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.
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.
['Lai|Keane K Y|KKY|', 'Kweon|Soo-Mi|SM|', 'Chi|Feng|F|', 'Hwang|Edward|E|', 'Kabe|Yasuaki|Y|', 'Higashiyama|Reiichi|R|', 'Qin|Lan|L|', 'Yan|Rui|R|', 'Wu|Raymond P|RP|', 'Lai|Keith|K|', 'Fujii|Naoaki|N|', 'French|Samuel|S|', 'Xu|Jun|J|', 'Wang|Jian-Ying|JY|', 'Murali|Ramachandran|R|', 'Mishra|Lopa|L|', 'Lee|Ju-Seog|JS|', 'Ntambi|James M|JM|', 'Tsukamoto|Hidekazu|H|']
D000818:Animals D006528:Carcinoma, Hepatocellular D016022:Case-Control Studies D045744:Cell Line, Tumor D002779:Cholestasis D004052:Diethylnitrosamine D000067780:ELAV-Like Protein 1 D005229:Fatty Acids, Monounsaturated D055166:Hepatic Stellate Cells D006801:Humans D008103:Liver Cirrhosis D008113:Liver Neoplasms D060492:Low Density Lipoprotein Receptor-Related Protein-5 D060488:Low Density Lipoprotein Receptor-Related Protein-6 D008297:Male D051379:Mice D009367:Neoplasm Staging D009368:Neoplasm Transplantation D014411:Neoplastic Stem Cells D012333:RNA, Messenger D051381:Rats D017208:Rats, Wistar D013230:Stearoyl-CoA Desaturase D051780:Sterol Regulatory Element Binding Protein 1 D015996:Survival Rate D014158:Transcription, Genetic D060449:Wnt Signaling Pathway D051176:beta Catenin D028961:beta Karyopherins D020931:ran GTP-Binding Protein
HCC HuR Cancer Stem Cells Hepatocarcinogenesis