FGF15 promotes hepatic NPC1L1 degradation in lithogenic diet-fed mice
Abstract Background Cholesterol gallstone disease (CGD) is accompanied by biliary cholesterol supersaturation. Hepatic Niemann-Pick C1-like 1 (NPC1L1), which is present in humans but not in wild-type (WT) mice, promotes hepatocyte cholesterol uptake and decreases biliary cholesterol supersaturation....
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | Lipids in Health and Disease |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12944-022-01709-8 |
| _version_ | 1797996054980853760 |
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| author | Pingfan Mo Hongtan Chen Xin Jiang Fengling Hu Fenming Zhang Guodong Shan Wenguo Chen Sha Li Yiqiao Li Guoqiang Xu |
| author_facet | Pingfan Mo Hongtan Chen Xin Jiang Fengling Hu Fenming Zhang Guodong Shan Wenguo Chen Sha Li Yiqiao Li Guoqiang Xu |
| author_sort | Pingfan Mo |
| collection | DOAJ |
| description | Abstract Background Cholesterol gallstone disease (CGD) is accompanied by biliary cholesterol supersaturation. Hepatic Niemann-Pick C1-like 1 (NPC1L1), which is present in humans but not in wild-type (WT) mice, promotes hepatocyte cholesterol uptake and decreases biliary cholesterol supersaturation. In contrast, intestinal NPC1L1 promotes intestinal cholesterol absorption, increasing biliary cholesterol supersaturation. Ezetimibe (EZE) can inhibit both hepatic and intestinal NPC1L1. However, whether hepatic NPC1L1 can affect CGD progress remains unknown. Methods Mice expressing hepatic NPC1L1 (NPC1L1hepatic-OE mice) were generated using Adeno-associated viruses (AAV) gene delivery. The protein level and function of hepatic NPC1L1 were examined under chow diet, high fat-cholesterol diet (HFCD), and lithogenic diet (LD) feeding. Gallstone formation rates were examined with or without EZE treatment. Fibroblast growth factor 15 (FGF15) treatment and inhibition of fibroblast growth factor receptor 4 (FGFR4) were applied to verify the mechanism of hepatic NPC1L1 degradation. Results The HFCD-fed NPC1L1hepatic-OE mice retained the biliary cholesterol desaturation function of hepatic NPC1L1, whereas EZE treatment decreased biliary cholesterol saturation and did not cause CGD. The ubiquitination and degradation of hepatic NPC1L1 were discovered in LD-fed NPC1L1hepatic-OE mice. Treatment of FGF15 during HFCD feeding and inhibition of FGFR4 during LD feeding could affect the protein level and function of hepatic NPC1L1. Conclusions LD induces the ubiquitination and degradation of hepatic NPC1L1 via the FGF15-FGFR4 pathway. EZE may act as an effective preventative agent for CGD. |
| first_indexed | 2024-04-11T10:11:23Z |
| format | Article |
| id | doaj.art-173974eb9e6040c3a997f2e27fabdcc7 |
| institution | Directory Open Access Journal |
| issn | 1476-511X |
| language | English |
| last_indexed | 2024-04-11T10:11:23Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Lipids in Health and Disease |
| spelling | doaj.art-173974eb9e6040c3a997f2e27fabdcc72022-12-22T04:30:06ZengBMCLipids in Health and Disease1476-511X2022-10-0121111310.1186/s12944-022-01709-8FGF15 promotes hepatic NPC1L1 degradation in lithogenic diet-fed micePingfan Mo0Hongtan Chen1Xin Jiang2Fengling Hu3Fenming Zhang4Guodong Shan5Wenguo Chen6Sha Li7Yiqiao Li8Guoqiang Xu9Department of Gastroenterology, Zhejiang University School of Medicine, The First Affiliated HospitalDepartment of Gastroenterology, Zhejiang University School of Medicine, The First Affiliated HospitalDepartment of Gastroenterology, Zhejiang University School of Medicine, The First Affiliated HospitalDepartment of Gastroenterology, Zhejiang University School of Medicine, The First Affiliated HospitalDepartment of Gastroenterology, Zhejiang University School of Medicine, The First Affiliated HospitalDepartment of Gastroenterology, Zhejiang University School of Medicine, The First Affiliated HospitalDepartment of Gastroenterology, Zhejiang University School of Medicine, The First Affiliated HospitalDepartment of Gastroenterology, Zhejiang University School of Medicine, The First Affiliated HospitalUrology& Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital and Hangzhou Medical College Affiliated People’s HospitalDepartment of Gastroenterology, Zhejiang University School of Medicine, The First Affiliated HospitalAbstract Background Cholesterol gallstone disease (CGD) is accompanied by biliary cholesterol supersaturation. Hepatic Niemann-Pick C1-like 1 (NPC1L1), which is present in humans but not in wild-type (WT) mice, promotes hepatocyte cholesterol uptake and decreases biliary cholesterol supersaturation. In contrast, intestinal NPC1L1 promotes intestinal cholesterol absorption, increasing biliary cholesterol supersaturation. Ezetimibe (EZE) can inhibit both hepatic and intestinal NPC1L1. However, whether hepatic NPC1L1 can affect CGD progress remains unknown. Methods Mice expressing hepatic NPC1L1 (NPC1L1hepatic-OE mice) were generated using Adeno-associated viruses (AAV) gene delivery. The protein level and function of hepatic NPC1L1 were examined under chow diet, high fat-cholesterol diet (HFCD), and lithogenic diet (LD) feeding. Gallstone formation rates were examined with or without EZE treatment. Fibroblast growth factor 15 (FGF15) treatment and inhibition of fibroblast growth factor receptor 4 (FGFR4) were applied to verify the mechanism of hepatic NPC1L1 degradation. Results The HFCD-fed NPC1L1hepatic-OE mice retained the biliary cholesterol desaturation function of hepatic NPC1L1, whereas EZE treatment decreased biliary cholesterol saturation and did not cause CGD. The ubiquitination and degradation of hepatic NPC1L1 were discovered in LD-fed NPC1L1hepatic-OE mice. Treatment of FGF15 during HFCD feeding and inhibition of FGFR4 during LD feeding could affect the protein level and function of hepatic NPC1L1. Conclusions LD induces the ubiquitination and degradation of hepatic NPC1L1 via the FGF15-FGFR4 pathway. EZE may act as an effective preventative agent for CGD.https://doi.org/10.1186/s12944-022-01709-8Cholesterol gallstone diseaseNPC1L1EzetimibeUbiquitinationFGF15 |
| spellingShingle | Pingfan Mo Hongtan Chen Xin Jiang Fengling Hu Fenming Zhang Guodong Shan Wenguo Chen Sha Li Yiqiao Li Guoqiang Xu FGF15 promotes hepatic NPC1L1 degradation in lithogenic diet-fed mice Lipids in Health and Disease Cholesterol gallstone disease NPC1L1 Ezetimibe Ubiquitination FGF15 |
| title | FGF15 promotes hepatic NPC1L1 degradation in lithogenic diet-fed mice |
| title_full | FGF15 promotes hepatic NPC1L1 degradation in lithogenic diet-fed mice |
| title_fullStr | FGF15 promotes hepatic NPC1L1 degradation in lithogenic diet-fed mice |
| title_full_unstemmed | FGF15 promotes hepatic NPC1L1 degradation in lithogenic diet-fed mice |
| title_short | FGF15 promotes hepatic NPC1L1 degradation in lithogenic diet-fed mice |
| title_sort | fgf15 promotes hepatic npc1l1 degradation in lithogenic diet fed mice |
| topic | Cholesterol gallstone disease NPC1L1 Ezetimibe Ubiquitination FGF15 |
| url | https://doi.org/10.1186/s12944-022-01709-8 |
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