Activation of pluripotent genes in hepatic progenitor cells in the transition of nonalcoholic steatohepatitis to pre-malignant lesions

Xu, Gang; Ye, Juan; Liu, Xue Jing; Zhang, Ning Ping; Zhao, Yi; Fan, Jia; Liu, Xiu Ping; Wu, Jian

doi:10.1038/labinvest.2017.84

Cited by 19 publications

(30 citation statements)

References 46 publications

(50 reference statements)

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“…The protein of KIAA1462, JCAD was highly expressed in NASH-associated HCC specimens and its expression is inducible by fatty acid overload. Thereafter, we investigated JCAD expression during NASH progression in a mouse model of NASH-precarcinoma lesions (22).…”

Section: Discussionmentioning

confidence: 99%

“…Male BALB/c nude mice (4-5 weeks of age) from Slack Company were used to establish a subcutaneous xenograft tumor model. All mice were housed in a specific pathogen-free facility with 12-hour light/dark cycle at [21][22][23] C. All animal experimental protocols were approved by the Animal Ethic Committee of Fudan University School of Basic Medical Sciences, and performed in the line with NIH Guidelines for Experimental Animal Handling and Use, as well as the national, municipal, and university regulations.…”

Section: Animalsmentioning

confidence: 99%

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JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity

et al. 2017

Cancer Research

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Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents are rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared with pericarcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation, whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting.

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Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity

et al. 2017

Cancer Research

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“…no. D12492; Research Diet, New Brunswick, NJ, USA) with tap water (HFCD) (for nutritional composites, please see Supplemental Table 1); (4) high-fat/calorie diet plus high fructose/glucose in drinking water (HFCD-HF/G) as we reported recently [13]. The body weight and diet consumption of mice was monitored weekly.…”

Section: Animals and Dietsmentioning

confidence: 99%

“…Image segmentation was conducted using a volume-editing tool, and volumes were quantified using the region of interest module within the software package (AnalyzeDirect, Overland Park, KS, USA). The adipose content and distribution were calculated with a software (Analyze 12.0) as we reported previously [13].…”

Section: Quantitative Computed Tomography Scan Of Whole Bodymentioning

confidence: 99%

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Characterization of a murine nonalcoholic steatohepatitis model induced by high fat high calorie diet plus fructose and glucose in drinking water

Liu

Duan

Liu

et al. 2018

Laboratory Investigation

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There are varieties of murine models of nonalcoholic steatohepatitis (NASH) with different pathophysiologic characteristics. For preclinical assessment, a standardized model would allow comparisons of various pharmacotherapeutic candidates in efficacy, pharmacokinetics, pharmaco-metabolism, and adverse effects under a same system. The present study aims to characterize murine NASH models by comparing end-points of major abnormalities. NASH was induced by feeding high fructose/glucose in drinking water (HF/G), high-fat/calorie diet (HFCD), and in combination (HFCD-HF/G) in mice for 8 or 16 weeks. HF/G feeding caused a minimal fat accumulation and increase in free fatty acids (FFA). In contrast, HFCD-HF/G feeding resulted in a remarkable increase in body weight, subcutaneous and visceral adipose tissue, macrosteatosis with a nearly seven-fold increase in triglyceride and FFA content, accompanied with marked hepatocellular injury, inflammatory responses, fibrosis, and insulin resistance, and represented as typical NASH in histopathology, metabolic, and adipokine profiles in a progressive manner. Meanwhile, mice fed HFCD displayed significant steatosis, necroptosis, fibrosis, insulin resistance, metabolic, and adipokine profiles, and the extent is less than those fed HFCD-HF/G. Significant MCP-1, CCR-2, and NLRP-1/3 activation were found in mice fed HFCD and HFCD-HF/G for 16 weeks, whereas gene expression of CPT-1 and ACOX-1 was down-regulated in these two groups in comparison to the controls. Nuclear receptors, such as SREBP-1c, FXR, LXR-α, PPAR-α, and PPAR-γ, were strikingly elevated in the HFCD-HF/G group. In conclusion, feeding HFCD-HF/G resulted in a reliable NASH model in mice with remarkable necroptosis, steatosis, fibrosis, and insulin resistance as well as a disordered profile of lipid metabolism and adipokine, and HFCD caused significant NASH features in histopathology and metabolic profiles only at a late stage. Whereas HF/G feeding barely led to minimal fat accumulation, some changes at molecular levels and metabolic disturbance in mice.

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Transcription factor SOX2 contributes to nonalcoholic fatty liver disease development by regulating the expression of the fatty acid transporter CD36

Shen

Chen

et al. 2021

FEBS Letters

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Activation of pluripotent genes in hepatic progenitor cells in the transition of nonalcoholic steatohepatitis to pre-malignant lesions

Cited by 19 publications

References 46 publications

JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity

JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity

Characterization of a murine nonalcoholic steatohepatitis model induced by high fat high calorie diet plus fructose and glucose in drinking water

Transcription factor SOX2 contributes to nonalcoholic fatty liver disease development by regulating the expression of the fatty acid transporter CD36

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