Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation
Abstract Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24‐dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti‐i...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-08-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202216845 |
| _version_ | 1797280711860813824 |
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| author | Enchen Zhou Xiaoke Ge Hiroyuki Nakashima Rumei Li Hendrik J P van derZande Cong Liu Zhuang Li Christoph Müller Franz Bracher Yassene Mohammed Jan Freark deBoer Folkert Kuipers Bruno Guigas Christopher K Glass Patrick C N Rensen Martin Giera Yanan Wang |
| author_facet | Enchen Zhou Xiaoke Ge Hiroyuki Nakashima Rumei Li Hendrik J P van derZande Cong Liu Zhuang Li Christoph Müller Franz Bracher Yassene Mohammed Jan Freark deBoer Folkert Kuipers Bruno Guigas Christopher K Glass Patrick C N Rensen Martin Giera Yanan Wang |
| author_sort | Enchen Zhou |
| collection | DOAJ |
| description | Abstract Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24‐dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti‐inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3‐Leiden. CETP mice, a well‐established translational model that develops diet‐induced human‐like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet‐induced hepatic steatosis and inflammation in a strictly LXRα‐dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH. |
| first_indexed | 2024-03-07T16:44:11Z |
| format | Article |
| id | doaj.art-4c911682d99b44c88efeac537e3e77c7 |
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| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:44:11Z |
| publishDate | 2023-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-4c911682d99b44c88efeac537e3e77c72024-03-03T06:49:31ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-08-01158n/an/a10.15252/emmm.202216845Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammationEnchen Zhou0Xiaoke Ge1Hiroyuki Nakashima2Rumei Li3Hendrik J P van derZande4Cong Liu5Zhuang Li6Christoph Müller7Franz Bracher8Yassene Mohammed9Jan Freark deBoer10Folkert Kuipers11Bruno Guigas12Christopher K Glass13Patrick C N Rensen14Martin Giera15Yanan Wang16Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The NetherlandsDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The NetherlandsDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The NetherlandsDepartment of Pediatrics University of Groningen, University Medical Center Groningen Groningen The NetherlandsDepartment of Parasitology Leiden University Medical Center Leiden The NetherlandsDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The NetherlandsDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The NetherlandsDepartment of Pharmacy, Center for Drug Research Ludwig Maximilians University Munich GermanyDepartment of Pharmacy, Center for Drug Research Ludwig Maximilians University Munich GermanyThe Center for Proteomics and Metabolomics Leiden University Medical Center Leiden The NetherlandsDepartment of Pediatrics University of Groningen, University Medical Center Groningen Groningen The NetherlandsDepartment of Pediatrics University of Groningen, University Medical Center Groningen Groningen The NetherlandsDepartment of Parasitology Leiden University Medical Center Leiden The NetherlandsDepartment of Cellular and Molecular Medicine and Department of Medicine University of California San Diego La Jolla CA USADepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The NetherlandsThe Center for Proteomics and Metabolomics Leiden University Medical Center Leiden The NetherlandsDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The NetherlandsAbstract Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24‐dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti‐inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3‐Leiden. CETP mice, a well‐established translational model that develops diet‐induced human‐like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet‐induced hepatic steatosis and inflammation in a strictly LXRα‐dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH.https://doi.org/10.15252/emmm.202216845desmosterolKupffer cellliver X receptornonalcoholic steatohepatitisΔ24‐dehydrocholesterol reductase |
| spellingShingle | Enchen Zhou Xiaoke Ge Hiroyuki Nakashima Rumei Li Hendrik J P van derZande Cong Liu Zhuang Li Christoph Müller Franz Bracher Yassene Mohammed Jan Freark deBoer Folkert Kuipers Bruno Guigas Christopher K Glass Patrick C N Rensen Martin Giera Yanan Wang Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation EMBO Molecular Medicine desmosterol Kupffer cell liver X receptor nonalcoholic steatohepatitis Δ24‐dehydrocholesterol reductase |
| title | Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation |
| title_full | Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation |
| title_fullStr | Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation |
| title_full_unstemmed | Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation |
| title_short | Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation |
| title_sort | inhibition of dhcr24 activates lxrα to ameliorate hepatic steatosis and inflammation |
| topic | desmosterol Kupffer cell liver X receptor nonalcoholic steatohepatitis Δ24‐dehydrocholesterol reductase |
| url | https://doi.org/10.15252/emmm.202216845 |
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