S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and LipogenesisSummary
Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is becoming a severe liver disorder worldwide. Autophagy plays a critical role in liver steatosis. However, the role of autophagy in NAFLD remains exclusive and under debate. In this study, we investigated the role of S100 calcium b...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-01-01
|
| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X20301697 |
| _version_ | 1830357949434822656 |
|---|---|
| author | Linqiang Zhang Zhiguo Zhang Chengbin Li Tingting Zhu Jing Gao Hu Zhou Yingzhuan Zheng Qing Chang Mingshan Wang Jieyu Wu Liyuan Ran Yingjie Wu Huilai Miao Xiaoju Zou Bin Liang |
| author_facet | Linqiang Zhang Zhiguo Zhang Chengbin Li Tingting Zhu Jing Gao Hu Zhou Yingzhuan Zheng Qing Chang Mingshan Wang Jieyu Wu Liyuan Ran Yingjie Wu Huilai Miao Xiaoju Zou Bin Liang |
| author_sort | Linqiang Zhang |
| collection | DOAJ |
| description | Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is becoming a severe liver disorder worldwide. Autophagy plays a critical role in liver steatosis. However, the role of autophagy in NAFLD remains exclusive and under debate. In this study, we investigated the role of S100 calcium binding protein A11 (S100A11) in the pathogenesis of hepatic steatosis. Methods: We performed liver proteomics in a well-established tree shrew model of NAFLD. The expression of S100A11 in different models of NAFLD was detected by Western blot and/or quantitative polymerase chain reaction. Liver S100A11 overexpression mice were generated by injecting a recombinant adenovirus gene transfer vector through the tail vein and then induced by a high-fat and high-cholesterol diet. Cell lines with S100a11 stable overexpression were established with a recombinant lentiviral vector. The lipid content was measured with either Bodipy staining, Oil Red O staining, gas chromatography, or a triglyceride kit. The autophagy and lipogenesis were detected in vitro and in vivo by Western blot and quantitative polymerase chain reaction. The functions of Sirtuin 1, histone deacetylase 6 (HDAC6), and FOXO1 were inhibited by specific inhibitors. The interactions between related proteins were analyzed by a co-immunoprecipitation assay and immunofluorescence analysis. Results: The expression of S100A11 was up-regulated significantly in a time-dependent manner in the tree shrew model of NAFLD. S100A11 expression was induced consistently in oleic acid–treated liver cells as well as the livers of mice fed a high-fat diet and NAFLD patients. Both in vitro and in vivo overexpression of S100A11 could induce hepatic lipid accumulation. Mechanistically, overexpression of S100A11 activated an autophagy and lipogenesis process through up-regulation and acetylation of the transcriptional factor FOXO1, consequently promoting lipogenesis and lipid accumulation in vitro and in vivo. Inhibition of HDAC6, a deacetylase of FOXO1, showed similar phenotypes to S100A11 overexpression in Hepa 1–6 cells. S100A11 interacted with HDAC6 to inhibit its activity, leading to the release and activation of FOXO1. Under S100A11 overexpression, the inhibition of FOXO1 and autophagy could alleviate the activated autophagy as well as up-regulated lipogenic genes. Both FOXO1 and autophagy inhibition and Dgat2 deletion could reduce liver cell lipid accumulation significantly. Conclusions: A high-fat diet promotes liver S100A11 expression, which may interact with HDAC6 to block its binding to FOXO1, releasing or increasing the acetylation of FOXO1, thus activating autophagy and lipogenesis, and accelerating lipid accumulation and liver steatosis. These findings indicate a completely novel S100A11-HDAC6-FOXO1 axis in the regulation of autophagy and liver steatosis, providing potential possibilities for the treatment of NAFLD. |
| first_indexed | 2024-12-20T02:32:36Z |
| format | Article |
| id | doaj.art-c30626bacd0f47a391b32b3098d55670 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-20T02:32:36Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-c30626bacd0f47a391b32b3098d556702022-12-21T19:56:32ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-01113697724S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and LipogenesisSummaryLinqiang Zhang0Zhiguo Zhang1Chengbin Li2Tingting Zhu3Jing Gao4Hu Zhou5Yingzhuan Zheng6Qing Chang7Mingshan Wang8Jieyu Wu9Liyuan Ran10Yingjie Wu11Huilai Miao12Xiaoju Zou13Bin Liang14Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan, China; Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, ChinaKey Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, ChinaCenter for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan, ChinaKey Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, ChinaDepartment of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaCollege of Life Sciences, Yunnan Normal University, Kunming, Yunnan, ChinaCenter for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan, China; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, ChinaHoward Hughes Medical Institute, Department of Ecology and Evolutionary Biology, University of California Santa Cruz, Santa Cruz, CaliforniaKey Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, ChinaInstitute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, ChinaInstitute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China; Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong Provincial Hospital, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, China; Yingjie WuDepartment of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Huilai MiaoSchool of Traditional Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, China; Xiaoju ZouCenter for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan, China; Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Correspondence Address correspondence to: Bin Liang, School of Life Sciences, Chenggong Campus, Yunnan University South Section, East Outer Ring Road, Chenggong District, Kunming, Yunnan province 650500, People's Republic of China. Fax: +86-871-65181927.Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is becoming a severe liver disorder worldwide. Autophagy plays a critical role in liver steatosis. However, the role of autophagy in NAFLD remains exclusive and under debate. In this study, we investigated the role of S100 calcium binding protein A11 (S100A11) in the pathogenesis of hepatic steatosis. Methods: We performed liver proteomics in a well-established tree shrew model of NAFLD. The expression of S100A11 in different models of NAFLD was detected by Western blot and/or quantitative polymerase chain reaction. Liver S100A11 overexpression mice were generated by injecting a recombinant adenovirus gene transfer vector through the tail vein and then induced by a high-fat and high-cholesterol diet. Cell lines with S100a11 stable overexpression were established with a recombinant lentiviral vector. The lipid content was measured with either Bodipy staining, Oil Red O staining, gas chromatography, or a triglyceride kit. The autophagy and lipogenesis were detected in vitro and in vivo by Western blot and quantitative polymerase chain reaction. The functions of Sirtuin 1, histone deacetylase 6 (HDAC6), and FOXO1 were inhibited by specific inhibitors. The interactions between related proteins were analyzed by a co-immunoprecipitation assay and immunofluorescence analysis. Results: The expression of S100A11 was up-regulated significantly in a time-dependent manner in the tree shrew model of NAFLD. S100A11 expression was induced consistently in oleic acid–treated liver cells as well as the livers of mice fed a high-fat diet and NAFLD patients. Both in vitro and in vivo overexpression of S100A11 could induce hepatic lipid accumulation. Mechanistically, overexpression of S100A11 activated an autophagy and lipogenesis process through up-regulation and acetylation of the transcriptional factor FOXO1, consequently promoting lipogenesis and lipid accumulation in vitro and in vivo. Inhibition of HDAC6, a deacetylase of FOXO1, showed similar phenotypes to S100A11 overexpression in Hepa 1–6 cells. S100A11 interacted with HDAC6 to inhibit its activity, leading to the release and activation of FOXO1. Under S100A11 overexpression, the inhibition of FOXO1 and autophagy could alleviate the activated autophagy as well as up-regulated lipogenic genes. Both FOXO1 and autophagy inhibition and Dgat2 deletion could reduce liver cell lipid accumulation significantly. Conclusions: A high-fat diet promotes liver S100A11 expression, which may interact with HDAC6 to block its binding to FOXO1, releasing or increasing the acetylation of FOXO1, thus activating autophagy and lipogenesis, and accelerating lipid accumulation and liver steatosis. These findings indicate a completely novel S100A11-HDAC6-FOXO1 axis in the regulation of autophagy and liver steatosis, providing potential possibilities for the treatment of NAFLD.http://www.sciencedirect.com/science/article/pii/S2352345X20301697NAFLDS100A11FOXO1AutophagyLipid Metabolism |
| spellingShingle | Linqiang Zhang Zhiguo Zhang Chengbin Li Tingting Zhu Jing Gao Hu Zhou Yingzhuan Zheng Qing Chang Mingshan Wang Jieyu Wu Liyuan Ran Yingjie Wu Huilai Miao Xiaoju Zou Bin Liang S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and LipogenesisSummary Cellular and Molecular Gastroenterology and Hepatology NAFLD S100A11 FOXO1 Autophagy Lipid Metabolism |
| title | S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and LipogenesisSummary |
| title_full | S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and LipogenesisSummary |
| title_fullStr | S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and LipogenesisSummary |
| title_full_unstemmed | S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and LipogenesisSummary |
| title_short | S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and LipogenesisSummary |
| title_sort | s100a11 promotes liver steatosis via foxo1 mediated autophagy and lipogenesissummary |
| topic | NAFLD S100A11 FOXO1 Autophagy Lipid Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X20301697 |
| work_keys_str_mv | AT linqiangzhang s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT zhiguozhang s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT chengbinli s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT tingtingzhu s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT jinggao s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT huzhou s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT yingzhuanzheng s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT qingchang s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT mingshanwang s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT jieyuwu s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT liyuanran s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT yingjiewu s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT huilaimiao s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT xiaojuzou s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary AT binliang s100a11promotesliversteatosisviafoxo1mediatedautophagyandlipogenesissummary |