The sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR30
The prevalence of nonalcoholic steatohepatitis (NASH) caused by estrogen deficiency increased sharply in recent decades and has become a major threat to liver health in postmenopausal women. There is no effective strategy to control the incidence and development of NASH. Dehydroepiandrosterone (DHEA...
Guardado en:
| Autores principales: | , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Elsevier
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/7ce63b9390d9470c8ce1f21674530925 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:7ce63b9390d9470c8ce1f21674530925 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:7ce63b9390d9470c8ce1f216745309252021-11-14T04:32:43ZThe sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR302213-231710.1016/j.redox.2021.102187https://doaj.org/article/7ce63b9390d9470c8ce1f216745309252021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2213231721003475https://doaj.org/toc/2213-2317The prevalence of nonalcoholic steatohepatitis (NASH) caused by estrogen deficiency increased sharply in recent decades and has become a major threat to liver health in postmenopausal women. There is no effective strategy to control the incidence and development of NASH. Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid with immune and metabolic regulatory properties, and its level markedly declines with increasing age in humans. Importantly, DHEA can convert into active sex hormones depending on the local needs of target tissues with little diffusion, which serves to avoid systemic side-effects from other tissues’ exposure to estrogen. Here, we found that DHEA prevented the incidence and development of NASH, which is characterized by the reduction of hepatic steatosis, fibrosis, and inflammation in female mice fed with high-fat/high-cholesterol diets and effectively attenuated lipid accumulation, inflammatory response, and oxidative stress in palmitic acid-challenged hepatocytes. Mechanistically, in vitro and in vivo studies showed that the anti-NASH function of DHEA depended on its biotransformation into estrogen rather than androgen, and which up-regulates the expression of G protein-coupled estrogen receptor (GPR30), a non-classical estrogen receptor. The activation of GPR30-mediated AMP-activated protein kinase signaling is a necessary prerequisite for the alleviative effects of DHEA on NASH. Collectively, our data show the mechanisms of DHEA treatment and its effects on NASH that were previously overlooked; the data also show that GPR30 can be used as a target for treating lipid metabolism disorders and related diseases, such as NASH. Furthermore, these findings have the potential to help researchers develop new strategies for preventing NASH in postmenopausal women.Longlong LiHongjun WangYao YaoJi CaoZhihao JiangWeiyuan YanXu ChuQian LiMiaomiao LuHaitian MaElsevierarticleDehydroepiandrosteroneBiotransformationNonalcoholic steatohepatitisAMP-Activated protein kinaseG protein-coupled estrogen receptorMedicine (General)R5-920Biology (General)QH301-705.5ENRedox Biology, Vol 48, Iss , Pp 102187- (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Dehydroepiandrosterone Biotransformation Nonalcoholic steatohepatitis AMP-Activated protein kinase G protein-coupled estrogen receptor Medicine (General) R5-920 Biology (General) QH301-705.5 |
| spellingShingle |
Dehydroepiandrosterone Biotransformation Nonalcoholic steatohepatitis AMP-Activated protein kinase G protein-coupled estrogen receptor Medicine (General) R5-920 Biology (General) QH301-705.5 Longlong Li Hongjun Wang Yao Yao Ji Cao Zhihao Jiang Weiyuan Yan Xu Chu Qian Li Miaomiao Lu Haitian Ma The sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR30 |
| description |
The prevalence of nonalcoholic steatohepatitis (NASH) caused by estrogen deficiency increased sharply in recent decades and has become a major threat to liver health in postmenopausal women. There is no effective strategy to control the incidence and development of NASH. Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid with immune and metabolic regulatory properties, and its level markedly declines with increasing age in humans. Importantly, DHEA can convert into active sex hormones depending on the local needs of target tissues with little diffusion, which serves to avoid systemic side-effects from other tissues’ exposure to estrogen. Here, we found that DHEA prevented the incidence and development of NASH, which is characterized by the reduction of hepatic steatosis, fibrosis, and inflammation in female mice fed with high-fat/high-cholesterol diets and effectively attenuated lipid accumulation, inflammatory response, and oxidative stress in palmitic acid-challenged hepatocytes. Mechanistically, in vitro and in vivo studies showed that the anti-NASH function of DHEA depended on its biotransformation into estrogen rather than androgen, and which up-regulates the expression of G protein-coupled estrogen receptor (GPR30), a non-classical estrogen receptor. The activation of GPR30-mediated AMP-activated protein kinase signaling is a necessary prerequisite for the alleviative effects of DHEA on NASH. Collectively, our data show the mechanisms of DHEA treatment and its effects on NASH that were previously overlooked; the data also show that GPR30 can be used as a target for treating lipid metabolism disorders and related diseases, such as NASH. Furthermore, these findings have the potential to help researchers develop new strategies for preventing NASH in postmenopausal women. |
| format |
article |
| author |
Longlong Li Hongjun Wang Yao Yao Ji Cao Zhihao Jiang Weiyuan Yan Xu Chu Qian Li Miaomiao Lu Haitian Ma |
| author_facet |
Longlong Li Hongjun Wang Yao Yao Ji Cao Zhihao Jiang Weiyuan Yan Xu Chu Qian Li Miaomiao Lu Haitian Ma |
| author_sort |
Longlong Li |
| title |
The sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR30 |
| title_short |
The sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR30 |
| title_full |
The sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR30 |
| title_fullStr |
The sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR30 |
| title_full_unstemmed |
The sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR30 |
| title_sort |
sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the ampk pathway mediated by gpr30 |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/7ce63b9390d9470c8ce1f21674530925 |
| work_keys_str_mv |
AT longlongli thesexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT hongjunwang thesexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT yaoyao thesexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT jicao thesexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT zhihaojiang thesexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT weiyuanyan thesexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT xuchu thesexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT qianli thesexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT miaomiaolu thesexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT haitianma thesexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT longlongli sexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT hongjunwang sexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT yaoyao sexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT jicao sexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT zhihaojiang sexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT weiyuanyan sexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT xuchu sexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT qianli sexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT miaomiaolu sexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 AT haitianma sexsteroidprecursordehydroepiandrosteronepreventsnonalcoholicsteatohepatitisbyactivatingtheampkpathwaymediatedbygpr30 |
| _version_ |
1718429964760514560 |