Gut
Abstract
ObjectiveIncreased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC).
DesignWe investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specificFasnknockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type andFasnknockout mice. Human HCC cell lines were used for in vitro studies.
ResultsAblation ofFasnsignificantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged inFasnknockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss ofFasnpromoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis inFasnknockout mice. Similarly, silencing ofFASNresulted in increasedSREBP2activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR)expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture.
ConclusionOur study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.
| 论文编号: | DOI:10.1136/gutjnl-2018-317581 |
| 论文题目: | Cholesterol Biosynthesis Supports the Growth of Hepatocarcinoma Lesions Depleted of Fatty Acid Synthase in Mice and Humans |
| 英文论文题目: | Cholesterol Biosynthesis Supports the Growth of Hepatocarcinoma Lesions Depleted of Fatty Acid Synthase in Mice and Humans |
| 第一作者: | Li Che, Wenna Chi, Yu Qiao, Jie Zhang, Xinhua Song, Ye Liu, Lei Li, Jiaoyuan Jia, Maria G Pilo, Jingxiao Wang, Antonio Cigliano, Zhilong Ma, Wenhua Kuang, Zefang Tang, Zemin Zhang, Guanghou Shui, Silvia Ribback, Frank Dombrowski, Matthias Evert, Rosa Maria Pascale, Carla Cossu, Giovanni Mario Pes, Timothy F Osborne, Diego F Calvisi, Xin Chen, Ligong Chen |
| 英文第一作者: | Li Che, Wenna Chi, Yu Qiao, Jie Zhang, Xinhua Song, Ye Liu, Lei Li, Jiaoyuan Jia, Maria G Pilo, Jingxiao Wang, Antonio Cigliano, Zhilong Ma, Wenhua Kuang, Zefang Tang, Zemin Zhang, Guanghou Shui, Silvia Ribback, Frank Dombrowski, Matthias Evert, Rosa Maria Pascale, Carla Cossu, Giovanni Mario Pes, Timothy F Osborne, Diego F Calvisi, Xin Chen, Ligong Chen |
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| 发表年度: | 2020-01-20 |
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| 摘要: | ObjectiveIncreased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC). DesignWe investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specificFasnknockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type andFasnknockout mice. Human HCC cell lines were used for in vitro studies. ResultsAblation ofFasnsignificantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged inFasnknockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss ofFasnpromoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis inFasnknockout mice. Similarly, silencing ofFASNresulted in increasedSREBP2activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR)expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture. ConclusionOur study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC. |
| 英文摘要: | ObjectiveIncreased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC). DesignWe investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specificFasnknockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type andFasnknockout mice. Human HCC cell lines were used for in vitro studies. ResultsAblation ofFasnsignificantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged inFasnknockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss ofFasnpromoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis inFasnknockout mice. Similarly, silencing ofFASNresulted in increasedSREBP2activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR)expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture. ConclusionOur study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC. |
| 刊物名称: | Gut |
| 英文刊物名称: | Gut |
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| 其它备注: | Li Che, Wenna Chi, Yu Qiao, Jie Zhang, Xinhua Song, Ye Liu, Lei Li, Jiaoyuan Jia, Maria G Pilo, Jingxiao Wang, Antonio Cigliano, Zhilong Ma, Wenhua Kuang, Zefang Tang, Zemin Zhang, Guanghou Shui, Silvia Ribback, Frank Dombrowski, Matthias Evert, Rosa Maria Pascale, Carla Cossu, Giovanni Mario Pes, Timothy F Osborne, Diego F Calvisi, Xin Chen, Ligong Chen. Cholesterol Biosynthesis Supports the Growth of Hepatocarcinoma Lesions Depleted of Fatty Acid Synthase in Mice and Humans. Gut. DOI:10.1136/gutjnl-2018-317581 |
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