Abstract 2550: Lack of FGF21 accelerates NASH-HCC transition via up-regulation of hepatic SPHK1-S1P-HIPPO signaling in murine models
Authors: Xiaoju Shi, Robert C. Martin, Youxi Yu, Yujia Chen, Xingtong Wang, Guangyi Wang, Guoyue Lv, Ping Zhang, Yan Li
Journal: Cancer Research (2020)

Abstract Background: Non-alcoholic fatty liver disease(NAFLD) encompasses a broad spectrum of disorders, ranging from non-progressive bland steatosis to non-alcoholic hepatitis (NASH), cirrhosis, and malignant transformation into hepatocellular carcinoma (HCC). Accumulating evidence indicates that lipid metabolic reprogramming mediates the transition from NASH to HCC, however the NASH related carcinogenesis and role of FGF21 played during NASH-HCC transition are largely unknown. while fibroblast growth factor 21 (FGF21) exerts a key role in lipid homeostasis and play a promising therapeutic candidate for the treatment of obesity and diabetes. Aim: To investigate the effect of FGF21 on lipid metabolic reprogramming during the NASH-HCC carcinogenetic transformation and to reveal the potential NASH-HCC mechanism. Methods: Three NASH-HCC transition models were established in FGF21 knockout (KO) mice, with treatment of DEN at aged 2 weeks at 40 mg/kg body weight (i.p.) and feeding, 1) high fat diet (HFD, 60% kcal% fat); 2) western-style high fat diet (WSHFD, 60% kcal% fat and 19% kcal% fructose); and 3) methionine/choline-deficient diet (MCD). The cellular and molecular events, in turn, de novo lipogenesis, sphingolipid metabolism, white adipose tissue (WAT) lipolysis, insulin resistance (IR), release of free fatty acids (FFAs), metabolites of gut flora, carcinogenesis signaling pathways and NASH-HCC initiation, were determined both in vivo and in vitro. The in vitro studies were performed using shRNA-FGF21 knock down hepatocyte and HCC cell lines. Results: Aberrant lipid components, gut microbiome, hepatic Hippo-YAP and NF-kB signaling were found consistently in the NASH-HCC tissues from FGF21-KO mice with 3 diets treatments, compared to the wild type controls. Increased de novo lipogenesis, FFAs overflow to the liver, and inflammation agents from the metabolites of gut flora upregulated the hepatic sphingosine Kinase 1 (SPHK1) expression and its product sphingosine-1-phosphate (S1P), subsequently induced YAP dephosphorylation and nuclear localization. rhFGF21 or SPHK1 inhibitor (SKI-II) treatment significantly decreased the tumor volumes via alleviation of FFAs and S1P productions. Use of curcumin to modulate gut microbiota resulted in suppression of NASH-HCC growth in mice. Conclusion: 1) lack of FGF21 played a key role in hepatic lipid metabolism disorder in liver; 2) lack of FGF21 accelerated the SPHK1-S1P-HIPPO signaling promoted NASH-HCC transition; 3) administration of rhFGF21 not only attenuates NASH, but also prevents HCC carcinogenetic transformation via down-regulation of the SPHK1-S1P-HIPPO axis. This work was supported by an Institutional Development Award (IDeA) from the NIGMS of the National Institutes of Health under grant number P20GM113226. Key Words: Fibroblast growth factor 21; Steatohepatities; Hepatocellular carcinoma; Free fatty acid; Sphingolipid Citation Format: Xiaoju Shi, Robert C. Martin, Youxi Yu, Yujia Chen, Xingtong Wang, Guangyi Wang, Guoyue Lv, Ping Zhang, Yan Li. Lack of FGF21 accelerates NASH-HCC transition via up-regulation of hepatic SPHK1-S1P-HIPPO signaling in murine models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2550.