SJL disrupts the normal rhythmic release of prolactin (PRL) from the pituitary gland, leading to irregular PRL levels in the bloodstream.
This disruption dampens the rhythmicity of the hepatic PRL signaling pathway, contributing to increased fat production in the liver.
Under jetlag conditions, the expression of specific proteins related to liver function is inhibited, which may exacerbate fatty liver conditions.
Treatment with PRL at specific times improved liver health in jetlagged mice more effectively than standard PRL treatment.
The findings suggest that restoring the normal rhythm of PRL could help manage fatty liver conditions associated with SJL.
Simplified
BACKGROUND: The prevalence of circadian misalignment, particularly (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 Prlmice. 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 (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.
Key numbers
7.48 (5.75, 9.23) μg/L vs. 11.28 (8.53, 14.59) μg/L
Prolactin Levels Decrease
PRL levels at 8:00 in vs. non- subjects
ALT, AST, and TG levels elevated in JL group vs. NC group
Increased Liver Injury Markers
Comparison of liver injury markers in JL and NC mice
1 mg/kg
Therapeutic Effect of PRL
Dosage of PRL administered to jetlagged mice
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Declarations. Ethics approval and consent to participate: The study conformed to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of Nanjing Drum Tower Hospital, Nanjing University Medical School (2021-388-01). All participants signed informed consent prior to study inclusion and they did not receive any compensation. All animal studies were conducted in adherence to the guidelines of the Animal Ethics Committee of Nanjing Drum Tower Hospital (2021AE01044). Consent for publication: The results and writing of this manuscript followed a structured and standard format of academic paper. All authors approve the final version of the manuscript and agree to the publication. Competing interests: All authors declared that there are no potential conflicts of interest with respect to this manuscript.
