For: ISALPD/C travel award application
Stearoyl-CoA desaturase in alcoholic liver fibrosis and cancer
Lai KKY1, Kweon SM1, Chi F1, Hwang E1, Kabe Y2, French S1,3, Murali R1,4, Ntambi JM5, Tsukamoto H1,6
1Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, University of Southern California, Los Angeles, CA, USA. 2Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan. 3Harbor-UCLA Medical Center, Torrance, CA, USA. 4Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 5Departments of Biochemistry and Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA. 6Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.[Background] Evidence suggests that alcohol promotes liver fibrosis and hepatocellular carcinoma (HCC) by activation of Wnt/β-catenin pathway. Yet, Wnt targets essential for activation of hepatic stellate cell (HSC) and liver tumor-initiating stem cell-like cells (TICs), the primary cell types responsible for liver fibrosis and cancer, respectively, are unknown. Stearoyl-CoA desaturase (SCD) catalyzes the biosynthesis of the monounsaturated fatty acids (MUFA), oleic acid and palmitoleic acid, and is implicated in metabolic syndrome, tumorigenesis, and stemness, but SCD’s role in liver fibrosis and cancer is elusive. [Aim] Our study aimed to determine whether and how SCD promotes liver fibrosis and cancer. [Methods] To identify SCD as a Wnt-dependent gene, rodent primary HSCs, mouse liver TICs, and human HCC lines were assayed for Wnt pathway inhibition. Functional significance of SCD was tested by pharmacologic and genetic inhibition in mouse models of liver fibrosis, chronic alcoholic steatohepatitis (ASH), alcoholic neutrophilic hepatitis (AH), and alcohol-promoted TIC-dependent liver tumorigenesis. Nano-bead pull-down assay, LC-mass spectrometry, computational modeling, and ribonucleoprotein immunoprecipitation disclosed a novel mechanism of Wnt-SCD crosstalk. [Results] A shift from Scd1 to Scd2 expression is evident in chronic ASH and AH livers and in mouse TICs from alcohol-promoted HCC. Scd2 (rodent) and SCD (human) are novel Wnt target genes induced in TICs from alcohol-promoted HCC, HSCs from hepatotoxic and cholestatic liver fibrosis, and human HCC cell lines. Scd2 inhibition/knockdown ameliorates liver tumorigenesis and fibrosis in the respective models. Wnt co-receptor LRP5/6 is also induced in the models when SCD/Scd2 is induced. Mechanistically, the Wnt effector β-catenin enhances SREBP-1-dependent Scd transcription and is in turn stabilized by MUFA generated by SCD/Scd2. This positive loop is caused by HuR-induced mRNA stabilization of LRP5/6. As such, SCD/Scd2 inhibition reduces cytosolic HuR, LRP5/6 stability, β-catenin stabilization, HSC activation and TIC self-renewal, and attenuates liver fibrosis and tumorigenesis in vivo. [Conclusion] The newly disclosed Wnt-SCD/Scd2-LRP5/6 loop may serve as a novel therapeutic target for alcohol-promoted liver fibrosis and tumorigenesis.