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

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.

Coordinated changes of gut microbiome and lipidome differentiates nonalcoholic steatohepatitis (NASH) from isolated steatosis

“…Consistently, three studies published very recently provided various evidence to prove that activation of STING pathway contributes to liver inflammation and the progression of NASH . In addition, we observed that the mRNA of stearoyl‐CoA desaturases 1 ( Scd1 ) was significantly higher in mice with NASH (Figure D), which was consistent with the previous study that overexpression of SCD aggregated while pharmacological inhibitors of SCD attenuated liver fibrosis . We have several more potential targets selected from the transcriptome results are being investigated currently.…”

“…[32][33][34] In addition, we observed that the mRNA of stearoyl-CoA desaturases 1 (Scd1) was significantly higher in mice with NASH ( Figure 3D), which was consistent with the previous study that overexpression of SCD aggregated while pharmacological inhibitors of SCD attenuated liver fibrosis. 35 We have several more potential targets selected from the transcriptome results are being investigated currently. Overall, in our view, on one hand, the transcriptome results confirmed the mice with isolated steatosis and NASH model used in this study was the ideal one to study the transition of NASH from isolated steatosis; on the other hand, these findings will give rise to more novel targets for NASH prevention.…”

The role of YAP/TAZ activity in cancer metabolic reprogramming

“…Several evidences suggest that SCD1 is positively relation with a variety of malignant tumors [54–56]. A recent study reveals that SCD 1 promotes nuclear localization and transcriptional activity of YAP/TAZ to regulate lung cancer stemness (Fig.…”

Inhibition of Stearoyl-CoA Desaturase-1 Activity Suppressed SREBP Signaling in Colon Cancer Cells and Their Spheroid Growth

“…We recently showed that SCD1 is upregulated in CSC-like cell populations compared with non-CSC populations in human liver cancer cell lines [12,13]. Other studies also shed light on the roles of unsaturated fatty acids in maintaining CSC stemness by activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [14] and Wnt-β-catenin [15] signaling pathways. These studies indicate that lipid desaturation is a metabolic signature, and SCD1 may be an important therapeutic target in CSCs.…”