The Effect Of FoxO1 In Stress-induced Liver Lipid Deposition

With the the progress of society and development of science and technology,stress has become an unavoidable event in people’s life,and its complexity and intensity have also increased.According to the length of time,stress can be divided into acute stress and chronic stress.Chronic stress refers to the long-term and long-lasting tension in the body,which can cause internal environment disorder and various pathological changes including hepatic steatosis.However,the exact mechanism of stress-induced lipid deposition in the liver is not clear.As generally opinion,lipid deposition in the liver is considered a "patent" for obese patients and is thought to be caused by long-term bad habits and lifestyles,but more and more "lean" is detected with fatty liver,especially in the people with long-term chronic stress.Therefore,it is of great significance to reveal the pathways and mechanisms of chronic stress-induced liver lipid deposition and to find effective prevention and treatment methods.FoxO1,a member of the forkhead O family,is a key molecule that regulates cell growth,differentiation and metabolism,which plays an important role in the regulation of glucose metabolism.More and more studies have shown that FoxO1 also plays a key role in lipid metabolism.However,the role of FoxO1 in stress-induced liver lipid deposition and its specific mechanisms are still rarely reported.Research objective: To clarify the key role of FoxO1 in stress-induced lipid deposition in the liver,and to further explore the specific mechanism of the liver FoxO1 in lipid deposition.Research methods: 1、Male C57BL/6 mice were divided into four groups: control group,chronic stress group,chronic stress + FoxO1 inhibitor group and FoxO1 inhibitor group,which were respectively treated for 6 weeks.Hepatic fat assay and Oil red O staining were used to assess liver lipid deposition in mice,while the levels of FoxO1 protein and its phosphorylation in liver were detected by Western blot,the transcriptional level of FoxO1 gene and its classical downstream genes by Real-Time Fluorescence quantitative PCR;2、To explore the mechanism of FoxO1 on stress-induced liver lipid deposition,we detected the transcriptional level of lipid metabolism-related genes in liver of four groups of mice,and the quatity of food intake、weight and glucose metabolism;3、Hepa1-6 cells were divided into four groups: control group,corticosterone-treated group,corticosterone + FoxO1 inhibitor-treated group and FoxO1 inhibitor-treated group for 48 h respectively.Lipid deposition in the four groups was evaluated by oil red O staining,while the FoxO1 protein and its phosphorylation levels were detected by Western blot.Real-Time Fluorescent quantitative PCR was used to detect the transcriptional level of FoxO1 gene and its downstream regulatory genes、lipid metabolism-related genes in liver of four groups.Results:1、Chronic stress promoted liver triglyceride deposition in mice,increased the contents of triglyceride,free fatty acid in serum significantly,while liver FoxO1 was activated.FoxO1 inhibitors could inhibit FoxO1 activity,improve liver triglyceride deposition in mice and reduce the contents of triglyceride,free fatty acid in serum.Four groups of mice liver and serum cholesterol content no significant difference;2、Chronic stress decreased body weight gain and food intake in mice and increased the transcriptions of triglyceride gene Fasn,fatty acid uptake genes FATP and FABP,cholesterol synthesis gene HMG-CoAR and cholesterol oxidation gene CYP7A1,while FoxO1 inhibitor reduced these gene transcription levels,but no effection on body weight gain and food intake.There were no significant differences in the fasting blood glucose,postprandial blood glucose,insulin,glucose tolerance and insulin resistance,and the transcription levels of ACC1,SCD1,CD36,PPARα,Acox1,Lcad,Mcad,Pdk4,Cpt1 a,Ucp2 and ABCG1 in four groups of mice.3、Corticosterone induced lipid deposition,while activated FoxO1,increased the transcription of Fasn.FoxO1 inhibitor suppressed the activity of FoxO1,while reduced lipid deposition and decrease the transcription of Fasn.Conclusion:Chronic stress could lead to liver lipid deposition in mice,which through activation of FoxO1 by corticosterone,followed by promotion of hepatic triglyceride synthesis and free fatty acid intake.