Social jetlag elicits fatty liver via perturbed circulating prolactin rhythm-mediated circadian remodeling of hepatic lipid metabolism
Abstract Background The prevalence of circadian misalignment, particularly social jetlag (SJL), contributes significantly to the epidemic of metabolic disorders. However, the precise impact of SJL on the liver has remained poorly elucidated. Methods The rhythmicity of circulating prolactin (PRL) was...
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BMC
2025-06-01
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| Online Access: | https://doi.org/10.1186/s40779-025-00609-z |
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| author | Peng-Zi Zhang Ying-Huan Shi Yu-Xin Guo Ya-Yuan Li Hong-Li Yin Tian-Yu Wu Ye Zhu Jia-Xuan Jiang Yan Bi |
| author_facet | Peng-Zi Zhang Ying-Huan Shi Yu-Xin Guo Ya-Yuan Li Hong-Li Yin Tian-Yu Wu Ye Zhu Jia-Xuan Jiang Yan Bi |
| author_sort | Peng-Zi Zhang |
| collection | DOAJ |
| description | Abstract Background The prevalence of circadian misalignment, particularly social jetlag (SJL), contributes significantly to the epidemic of metabolic disorders. However, the precise impact of SJL on the liver has remained poorly elucidated. Methods The rhythmicity of circulating prolactin (PRL) was evaluated in subjects with SJL and mice under SJL. The causative mechanism of SJL on fatty liver was explored using jetlag model in wild-type and Prl −/− mice. Luciferase reporter assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation analysis were used to study the transcriptional mechanism of retinoic acid receptor-related orphan receptor α on PRL. RNA-seq on human and mice liver as well as circadian analysis were used to study the mechanism of SJL-associated desynchronized PRL on hepatic lipid metabolism. The therapeutic effect of PRL intervention on SJL-induced mice at different time points was compared. Results SJL increases the risk of metabolic dysfunction-associated steatotic liver disease (MASLD), mediated by the disruption of the rhythmicity of serum PRL. In particular, SJL inhibits the rhythmic transcription of PRL in the pituitary, leading to desynchronized PRL levels in circulation. Under jetlag conditions, the rhythmicity of the hepatic PRL signaling pathway was significantly dampened, which resulted in increased lipogenesis via inhibited hepatic mitogen-activated protein kinase/cyclin D1 expressions. Notably, PRL treatment at PRL nadir in jetlagged mice decreased hepatic lipid content and liver injury markers to a greater extent compared with conventional PRL administration. Conclusions Reprogrammed hepatic PRL signaling pathway with concomitant dysregulated lipid metabolism homeostasis was the causative mechanism of fatty liver under SJL, which was mediated through derailed serum PRL rhythm. Restoration of PRL rhythm could effectively alleviate SJL-induced fatty liver, providing new insight into treating MASLD. |
| format | Article |
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| institution | OA Journals |
| issn | 2054-9369 |
| language | English |
| publishDate | 2025-06-01 |
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| series | Military Medical Research |
| spelling | doaj-art-812ebbf195df4dfe9dae8cbce7e129fa2025-08-20T02:05:49ZengBMCMilitary Medical Research2054-93692025-06-0112111810.1186/s40779-025-00609-zSocial jetlag elicits fatty liver via perturbed circulating prolactin rhythm-mediated circadian remodeling of hepatic lipid metabolismPeng-Zi Zhang0Ying-Huan Shi1Yu-Xin Guo2Ya-Yuan Li3Hong-Li Yin4Tian-Yu Wu5Ye Zhu6Jia-Xuan Jiang7Yan Bi8Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityNational Key Laboratory for Novel Software Technology and the National Institute of Healthcare Data Science, Nanjing UniversityDepartment of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityNational Key Laboratory for Novel Software Technology and the National Institute of Healthcare Data Science, Nanjing UniversityDepartment of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityAbstract Background The prevalence of circadian misalignment, particularly social jetlag (SJL), contributes significantly to the epidemic of metabolic disorders. However, the precise impact of SJL on the liver has remained poorly elucidated. Methods The rhythmicity of circulating prolactin (PRL) was evaluated in subjects with SJL and mice under SJL. The causative mechanism of SJL on fatty liver was explored using jetlag model in wild-type and Prl −/− mice. Luciferase reporter assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation analysis were used to study the transcriptional mechanism of retinoic acid receptor-related orphan receptor α on PRL. RNA-seq on human and mice liver as well as circadian analysis were used to study the mechanism of SJL-associated desynchronized PRL on hepatic lipid metabolism. The therapeutic effect of PRL intervention on SJL-induced mice at different time points was compared. Results SJL increases the risk of metabolic dysfunction-associated steatotic liver disease (MASLD), mediated by the disruption of the rhythmicity of serum PRL. In particular, SJL inhibits the rhythmic transcription of PRL in the pituitary, leading to desynchronized PRL levels in circulation. Under jetlag conditions, the rhythmicity of the hepatic PRL signaling pathway was significantly dampened, which resulted in increased lipogenesis via inhibited hepatic mitogen-activated protein kinase/cyclin D1 expressions. Notably, PRL treatment at PRL nadir in jetlagged mice decreased hepatic lipid content and liver injury markers to a greater extent compared with conventional PRL administration. Conclusions Reprogrammed hepatic PRL signaling pathway with concomitant dysregulated lipid metabolism homeostasis was the causative mechanism of fatty liver under SJL, which was mediated through derailed serum PRL rhythm. Restoration of PRL rhythm could effectively alleviate SJL-induced fatty liver, providing new insight into treating MASLD.https://doi.org/10.1186/s40779-025-00609-zSocial jetlagProlactinCircadian rhythmMetabolic dysfunction-associated steatotic liver disease (MASLD) |
| spellingShingle | Peng-Zi Zhang Ying-Huan Shi Yu-Xin Guo Ya-Yuan Li Hong-Li Yin Tian-Yu Wu Ye Zhu Jia-Xuan Jiang Yan Bi Social jetlag elicits fatty liver via perturbed circulating prolactin rhythm-mediated circadian remodeling of hepatic lipid metabolism Military Medical Research Social jetlag Prolactin Circadian rhythm Metabolic dysfunction-associated steatotic liver disease (MASLD) |
| title | Social jetlag elicits fatty liver via perturbed circulating prolactin rhythm-mediated circadian remodeling of hepatic lipid metabolism |
| title_full | Social jetlag elicits fatty liver via perturbed circulating prolactin rhythm-mediated circadian remodeling of hepatic lipid metabolism |
| title_fullStr | Social jetlag elicits fatty liver via perturbed circulating prolactin rhythm-mediated circadian remodeling of hepatic lipid metabolism |
| title_full_unstemmed | Social jetlag elicits fatty liver via perturbed circulating prolactin rhythm-mediated circadian remodeling of hepatic lipid metabolism |
| title_short | Social jetlag elicits fatty liver via perturbed circulating prolactin rhythm-mediated circadian remodeling of hepatic lipid metabolism |
| title_sort | social jetlag elicits fatty liver via perturbed circulating prolactin rhythm mediated circadian remodeling of hepatic lipid metabolism |
| topic | Social jetlag Prolactin Circadian rhythm Metabolic dysfunction-associated steatotic liver disease (MASLD) |
| url | https://doi.org/10.1186/s40779-025-00609-z |
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