Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis
Abstract Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy wit...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-50328-5 |
| _version_ | 1797371210351247360 |
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| author | Henrik H. Hansen Susanne Pors Maja W. Andersen Mogens Vyberg Jacob Nøhr-Meldgaard Malte Hasle Nielsen Denise Oró Martin Rønn Madsen Monika Lewinska Mathias B. Møllerhøj Andreas Nygaard Madsen Michael Feigh |
| author_facet | Henrik H. Hansen Susanne Pors Maja W. Andersen Mogens Vyberg Jacob Nøhr-Meldgaard Malte Hasle Nielsen Denise Oró Martin Rønn Madsen Monika Lewinska Mathias B. Møllerhøj Andreas Nygaard Madsen Michael Feigh |
| author_sort | Henrik H. Hansen |
| collection | DOAJ |
| description | Abstract Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy with semaglutide (glucagon-like-receptor-1 receptor agonist) and lanifibranor (pan-peroxisome proliferator-activated receptor agonist) in a diet-induced obese (DIO) mouse model of NASH-HCC. Disease progression was characterized in male C57BL/6 J mice fed the GAN (Gubra Amylin NASH) diet high in fat, fructose and cholesterol for 12–72 weeks (n = 15 per group). Other GAN DIO-NASH-HCC mice fed the GAN diet for 54 weeks and with biopsy-confirmed NASH (NAFLD Activity Score ≥ 5) and advanced fibrosis (stage F3) received vehicle (n = 16), semaglutide (30 nmol/kg, s.c., n = 15), or lanifibranor (30 mg/kg, p.o., n = 15) once daily for 14 weeks. GAN DIO-NASH-HCC mice demonstrated progressive NASH, fibrosis and HCC burden. Tumors presented with histological and molecular signatures of poor prognostic HCC. Consistent with clinical trial outcomes in NASH patients, both lanifibranor and semaglutide improved NASH while only lanifibranor reduced fibrosis in GAN DIO-NASH-HCC mice. Notably, only semaglutide reduced tumor burden in GAN DIO-NASH-HCC mice. In conclusion, the GAN DIO-NASH-HCC mouse is a clinical translational model of NASH-HCC. Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC. |
| first_indexed | 2024-03-08T18:15:33Z |
| format | Article |
| id | doaj.art-6927b3ad4ca84f23baf16f380b108cdf |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-08T18:15:33Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-6927b3ad4ca84f23baf16f380b108cdf2023-12-31T12:09:58ZengNature PortfolioScientific Reports2045-23222023-12-0113111910.1038/s41598-023-50328-5Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosisHenrik H. Hansen0Susanne Pors1Maja W. Andersen2Mogens Vyberg3Jacob Nøhr-Meldgaard4Malte Hasle Nielsen5Denise Oró6Martin Rønn Madsen7Monika Lewinska8Mathias B. Møllerhøj9Andreas Nygaard Madsen10Michael Feigh11GubraGubraGubraCenter for RNA Medicine, Department of Clinical Medicine, Aalborg UniversityGubraGubraGubraGubraGubraGubraGubraGubraAbstract Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy with semaglutide (glucagon-like-receptor-1 receptor agonist) and lanifibranor (pan-peroxisome proliferator-activated receptor agonist) in a diet-induced obese (DIO) mouse model of NASH-HCC. Disease progression was characterized in male C57BL/6 J mice fed the GAN (Gubra Amylin NASH) diet high in fat, fructose and cholesterol for 12–72 weeks (n = 15 per group). Other GAN DIO-NASH-HCC mice fed the GAN diet for 54 weeks and with biopsy-confirmed NASH (NAFLD Activity Score ≥ 5) and advanced fibrosis (stage F3) received vehicle (n = 16), semaglutide (30 nmol/kg, s.c., n = 15), or lanifibranor (30 mg/kg, p.o., n = 15) once daily for 14 weeks. GAN DIO-NASH-HCC mice demonstrated progressive NASH, fibrosis and HCC burden. Tumors presented with histological and molecular signatures of poor prognostic HCC. Consistent with clinical trial outcomes in NASH patients, both lanifibranor and semaglutide improved NASH while only lanifibranor reduced fibrosis in GAN DIO-NASH-HCC mice. Notably, only semaglutide reduced tumor burden in GAN DIO-NASH-HCC mice. In conclusion, the GAN DIO-NASH-HCC mouse is a clinical translational model of NASH-HCC. Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC.https://doi.org/10.1038/s41598-023-50328-5 |
| spellingShingle | Henrik H. Hansen Susanne Pors Maja W. Andersen Mogens Vyberg Jacob Nøhr-Meldgaard Malte Hasle Nielsen Denise Oró Martin Rønn Madsen Monika Lewinska Mathias B. Møllerhøj Andreas Nygaard Madsen Michael Feigh Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis Scientific Reports |
| title | Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis |
| title_full | Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis |
| title_fullStr | Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis |
| title_full_unstemmed | Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis |
| title_short | Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis |
| title_sort | semaglutide reduces tumor burden in the gan diet induced obese and biopsy confirmed mouse model of nash hcc with advanced fibrosis |
| url | https://doi.org/10.1038/s41598-023-50328-5 |
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