Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue
Abstract Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty...
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Nature Publishing Group
2025-02-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-025-01403-6 |
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| author | Shi-Young Park Yoonil Cho Sae-Mi Son Jang Ho Hur Yeongmin Kim Hyunhee Oh Hui-Young Lee Sungwon Jung Sanghee Park Il-Young Kim Se-Jin Lee Cheol Soo Choi |
| author_facet | Shi-Young Park Yoonil Cho Sae-Mi Son Jang Ho Hur Yeongmin Kim Hyunhee Oh Hui-Young Lee Sungwon Jung Sanghee Park Il-Young Kim Se-Jin Lee Cheol Soo Choi |
| author_sort | Shi-Young Park |
| collection | DOAJ |
| description | Abstract Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanisms by which the ER stress response protects against NAFLD remain largely unknown. Recently, activin E has been linked to metabolic diseases such as insulin resistance and NAFLD. However, the physiological conditions and regulatory mechanisms driving hepatic Inhbe expression (which encodes activin E) as well as the metabolic role of activin E in NAFLD require further investigation. Here we found that hepatic Inhbe expression increased under prolonged fasting and ER stress conditions, which was mediated by ATF4, as determined by promoter analysis in a mouse model. Consistently, a positive correlation between INHBE and ATF4 expression levels in relation to NAFLD status was confirmed using public human NAFLD datasets. To investigate the role of activin E in hepatic steatosis, we assessed the fluxes of the lipid metabolism in an Inhbe-knockout mouse model. These mice displayed a lean phenotype but developed severe hepatic steatosis under a high-fat diet. The deficiency of Inhbe resulted in increased lipolysis in adipose tissue, leading to increased fatty acid influx into the liver. Conversely, hepatic overexpression of Inhbe ameliorated hepatic steatosis by suppressing lipolysis in adipose tissue through ALK7–Smad signaling. In conclusion, activin E serves as a regulatory hepatokine that prevents fatty acid influx into the liver, thereby protecting against NAFLD. |
| format | Article |
| id | doaj-art-08088f87897c4583a61ba99999d68506 |
| institution | DOAJ |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-08088f87897c4583a61ba99999d685062025-08-20T02:59:19ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-02-0157246647710.1038/s12276-025-01403-6Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissueShi-Young Park0Yoonil Cho1Sae-Mi Son2Jang Ho Hur3Yeongmin Kim4Hyunhee Oh5Hui-Young Lee6Sungwon Jung7Sanghee Park8Il-Young Kim9Se-Jin Lee10Cheol Soo Choi11Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon UniversityKorea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon UniversityKorea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon UniversityKorea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon UniversityDepartment of Health Sciences and Technology, GAIHST, Gachon UniversityKorea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon UniversityKorea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon UniversityDepartment of Genome Medicine and Science, Gachon University College of MedicineIntegrative Metabolic Fluxomics Lab, Lee Gil Ya Cancer and Diabetes Institute, Gachon UniversityKorea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon UniversityThe Jackson Laboratory for Genomic MedicineKorea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon UniversityAbstract Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanisms by which the ER stress response protects against NAFLD remain largely unknown. Recently, activin E has been linked to metabolic diseases such as insulin resistance and NAFLD. However, the physiological conditions and regulatory mechanisms driving hepatic Inhbe expression (which encodes activin E) as well as the metabolic role of activin E in NAFLD require further investigation. Here we found that hepatic Inhbe expression increased under prolonged fasting and ER stress conditions, which was mediated by ATF4, as determined by promoter analysis in a mouse model. Consistently, a positive correlation between INHBE and ATF4 expression levels in relation to NAFLD status was confirmed using public human NAFLD datasets. To investigate the role of activin E in hepatic steatosis, we assessed the fluxes of the lipid metabolism in an Inhbe-knockout mouse model. These mice displayed a lean phenotype but developed severe hepatic steatosis under a high-fat diet. The deficiency of Inhbe resulted in increased lipolysis in adipose tissue, leading to increased fatty acid influx into the liver. Conversely, hepatic overexpression of Inhbe ameliorated hepatic steatosis by suppressing lipolysis in adipose tissue through ALK7–Smad signaling. In conclusion, activin E serves as a regulatory hepatokine that prevents fatty acid influx into the liver, thereby protecting against NAFLD.https://doi.org/10.1038/s12276-025-01403-6 |
| spellingShingle | Shi-Young Park Yoonil Cho Sae-Mi Son Jang Ho Hur Yeongmin Kim Hyunhee Oh Hui-Young Lee Sungwon Jung Sanghee Park Il-Young Kim Se-Jin Lee Cheol Soo Choi Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue Experimental and Molecular Medicine |
| title | Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue |
| title_full | Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue |
| title_fullStr | Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue |
| title_full_unstemmed | Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue |
| title_short | Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue |
| title_sort | activin e is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue |
| url | https://doi.org/10.1038/s12276-025-01403-6 |
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