| As the increase of age,the function of the body system is gradually declining,which is manifested in the changes about the living habits of the elderly and the functional state of the organs.The living habits of the elderly,such as the abnormality of the biological rhythm,are manifested by the advanced phase of the circadian rhythm(early sleep early),the decrease in amplitude(slow sleep depth,poor quality),shortened cycle(memory reduction),the lowered amplitude or the phase advanced of body temperature and hormone.Moreover,organ function status also changes,especially the metabolic pattern of the main metabolic organs,leading to metabolic syndrome-related symptoms such as obesity,hyperglycemia,insulin resistance and fatty liver.Similarly,abnormalities of circadian rhythm can also lead to changes in metabolic patterns with age increased.Therefore,studying the mechanism and the interaction of abnormal biological rhythm and organ metabolism pattern in the process of age increase have an important practical significance for improving the body state of the elderly and improving the quality of life.The liver acts as a metabolically-regulated organ and is regulated by the central rhythm.The peripheral biological rhythm and metabolic function of the liver are tightly coupled,and the interaction between circadian rhythm and metabolism ensures the normal functioning of the liver.Many reports and our research found that during the age increase process,lipid accumulation increased;the number of lipid droplets became larger;lipid decomposition was impaired;fatty acid oxidation was inhibited,and a series of metabolic disorders occurred in liver.Obviously,the metabolic pattern of hepatocytes changes during the age increase process.The body exhibits the above characteristics of metabolic aging.However,the specific mechanism of changes in hepatocyte metabolism patterns during the age increase process is unclear.We found that the amplitude and phase of genes related to liver biorthythm were significantly changed during the age increase process: Bmal1,Per1,Per2,Clock,Cry1,and Rev-erb amplitude were significantly increased.The peak point of Per1,Per2,and Rev-erb m RNA were shifted either before or after.Therefore,we believe that the interaction between peripheral biorhythms and metabolic patterns of the liver during the age increase process will trigger the aging of the liver once the coupling is lost.Therefore,we believe that the peripheral biological rhythms and metabolic patterns of the liver interact with each other during the age increase process,and once the coupling is lost,it will trigger the aging of the liver.Circadian rhythms are primarily regulated by light and dietary cycles.The metabolic processes and metabolites in the organism follow a certain cycle rhythm according to the changes of day and night and three meals.The change of diet time can directly regulate the biological rhythm of the central and peripheral tissues.Therefore,whether the peripheral biological rhythm and metabolic pattern of the liver can be changed by illumination and food traction,thereby affecting the central rhythm and improving the metabolic aging state of the body is a problem worthy of discussion.To achieve this goal,it is necessary to have a deep understanding of the coupling of peripheral biological rhythms and metabolic patterns of hepatocytes,as well as changes in the aging process.However,although we have learned that the regulation of the peripheral rhythm of the main clock on various tissues and organs depends mainly on the adrenergic receptor-mediated signaling pathway,the mediator of the primary clock in hepatocytes and the signal factor which coupled the peripheral biological rhythms and metabolic patterns is not yet clear and further research is needed.Early growth response-1(Egr-1)is a member of the early stress response gene family that recognizes the transcription of a highly conserved GC-based promoter sequence-regulated gene downstream.Our results showed that Egr-1 expressed rhythmic expression in the liver of adult mice and could regulate the transcriptional activity of the liver biorhythm gene Per1;with the increase of age,the phase of Egr-1m RNA and protein peak expression was shifted forward.The expression level of Egr-1 is significantly reduced.So,can Egr-1 act as a mediator of the primary clock in hepatocytes and a signal coupled to peripheral biological rhythms and metabolic patterns?To investigate the effect of liver Egr-1 on liver biorhythm and metabolism patterns at the overall animal level,we constructed Egr-1-floxed mice and specifically knocked out liver parenchymal cells Egr-1 using Alb-Cre transgenic mice.The loss of Egr-1caused the lipid accumulation of hepatocytes in mice from 6-month-old to be significantly higher than that in wild type mice.The triglyceride level was significantly increased,and a large number of large lipid droplets appeared.Fatty acid levels increased.At 21 months of age,knockout mice were obese and had fatty liver and mild fibrosis in the same age;Egr-1 null mice had a lower overall survival rate.The content of β-galactosidase,which is a marker of aging,is higher than that of wild-type mice in the same age,and the body appears metabolically aging prematurely.At the same time,the deletion of Egr-1 causes a rhythm disorder of the circadian clock gene.Thus,Egr-1 can regulate liver lipid accumulation and metabolic disorders during aging.To investigate the specific mechanism of Egr-1 regulation of hepatic lipid metabolism and biorhythm,we selected wild-type and liver-specific knockout Egr-1mice at the highest point of Egr-1 expression at 2 months(ZT13),6 months(ZT9),and12 months(ZT1)of age.The liver was subjected to RNA sequencing,and the analysis results confirmed that the biorhythm coupling of Egr-1/Cidea can regulate the lipid homeostasis of the liver.Cidea is a member of the CIDE family that specifically promotes lipid turnover and fusion of large lipid droplets.To detect changes in the amplitude rhythm of Cidea during the age increase process,we found that the amplitude of Cidea increased and the phase shifted forward.Deletion of Egr-1 can result in an increase in the amplitude of the rhythm of Cidea.Overexpression of Sh Cidea by adenovirus,knocking down expression of Cidea,can alleviate lipid accumulation caused by Egr-1 deletion.We recovered the phase of Egr-1 to adulthood by light advancement for 4 hours,and found that the amplitude of Cidea decreased and the body’s lipid accumulation was alleviated.It is further explained that the biorhythm coupling of Egr-1/Cidea can regulate lipid accumulation in the liver.In summary,we found that Egr-1 is a key factor in responding to central rhythms and coordinating peripheral biological rhythms and metabolic patterns in the liver.Egr-1 ensures the normal physiological youngness of the liver and the individual through the dual regulation of peripheral biological rhythms and lipid metabolism of hepatocytes.With the increase of age,the rhythm phase of Egr-1 is advanced,and the expression pattern of its downstream regulatory genes,including the biorhythm-related gene Per1 and the lipid metabolism-related gene Cidea,is fundamentally changed,and thus the hepatocyte periphery is made.The biological rhythm is disordered and the metabolic pattern changes,leading to metabolic aging of the liver.This metabolic aging state is further fed back to the central rhythm,causing the individual to exhibit aging changes in life habits and metabolic imbalances.At the same time,we have found an intervention strategy to effectively improve the metabolic function of the aging liver,which is completed by the advancement of illumination.This will help us to better restore the normal biological rhythm and lipid metabolism patterns of the aging liver,thereby improving the aging state of the body and providing a new idea for delaying aging. |
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