C496–c507 (2022).
pubmed: 35108117
doi: 10.1152/ajpcell.00355.2021