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
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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.
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Selective inhibition of stearoyl-CoA desaturase 1 in HSCs reduced their activation and inhibited fibrosis in rodent models.
“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]
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RETRACTED ARTICLE: Circular RNA circStag1 promotes bone regeneration by interacting with HuR
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The altered lipidome of hepatocellular carcinoma
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Metabolic Reprogramming of Thyroid Cancer Cells and Crosstalk in Their Microenvironment
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Unveiling the MUFA–Cancer Connection: Insights from Endogenous and Exogenous Perspectives
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Self-citationCancer Stem Cell and Hepatic Stellate Cells in Hepatocellular Carcinoma
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Stearoyl-CoA desaturase 1 as a therapeutic target for cancer: a focus on hepatocellular carcinoma
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Self-citationHu Antigen R (HuR) Protein Structure, Function and Regulation in Hepatobiliary Tumors
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Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma
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Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine
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CBP-mediated Wnt3a/β-catenin signaling promotes cervical oncogenesis initiated by Piwil2
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The role of Evi/Wntless in exporting Wnt proteins
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A Lipidomic Signature Complements Stemness Features Acquisition in Liver Cancer Cells
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Liver Steatosis: A Marker of Metabolic Risk in Children
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- 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 · 2015: 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
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