title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California.
authors.forename: Keane K Y
authors.initials: KKY
authors.lastname: Lai
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California.
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Kweon
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California.
authors.forename: Feng
authors.initials: F
authors.lastname: Chi
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California.
authors.forename: Edward
authors.initials: E
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kabe
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California.
authors.forename: Reiichi
authors.initials: R
authors.lastname: Higashiyama
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California.
authors.forename: Lan
authors.initials: L
authors.lastname: Qin
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California.
authors.forename: Rui
authors.initials: R
authors.lastname: Yan
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California.
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Wu
authors.affiliation: Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Keith
authors.initials: K
authors.lastname: Lai
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Fujii
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California; Harbor-University of California Los Angeles Medical Center, Torrance, California.
authors.forename: Samuel
authors.initials: S
authors.lastname: French
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Departments of Surgery and Pathology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Murali
authors.affiliation: Department of Surgery and Cancer Center, George Washington University, Washington, District of Columbia.
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Departments of Biochemistry and Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: James M
authors.initials: JM
authors.lastname: Ntambi
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, California; Department of Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, California. Electronic address: htsukamo@usc.edu.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002779:Cholestasis / Q000150:complications; D004052:Diethylnitrosamine; D000067780:ELAV-Like Protein 1 / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D055166:Hepatic Stellate Cells; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013230:Stearoyl-CoA Desaturase / Q000235:genetics* / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D015996:Survival Rate; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism; D028961:beta Karyopherins / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000378:metabolism
chemical_list: D000067780:ELAV-Like Protein 1; C000593997:Elavl1 protein, mouse; D005229:Fatty Acids, Monounsaturated; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; C000597150:Tnpo1 protein, mouse; D051176:beta Catenin; D028961:beta Karyopherins; D004052:Diethylnitrosamine; C000621685:Scd2 protein, mouse; D013230:Stearoyl-CoA Desaturase; D020931:ran GTP-Binding Protein
keywords: Cancer Stem Cells; HCC; Hepatocarcinogenesis; HuR