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Background & Aims Stearoyl-CoA desaturase (SCD) synthesizes monounsaturated fatty acids (MUFAs) and has been associated with 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 non-tumor liver samples collected from patients, and correlate 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 expression and stability of low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6), by immunoblot and quantitative PCR analyses. Results SCD was overexpressed in activated HSC and HCC cells from patients; levels of SCD mRNA correlated with HCC stage and patient survival time. In rodent HSCs and TICs, the Wnt effector beta-catenin increased sterol regulatory element binding protein 1-dependent transcription of Scd, and beta-catenin was in return stabilized by MUFAs generated by SCD. This loop required MUFA inhibition of binding of RAS-related nuclear protein 1 to transportin 1 and reduced nuclear import of elav-like protein 1 (ELAVL1), increasing cytosolic levels of ELAVL1 and ELAVL1-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 formation of diethyl nitrosamine-induced liver tumors in mice. Conclusions In rodent HSCs and TICs, we found Scd expression to be regulated by Wnt–beta-catenin signaling and MUFAs produced by SCD to provide a positive-feedback loop that amplifies Wnt signaling via stabilization of Lrp5 and Lrp6 mRNAs, leading to liver fibrosis and tumor growth. SCD expressed by HSCs promoted liver tumor development. SCD expression was increased in HCCs from patients compared with non-tumor tissue, and correlated positively with tumor state and inversely with patient survival time.

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