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Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via Wnt Signaling and Stabilization of Low Density Lipoprotein Receptor-related Proteins 5 and 6
- Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Liver Cirrhosis
Male
Transcription, Genetic
medicine.disease_cause
ELAV-Like Protein 1
Fatty Acids, Monounsaturated
Mice
0302 clinical medicine
Diethylnitrosamine
Wnt Signaling Pathway
beta Catenin
Cholestasis
Liver Neoplasms
Gastroenterology
Wnt signaling pathway
LRP6
LRP5
beta Karyopherins
Survival Rate
Low Density Lipoprotein Receptor-Related Protein-5
030220 oncology & carcinogenesis
Low Density Lipoprotein Receptor-Related Protein-6
Transportin 1
Neoplastic Stem Cells
Sterol Regulatory Element Binding Protein 1
Stearoyl-CoA Desaturase
congenital, hereditary, and neonatal diseases and abnormalities
Liver tumor
Carcinoma, Hepatocellular
Biology
Article
03 medical and health sciences
Cancer stem cell
Cell Line, Tumor
medicine
Hepatic Stellate Cells
Animals
Humans
RNA, Messenger
Rats, Wistar
Neoplasm Staging
Hepatology
medicine.disease
Molecular biology
Rats
030104 developmental biology
ran GTP-Binding Protein
Case-Control Studies
Hepatic stellate cell
Cancer research
Carcinogenesis
Neoplasm Transplantation
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....61db4a73f19c7ea31fe8d204c351dad8