DHCR7 inhibition ameliorates MetALD and HCC in mice and human 3D liver spheroids
Background & Aims: Metabolic dysfunction and alcohol-associated liver disease (MetALD) results in the development of liver steatosis, inflammation, fibrosis, and hepatocellular carcinoma (HCC). De novo lipogenesis and cholesterol synthesis play an important role in the pathogenesis of MetALD...
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Elsevier
2025-07-01
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| author | Gen Yamamoto Raquel Carvalho-Gontijo Weber Wonseok Lee Vivian Zhang Haeum Jang Sadatsugu Sakane Xiao Liu Hyun Young Kim David A. Brenner Na Li Tatiana Kisseleva |
| author_facet | Gen Yamamoto Raquel Carvalho-Gontijo Weber Wonseok Lee Vivian Zhang Haeum Jang Sadatsugu Sakane Xiao Liu Hyun Young Kim David A. Brenner Na Li Tatiana Kisseleva |
| author_sort | Gen Yamamoto |
| collection | DOAJ |
| description | Background & Aims: Metabolic dysfunction and alcohol-associated liver disease (MetALD) results in the development of liver steatosis, inflammation, fibrosis, and hepatocellular carcinoma (HCC). De novo lipogenesis and cholesterol synthesis play an important role in the pathogenesis of MetALD. DHCR7 (7-dehydrocholesterol reductase) regulates the last stages of cholesterol production. Methods: We investigated whether targeting DHCR7 can ameliorate the development of MetALD and HCC using experimental models and 3D human liver spheroids. Results: Here, we demonstrate that partial genetic ablation of the Dhcr7 gene and pharmacological blockade of DHCR7 activity with the AY9944 inhibitor suppresses hepatic steatosis (↓ lipid area, n = 15; p <0.001), inflammation (↓ F4/80, n = 6; p <0.01), fibrosis (↓ Sirius red, n = 6; p <0.01), and HCC (↓ AFP/YAP, n = 6; p <0.01) in diethylnitrosamine (DEN)-challenged high-fat diet (HFD) + ethanol (EtOH)-fed mice treated with AY9944 compared with control mice. To translate our findings, the effect of DHCR7 was tested using 3D human liver spheroids, which mimicked MetALD and MetALD-HCC. MetALD liver spheroids were composed of primary human hepatocytes, non-parenchymal cells, and hepatic stellate cells. In contrast, in MetALD-HCC spheroids, the HCC cell line HepG2 was used instead of hepatocytes. Therapeutic administration of AY9944 inhibited inflammation (↓ TNF, p <0.05) and fibrosis in MetALD spheroids (↓ ACTA2, p <0.001; COL1A1, p <0.05; TIMP1, p <0.01; SERPINE1, p <0.05). In turn, dsiRNA-based knockdown of DHCR7 reduced HepG2 proliferation (↓ PCNA, p <0.05; CCNE, p <0.05) and expression of MetALD-HCC markers (↓ AFP, p <0.05; GPC3, p <0.05; YAP, p <0.01). Conclusions: Our data demonstrate that targeting DHCR7 can become a strategy for the treatment of MetALD and HCC. Impact and implications: This study demonstrates the critical role of de novo lipogenesis and cholesterol synthesis in the pathogenesis of metabolic dysfunction and alcohol-associated liver disease (MetALD) and its progression to hepatocellular carcinoma (HCC). Our findings identified that the upregulation of DHCR7 contributes to the pathogenesis of MetALD and its inhibition suppresses hepatic steatosis, inflammation, fibrosis, and tumor proliferation. These findings are significant for researchers and clinicians, as they establish that genetic and pharmacological inhibition of DHCR7 is effective in both experimental models and translational 3D human liver spheroids. The results uncover the translational potential of DHCR7-targeted therapies for MetALD and HCC, offering practical implications for the development of novel treatment strategies. Further studies are necessary to optimize these approaches and address potential methodological limitations. |
| format | Article |
| id | doaj-art-25a385e7b4af423fa1c8605a4152ca52 |
| institution | DOAJ |
| issn | 2589-5559 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj-art-25a385e7b4af423fa1c8605a4152ca522025-08-20T03:10:30ZengElsevierJHEP Reports2589-55592025-07-017710141510.1016/j.jhepr.2025.101415DHCR7 inhibition ameliorates MetALD and HCC in mice and human 3D liver spheroidsGen Yamamoto0Raquel Carvalho-Gontijo Weber1Wonseok Lee2Vivian Zhang3Haeum Jang4Sadatsugu Sakane5Xiao Liu6Hyun Young Kim7David A. Brenner8Na Li9Tatiana Kisseleva10Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Surgery, University of California, San Diego, La Jolla, CA, USA; Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Surgery, University of California, San Diego, La Jolla, CA, USADepartment of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Surgery, University of California, San Diego, La Jolla, CA, USA; College of Pharmacy, Gachon University, Incheon, Republic of KoreaDepartment of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Surgery, University of California, San Diego, La Jolla, CA, USADepartment of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Surgery, University of California, San Diego, La Jolla, CA, USADepartment of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Surgery, University of California, San Diego, La Jolla, CA, USADepartment of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Surgery, University of California, San Diego, La Jolla, CA, USADepartment of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Surgery, University of California, San Diego, La Jolla, CA, USA; College of Pharmacy, Dankook University, Cheonan, Chungnam, Republic of KoreaDepartment of Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USADepartment of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Surgery, University of California, San Diego, La Jolla, CA, USA; College of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, P. R. China; Corresponding authors. Addresses: Department of Surgery, University of California, San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA (T. Kisseleva); 279 Zhouzhu RD, Pudong New District, Shanghai, 201318, P.R. China (N. Li).Department of Surgery, University of California, San Diego, La Jolla, CA, USA; Corresponding authors. Addresses: Department of Surgery, University of California, San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA (T. Kisseleva); 279 Zhouzhu RD, Pudong New District, Shanghai, 201318, P.R. China (N. Li).Background & Aims: Metabolic dysfunction and alcohol-associated liver disease (MetALD) results in the development of liver steatosis, inflammation, fibrosis, and hepatocellular carcinoma (HCC). De novo lipogenesis and cholesterol synthesis play an important role in the pathogenesis of MetALD. DHCR7 (7-dehydrocholesterol reductase) regulates the last stages of cholesterol production. Methods: We investigated whether targeting DHCR7 can ameliorate the development of MetALD and HCC using experimental models and 3D human liver spheroids. Results: Here, we demonstrate that partial genetic ablation of the Dhcr7 gene and pharmacological blockade of DHCR7 activity with the AY9944 inhibitor suppresses hepatic steatosis (↓ lipid area, n = 15; p <0.001), inflammation (↓ F4/80, n = 6; p <0.01), fibrosis (↓ Sirius red, n = 6; p <0.01), and HCC (↓ AFP/YAP, n = 6; p <0.01) in diethylnitrosamine (DEN)-challenged high-fat diet (HFD) + ethanol (EtOH)-fed mice treated with AY9944 compared with control mice. To translate our findings, the effect of DHCR7 was tested using 3D human liver spheroids, which mimicked MetALD and MetALD-HCC. MetALD liver spheroids were composed of primary human hepatocytes, non-parenchymal cells, and hepatic stellate cells. In contrast, in MetALD-HCC spheroids, the HCC cell line HepG2 was used instead of hepatocytes. Therapeutic administration of AY9944 inhibited inflammation (↓ TNF, p <0.05) and fibrosis in MetALD spheroids (↓ ACTA2, p <0.001; COL1A1, p <0.05; TIMP1, p <0.01; SERPINE1, p <0.05). In turn, dsiRNA-based knockdown of DHCR7 reduced HepG2 proliferation (↓ PCNA, p <0.05; CCNE, p <0.05) and expression of MetALD-HCC markers (↓ AFP, p <0.05; GPC3, p <0.05; YAP, p <0.01). Conclusions: Our data demonstrate that targeting DHCR7 can become a strategy for the treatment of MetALD and HCC. Impact and implications: This study demonstrates the critical role of de novo lipogenesis and cholesterol synthesis in the pathogenesis of metabolic dysfunction and alcohol-associated liver disease (MetALD) and its progression to hepatocellular carcinoma (HCC). Our findings identified that the upregulation of DHCR7 contributes to the pathogenesis of MetALD and its inhibition suppresses hepatic steatosis, inflammation, fibrosis, and tumor proliferation. These findings are significant for researchers and clinicians, as they establish that genetic and pharmacological inhibition of DHCR7 is effective in both experimental models and translational 3D human liver spheroids. The results uncover the translational potential of DHCR7-targeted therapies for MetALD and HCC, offering practical implications for the development of novel treatment strategies. Further studies are necessary to optimize these approaches and address potential methodological limitations.http://www.sciencedirect.com/science/article/pii/S2589555925000928Alcohol-induced liver injuryCholesterol synthesisSteatosisInflammationFibrosisTumor growth |
| spellingShingle | Gen Yamamoto Raquel Carvalho-Gontijo Weber Wonseok Lee Vivian Zhang Haeum Jang Sadatsugu Sakane Xiao Liu Hyun Young Kim David A. Brenner Na Li Tatiana Kisseleva DHCR7 inhibition ameliorates MetALD and HCC in mice and human 3D liver spheroids JHEP Reports Alcohol-induced liver injury Cholesterol synthesis Steatosis Inflammation Fibrosis Tumor growth |
| title | DHCR7 inhibition ameliorates MetALD and HCC in mice and human 3D liver spheroids |
| title_full | DHCR7 inhibition ameliorates MetALD and HCC in mice and human 3D liver spheroids |
| title_fullStr | DHCR7 inhibition ameliorates MetALD and HCC in mice and human 3D liver spheroids |
| title_full_unstemmed | DHCR7 inhibition ameliorates MetALD and HCC in mice and human 3D liver spheroids |
| title_short | DHCR7 inhibition ameliorates MetALD and HCC in mice and human 3D liver spheroids |
| title_sort | dhcr7 inhibition ameliorates metald and hcc in mice and human 3d liver spheroids |
| topic | Alcohol-induced liver injury Cholesterol synthesis Steatosis Inflammation Fibrosis Tumor growth |
| url | http://www.sciencedirect.com/science/article/pii/S2589555925000928 |
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