FXR-mediated inhibition of autophagy contributes to FA-induced TG accumulation and accordingly reduces FA-induced lipotoxicity
Abstract Background Excessive dietary fat intake induces lipid deposition and contributes to the progress of nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanisms are still unclear. Methods Yellow catfish were given two experimental diets with dietary lipid levels of 11.3 and...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-03-01
|
| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12964-020-0525-1 |
| _version_ | 1818998284426936320 |
|---|---|
| author | Kun Wu Tao Zhao Christer Hogstrand Yi-Chuang Xu Shi-Cheng Ling Guang-Hui Chen Zhi Luo |
| author_facet | Kun Wu Tao Zhao Christer Hogstrand Yi-Chuang Xu Shi-Cheng Ling Guang-Hui Chen Zhi Luo |
| author_sort | Kun Wu |
| collection | DOAJ |
| description | Abstract Background Excessive dietary fat intake induces lipid deposition and contributes to the progress of nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanisms are still unclear. Methods Yellow catfish were given two experimental diets with dietary lipid levels of 11.3 and 15.4%, respectively, for 56 days, and the contents of triglyceride (TG), nonesterified free fatty acids (NEFA) and bile acid (BA), RNA-seq, enzymatic activities and mRNA expression were deteremined in the liver tissues. Hepatocytes from yellow catfish liver tissues were isolated and cultured. Fatty acids (FA) (palmitic acid: OA, oleic acid =1:1), pathway inhibitors (MA, autophagy inhibitor; guggulsterone, FXR inhibitor) and agonist (rapamyicn, autophagy agonist; GW4064, FXR agonist) were used to incubate the cells. TG and NEFA contents, ultrastructural observation, autophagic vesicles and intracellular LD,apoptosis,western blot and Co-IP, and Immunofluorescence analysis, enzymatic activities and Q-PCR were decided. Results Using RNA sequencing, we found that high fat diets induced changes in expression of many genes associated with the pathways of lipid metabolism and autophagy. The mRNA profiles of the differentially expressed genes (DEG) indicated that high dietary fat-induced lipid deposition was predominantly influenced by the inhibition of autophagy. Using primary hepatocytes, we found that fatty acids (FA) suppressed autophagy, which in turn reduced cellular free FA level by decreasing triglyceride (TG) breakdown. Moreover, our study indicated that farnesoid X receptor (FXR)-cyclic AMP-responsive element-binding protein (CREB) axis was the pivotal physiological switch regulating FA-induced changes of autophagy and lipid metabolism, which represented cellular defenses against FA-induced lipotoxicity. Conclusion This discovery may provide new targets for treating pathological changes involved in the dysfunction of autophagy and metabolism, including NAFLD. Video Abstract Graphical abstract |
| first_indexed | 2024-12-20T21:59:05Z |
| format | Article |
| id | doaj.art-ffc1eca9f7e74b689bd2056b0603f71a |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-20T21:59:05Z |
| publishDate | 2020-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-ffc1eca9f7e74b689bd2056b0603f71a2022-12-21T19:25:24ZengBMCCell Communication and Signaling1478-811X2020-03-0118111610.1186/s12964-020-0525-1FXR-mediated inhibition of autophagy contributes to FA-induced TG accumulation and accordingly reduces FA-induced lipotoxicityKun Wu0Tao Zhao1Christer Hogstrand2Yi-Chuang Xu3Shi-Cheng Ling4Guang-Hui Chen5Zhi Luo6Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural UniversityKey Laboratory of Freshwater Animal Breeding, Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural UniversityDiabetes and Nutritional Sciences Division, School of Medicine, King’s College LondonKey Laboratory of Freshwater Animal Breeding, Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural UniversityKey Laboratory of Freshwater Animal Breeding, Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural UniversityKey Laboratory of Freshwater Animal Breeding, Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural UniversityKey Laboratory of Freshwater Animal Breeding, Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural UniversityAbstract Background Excessive dietary fat intake induces lipid deposition and contributes to the progress of nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanisms are still unclear. Methods Yellow catfish were given two experimental diets with dietary lipid levels of 11.3 and 15.4%, respectively, for 56 days, and the contents of triglyceride (TG), nonesterified free fatty acids (NEFA) and bile acid (BA), RNA-seq, enzymatic activities and mRNA expression were deteremined in the liver tissues. Hepatocytes from yellow catfish liver tissues were isolated and cultured. Fatty acids (FA) (palmitic acid: OA, oleic acid =1:1), pathway inhibitors (MA, autophagy inhibitor; guggulsterone, FXR inhibitor) and agonist (rapamyicn, autophagy agonist; GW4064, FXR agonist) were used to incubate the cells. TG and NEFA contents, ultrastructural observation, autophagic vesicles and intracellular LD,apoptosis,western blot and Co-IP, and Immunofluorescence analysis, enzymatic activities and Q-PCR were decided. Results Using RNA sequencing, we found that high fat diets induced changes in expression of many genes associated with the pathways of lipid metabolism and autophagy. The mRNA profiles of the differentially expressed genes (DEG) indicated that high dietary fat-induced lipid deposition was predominantly influenced by the inhibition of autophagy. Using primary hepatocytes, we found that fatty acids (FA) suppressed autophagy, which in turn reduced cellular free FA level by decreasing triglyceride (TG) breakdown. Moreover, our study indicated that farnesoid X receptor (FXR)-cyclic AMP-responsive element-binding protein (CREB) axis was the pivotal physiological switch regulating FA-induced changes of autophagy and lipid metabolism, which represented cellular defenses against FA-induced lipotoxicity. Conclusion This discovery may provide new targets for treating pathological changes involved in the dysfunction of autophagy and metabolism, including NAFLD. Video Abstract Graphical abstracthttp://link.springer.com/article/10.1186/s12964-020-0525-1Lipid metabolismRNA-seq transcriptomeAutophagyFXRLipotoxicity |
| spellingShingle | Kun Wu Tao Zhao Christer Hogstrand Yi-Chuang Xu Shi-Cheng Ling Guang-Hui Chen Zhi Luo FXR-mediated inhibition of autophagy contributes to FA-induced TG accumulation and accordingly reduces FA-induced lipotoxicity Cell Communication and Signaling Lipid metabolism RNA-seq transcriptome Autophagy FXR Lipotoxicity |
| title | FXR-mediated inhibition of autophagy contributes to FA-induced TG accumulation and accordingly reduces FA-induced lipotoxicity |
| title_full | FXR-mediated inhibition of autophagy contributes to FA-induced TG accumulation and accordingly reduces FA-induced lipotoxicity |
| title_fullStr | FXR-mediated inhibition of autophagy contributes to FA-induced TG accumulation and accordingly reduces FA-induced lipotoxicity |
| title_full_unstemmed | FXR-mediated inhibition of autophagy contributes to FA-induced TG accumulation and accordingly reduces FA-induced lipotoxicity |
| title_short | FXR-mediated inhibition of autophagy contributes to FA-induced TG accumulation and accordingly reduces FA-induced lipotoxicity |
| title_sort | fxr mediated inhibition of autophagy contributes to fa induced tg accumulation and accordingly reduces fa induced lipotoxicity |
| topic | Lipid metabolism RNA-seq transcriptome Autophagy FXR Lipotoxicity |
| url | http://link.springer.com/article/10.1186/s12964-020-0525-1 |
| work_keys_str_mv | AT kunwu fxrmediatedinhibitionofautophagycontributestofainducedtgaccumulationandaccordinglyreducesfainducedlipotoxicity AT taozhao fxrmediatedinhibitionofautophagycontributestofainducedtgaccumulationandaccordinglyreducesfainducedlipotoxicity AT christerhogstrand fxrmediatedinhibitionofautophagycontributestofainducedtgaccumulationandaccordinglyreducesfainducedlipotoxicity AT yichuangxu fxrmediatedinhibitionofautophagycontributestofainducedtgaccumulationandaccordinglyreducesfainducedlipotoxicity AT shichengling fxrmediatedinhibitionofautophagycontributestofainducedtgaccumulationandaccordinglyreducesfainducedlipotoxicity AT guanghuichen fxrmediatedinhibitionofautophagycontributestofainducedtgaccumulationandaccordinglyreducesfainducedlipotoxicity AT zhiluo fxrmediatedinhibitionofautophagycontributestofainducedtgaccumulationandaccordinglyreducesfainducedlipotoxicity |