The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6
Open accessAbstract
Background & aims Stearoyl-CoA desaturase (SCD) synthesizes monounsaturated fatty acids (MUFAs) and has been associated with the development of metabolic syndrome, tumorigenesis, and stem cell characteristics. We investigated whether and how SCD promotes liver fibrosis and tumor development in mice.Methods Rodent primary hepatic stellate cells (HSCs), mouse liver tumor-initiating stem cell-like cells (TICs), and human hepatocellular carcinoma (HCC) cell lines were exposed to Wnt signaling inhibitors and changes in gene expression patterns were analyzed. We assessed the functions of SCD by pharmacologic and conditional genetic manipulation in mice with hepatotoxic or cholestatic induction of liver fibrosis, orthotopic transplants of TICs, or liver tumors induced by administration of diethyl nitrosamine. We performed bioinformatic analyses of SCD expression in HCC vs nontumor liver samples collected from patients, and correlated levels with HCC stage and patient mortality. We performed nano-bead pull-down assays, liquid chromatography-mass spectrometry, computational modeling, and ribonucleoprotein immunoprecipitation analyses to identify MUFA-interacting proteins. We examined the effects of SCD inhibition on Wnt signaling, including the expression and stability of low-density lipoprotein-receptor-related proteins 5 and 6 (LRP5 and LRP6), by immunoblot and quantitative polymerase chain reaction analyses.Results SCD was overexpressed in activated HSC and HCC cells from patients; levels of SCD messenger RNA (mRNA) correlated with HCC stage and patient survival time. In rodent HSCs and TICs, the Wnt effector β-catenin increased sterol regulatory element binding protein 1-dependent transcription of Scd, and β-catenin in return was stabilized by MUFAs generated by SCD. This loop required MUFA inhibition of binding of Ras-related nuclear protein 1 (Ran1) to transportin 1 and reduced nuclear import of elav-like protein 1 (HuR), increasing cytosolic levels of HuR and HuR-mediated stabilization of mRNAs encoding LRP5 and LRP6. Genetic disruption of Scd and pharmacologic inhibitors of SCD reduced HSC activation and TIC self-renewal and attenuated liver fibrosis and tumorigenesis in mice. Conditional disruption of Scd2 in activated HSCs prevented growth of tumors from TICs and reduced the formation of diethyl nitrosamine-induced liver tumors in mice.Conclusions In rodent HSCs and TICs, we found SCD expression to be regulated by Wnt-β-catenin signaling, and MUFAs produced by SCD provided a forward loop to amplify Wnt signaling via stabilization of Lrp5 and Lrp6 mRNAs, contributing to liver fibrosis and tumor growth. SCD expressed by HSCs promoted liver tumor development in mice. Components of the identified loop linking HSCs and TICs might be therapeutic targets for liver fibrosis and tumors.
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.
Integrity signals
Registry
Cites
Statistics
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.
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?
In the citing paper
“The selective inhibition of stearoyl-CoA desaturase 1 in HSCs reduced their activation and inhibited fibrosis in rodent models.120”
From An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH (2023) · cites this paper as [120]
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
1 retracted
Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells
Chen, C., Tsukamoto, H., Liu, J.-C., Kashiwabara, C., Feldman, D. E., Sher, L. S., Dooley, S., French, S. W., Mishra, L., Petrovic, L., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci65859 · Cited by 161
Self-citationRetractedAutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility
Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009) · Journal of Computational Chemistry · doi:10.1002/jcc.21256 · Cited by 26,294
Wnt/β-catenin signaling and disease
Clevers, H., & Nusse, R. (2012) · Cell · doi:10.1016/j.cell.2012.05.012 · Cited by 5,554
Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver
Friedman, S. L. (2008) · Physiological Reviews · doi:10.1152/physrev.00013.2007 · Cited by 2,842
Hepatocellular carcinoma in cirrhosis: Incidence and risk factors
Fattovich, G., Stroffolini, T., Zagni, I., & Donato, F. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.09.014 · Cited by 2,587
Delcommenne, M., Tan, C., Gray, V., Rue, L., Woodgett, J. R., & Dedhar, S. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.19.11211 · Cited by 1,102
Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis
Kisseleva, T., Cong, M., Paik, Y., Scholten, D., Jiang, C., Benner, C., Iwaisako, K., Moore-Morris, T., Scott, B., Tsukamoto, H., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1201840109 · Cited by 805
Self-citationβ-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis
Monga, S. P. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.02.056 · Cited by 493
He, G., Dhar, D., Nakagawa, H., Font-Burgada, J., Ogata, H., Jiang, Y., Shalapour, S., Seki, E., Yost, S. E., Jepsen, K., et al. (2013) · Cell · doi:10.1016/j.cell.2013.09.031 · Cited by 476
miR-29 Modulates Wnt Signaling in Human Osteoblasts through a Positive Feedback Loop
Kapinas, K., Kessler, C. B., Ricks, T., Gronowicz, G., & Delany, A. M. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.116137 · Cited by 405
Ben‐David, U., Gan, Q.-F., Golan‐Lev, T., Arora, P., Yanuka, O., Oren, Y. S., Leikin-Frenkel, A. I., Graf, M. R., Garippa, R. J., Boehringer, M., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2012.11.015 · Cited by 312
Wang, J., Guo, Y., Chu, H., Guan, Y., Bi, J., & Wang, B. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140510015 · Cited by 290
Self-citationPersad, S., Troussard, A. A., McPhee, T. R., Mulholland, D. J., & Dedhar, S. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.6.1161 · Cited by 269
Roongta, U. V., Pabalan, J. G., Wang, X., Ryseck, R.-P., Fargnoli, J., Henley, B. J., Yang, W.-P., Zhu, J., Madireddi, M. T., Lawrence, R. M., et al. (2011) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-11-0126 · Cited by 266
Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis
Cheng, J. H., She, H., Han, Y., Wang, J., Xiong, S., Asahina, K., & Tsukamoto, H. (2007) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00263.2007 · Cited by 261
Self-citationAugenlicht, L. H., Davis, R. J., Lisanti, M. P., Zhurinsky, J., Troussard, A. A., D’Amico, M., Donehower, L. A., Takemaru, K., Moon, R. T., Ben‐Ze'ev, A., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000643200 · Cited by 241
Characterization of HSCD5, a novel human stearoyl-CoA desaturase unique to primates
Wang, J., Yu, L., Schmidt, R. E., Chen, S., Huang, X., Gould, K. E., & Cao, G. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.05.013 · Cited by 228
Self-citationInactivation of the Hippo tumour suppressor pathway by integrin-linked kinase
Serrano, I., McDonald, P. C., Lock, F. E., Muller, W. J., & Dedhar, S. (2013) · Nature Communications · doi:10.1038/ncomms3976 · Cited by 226
Tabor, D. E., Kim, J. B., Spiegelman, B. M., & Edwards, P. A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.29.20603 · Cited by 226
Structural basis for nuclear import complex dissociation by RanGTP
Lee, S. J., Matsuura, Y., Liu, S. M., & Stewart, M. (2005) · Nature · doi:10.1038/nature03578 · Cited by 219
Proteomic and Lipidomic Signatures of Lipid Metabolism in NASH-Associated Hepatocellular Carcinoma
Muir, K., Hazim, A. Z., He, Y., Peyressatre, M., Kim, D. Y., Song, X., & Beretta, L. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3797 · Cited by 183
Stearoyl-CoA desaturase-1 is a key factor for lung cancer-initiating cells
Noto, A., Raffa, S., Vitis, C. D., Roscilli, G., Malpicci, D., Coluccia, P., Napoli, A. D., Rícci, A., Giovagnoli, M. R., Aurisicchio, L., et al. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.444 · Cited by 159
Stearoyl CoA Desaturase Is Required to Produce Active, Lipid-Modified Wnt Proteins
Rios-Esteves, J., & Resh, M. D. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.08.027 · Cited by 157
Stellate cells and the development of liver cancer: Therapeutic potential of targeting the stroma
Coulouarn, C., & Clément, B. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.02.003 · Cited by 142
Miyazaki, M., Dobrzyń, A., Elias, P. M., & Ntambi, J. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503132102 · Cited by 141
Self-citationMenghini, R., Menini, S., Amoruso, R., Fiorentino, L., Casagrande, V., Marzano, V., Tornei, F., Bertucci, P., Iacobini, C., Sérino, M., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.10.079 · Cited by 127
Transportin‐1 and Transportin‐2: Protein nuclear import and beyond
Twyffels, L., Gueydan, C., & Kruys, V. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.04.023 · Cited by 107
Oloumi, A., Syam, S., & Dedhar, S. (2006) · Oncogene · doi:10.1038/sj.onc.1209752 · Cited by 94
Human antigen R contributes to hepatic stellate cell activation and liver fibrosis
Woodhoo, A., Iruarrizaga‐Lejarreta, M., Beraza, N., García‐Rodríguez, J. L., Embade, N., Fernández‐Ramos, D., Martínez-López, N., Juan, V. G., Arteta, B., Caballería, J., et al. (2012) · Hepatology · doi:10.1002/hep.25828 · Cited by 88
Cho, J., Dimri, M., & Dimri, G. P. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.422931 · Cited by 84
Bansal, S., Berk, M. P., Alkhouri, N., Partrick, D. A., Fung, J. J., & Feldstein, A. E. (2013) · Journal of Surgical Research · doi:10.1016/j.jss.2013.07.001 · Cited by 76
Discovery of piperidine-aryl urea-based stearoyl-CoA desaturase 1 inhibitors
Xin, Z., Zhao, H., Serby, M. D., Liu, B., Liu, M., Szczepankiewicz, B. G., Nelson, L. T. J., Smith, H. T., Suhar, T. S., Janis, R. S., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.06.088 · Cited by 75
Liu, L., Christodoulou‐Vafeiadou, E., Rao, J. N., Zou, T., Xiao, L., Chung, H. K., Yang, H., Gorospe, M., Kontoyiannis, D. L., & Wang, J. (2014) · Molecular Biology of the Cell · doi:10.1091/mbc.e14-03-0853 · Cited by 74
Self-citationMauvoisin, D., Charfi, C., Lounis, M. A., Rassart, É., & Mounier, C. (2012) · Cancer Science · doi:10.1111/cas.12032 · Cited by 73
Deb, A., Davis, B. H., Guo, J., Ni, A., Huang, J., Zhang, Z., Mu, H., & Dzau, V. J. (2007) · Stem Cells · doi:10.1634/stemcells.2007-0475 · Cited by 68
Porphyrin Accumulation in Mitochondria Is Mediated by 2-Oxoglutarate Carrier
Kabe, Y., Ohmori, M., Shinouchi, K., Tsuboi, Y., Hirao, S., Azuma, M., Watanabe, H., Okura, I., & Handa, H. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604729200 · Cited by 67
Self-citationPhospholipase D1 Drives a Positive Feedback Loop to Reinforce the Wnt/β-Catenin/TCF Signaling Axis
Kang, D. W., Lee, S.-H., Yoon, J. W., Park, W.-S., Choi, K., & Min, D. S. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3470 · Cited by 46
Wnt3a activates β1-integrin and regulates migration and adhesion of vascular smooth muscle cells
Wu, X., Wang, J., Jiang, H., Hu, Q. Z., Chen, J., Zhang, J., ZHU, R., LIU, W., & Li, B. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.1937 · Cited by 35
Self-citationShafiei, M. S., & Rockey, D. C. (2011) · Laboratory Investigation · doi:10.1038/labinvest.2011.155 · Cited by 29
Naves, M. A., Requião‐Moura, L., Soares, M. F., Silva-Júnior, J. A., Kirsztajn, G. M., & Teixeira, V. P. C. (2011) · Journal of Nephrology · doi:10.5301/jn.5000017 · Cited by 27
Liver-specific mono-unsaturated fatty acid synthase-1 inhibitor for anti-hepatitis C treatment
Nio, Y., Hasegawa, H., Okamura, H., Miyayama, Y., Akahori, Y., & Hijikata, M. (2016) · Antiviral Research · doi:10.1016/j.antiviral.2016.07.003 · Cited by 23
Cited by
Sorted by citations
Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions
Chen, Z., Han, F., Du, Y., Shi, H., & Zhou, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01332-8 · Cited by 1,612
Seitz, H. K., Bataller, R., Cortez-Pinto, H., Gao, B., Gual, A., Lackner, C., Mathurin, P., Mueller, S., Szabo, G., & Tsukamoto, H. (2018) · Nature Reviews Disease Primers · doi:10.1038/s41572-018-0014-7 · Cited by 1,271
Self-citationMetabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma
Du, D., Liu, C., Qin, M., Zhang, X., Xi, T., Yuan, S., Hao, H., & Xiong, J. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.09.019 · Cited by 665
Wnt–β-catenin signalling in liver development, health and disease
Perugorria, M. J., Olaizola, P., Labiano, I., Esparza-Baquer, A., Marzioni, M., Marín, J. J. G., Bujanda, L., & Bañales, J. M. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0075-9 · Cited by 622
Cancer stem cells in hepatocellular carcinoma — from origin to clinical implications
Lee, T. K., Guan, X., & Ma, S. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00508-3 · Cited by 463
Metadata
- Authors
- Lai, K. K. Y., Kweon, S.-M., Chi, F., Hwang, E., Kabe, Y., Higashiyama, R., Qin, L., Yan, R., Wu, R. P., Lai, K., Fujii, N., French, S., Xu, J., Wang, J.-Y., Murali, R., Mishra, L., Lee, J.-S., Ntambi, J. M., & Tsukamoto, H.
- Affiliations
- University of Southern California (US)
- Keio University (JP)
- St. Jude Children's Research Hospital (US)
- University of Maryland, Baltimore (US)
- George Washington University (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of Wisconsin–Madison (US)
- Corresponding author
- Tsukamoto, Hidekazu
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 152
- Issue
- 6
- Pages
- 1477-1491
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC5406249
- OpenAlex
- W2582893389
- Cited by
- 165
- References
- 41
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 12 · 2023: 30 · 2022: 30 · 2021: 20 · 2020: 21 · 2019: 15 · 2018: 17 · 2017: 1
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P50AA011999, R24AA12885, U01AA018663)
- American Cancer Society (IRG-58-007-54, R01DK062388)
- U.S. Department of Agriculture (W2005)
- U.S. Department of Veterans Affairs (5I01BX001991)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- liver fibrosis, hepatocellular carcinoma, Wnt signaling, LRP5, LRP6, monounsaturated fatty acids, hepatic stellate cells, cancer stem cells, HuR, mRNA stabilization, β-catenin, SREBP1, tumor self-renewal
- MeSH terms
- ELAV-Like Protein 1, Animals, Cholestasis, Diethylnitrosamine, Fatty Acids, Monounsaturated, Carcinoma, Hepatocellular, Humans, Liver Cirrhosis, Liver Neoplasms, Male, Neoplasm Staging, Neoplasm Transplantation, RNA, Messenger, Stearoyl-CoA Desaturase, Transcription, Genetic, Neoplastic Stem Cells, Survival Rate, Case-Control Studies, Rats, Wistar, ran GTP-Binding Protein, beta Karyopherins, Cell Line, Tumor, beta Catenin, Mice, Rats, Sterol Regulatory Element Binding Protein 1, Hepatic Stellate Cells, Wnt Signaling Pathway, Low Density Lipoprotein Receptor-Related Protein-6, Low Density Lipoprotein Receptor-Related Protein-5
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
