The Study On Mechanism About Aerobic Exercise Through HNF1?-PCSK9-LDLR Pathway To Stable Blood Lipid Effect

Objective:Hyperlipidemia(HL)is concentration of lipids in plasma beyond the normal range.Modern medicine is also known as dyslipidemia,Hyperlipidemia is a potential pathogenic factor for major diseases such as atherosclerosis and coronary heart disease.Prevention of hyperlipidemia has very important practical significance in controlling the morbidity and mortality of cardiovascular and cerebrovascular diseases.In recent years,studies have found that the imbalance of expression of some genes can cause abnormal changes in the receptor,apolipoprotein or enzyme involved in mediating the blood lipid balance in the body,the process of synthesis,transport and metabolism of lipoprotein is also abnormal,leading to the increase of blood lipid level in the body.Low-density lipoprotein receptor(LDLR)is express rich membrane glycoprotein that mounted on liver cell membrane,most of Most of its main function is to absorb Low density lipoprotein(LDL)from cycle into the cells,used in steroidal hormones such as synthesis and cell proliferation in the process of normal metabolism of the body,this metabolic process is known as LDLR pathway.Seidah and others found that proprotein convertase subtilisin/kexin type 9(PCSK9)since 2003,more and more researchers found that PCSK9 is by combining the epidermal growth factor(EGF)structure of the LDLR domain to get LDLR with PCSK9 common internalization,then they transferred to the lysosome degradation,so that the LDLR unable to return to play a role on the cell membrane surface.PCSK9 is thought to play a key role in cholesterol metabolism link,have also been more and more attention.Nuclear factor 1 alpha(HNF1 alpha)in human chromosome 12,is widely expressed in liver,kidney,intestine and pancreas,the lipid metabolism,detoxification and carbohydrate synthesis and storage,etc all play an extremely important role.Study found HNF1 alpha binding site is located in the proximal promoter of PCSK9,it is important for the PCSK9 gene transcription activation,and both have synergy,the PCSK9 gene have positive adjustment.Aerobic exercise refers to the oxygen supply fully under the situation of physical exercise,such as swimming,jogging,etc.Both animal and human studies have shown that moderate and effective aerobic exercise can effectively reduce the level of total cholesterol(TCHO),triglyceride(TG),and LDL-C(ldl-c)in serum.Meanwhile,high density lipoprotein cholesterol(hdl-c)level was increased [17-18].At present,the research on the mechanism of aerobic exercise in maintaining lipid balance is not complete,So this study puts forward hypothesis,research whether aerobic exercise can influence HNF1 alpha gene expression positive regulation of PCSK9 gene,which affects the liver LDLR expression level,and achieve the purpose of maintaining blood lipid balance.To this end,this study designed an experiment: the high-fat diet of C57BL/6J mice was raised as a hyperlipemia model.In vivo study body weight,blood lipid levels and the different group of mice liver pathology change,and in the liver HNF1 alpha,PCSK9 and LDL receptor m RNA and protein expression in different with the change of different intervention.Methods:1.By feeding high-fat forage and treadmill exercise mice,hyperlipidemia and aerobic exercise mice model was constructed,and test the mice body weight and blood lipid levels in four weeks,eight weeks,twelve weeks of high-fat feeding from each groups.2.6% slope,26 m/min per day�50 min,the pattern of six days a week for treadmill exercise,aerobic exercise mice model was constructed,and detect the type of aerobic exercise intervention at the fourth week,12 weeks body weight and blood lipid levels.3.When all 12 weeks intervention were end,take groups of mice liver tissue test through pathology and microscopic test,and test the m RNA and protein expression of HNF1 alpha?LDL receptor and PCSK9.Results:1.After 8 weaks of high-fat feeding(4 weeks of aerobic exercise)intervention,compared with NC group,M group's body weight and levels of TC?TG and LDL-C were obviously increased,and the HDL-C levels were decreased,all have statistically significant difference(p<0.05);compared with M group,ME group's body weight and levels of TC?TG and LDL-C were obviously decreased,and the HDL-C levels were increased,all have statistically significant difference(p<0.05);there were not have statistically significant difference in NE and NC group(p>0.05).2.After 12 weaks of high-fat feeding(8 weeks of aerobic exercise)intervention,compared with NC group,M group's body weight and levels of TC?TG and LDL-C were obviously increased,and the HDL-C levels were decreased,all have statistically significant difference(p<0.05);compared with M group,ME group's body weight and levels of TC?TG and LDL-C were obviously decreased,and the HDL-C levels were increased,all have statistically significant difference(p<0.05);there were not have statistically significant difference in NE and NC group(p>0.05).3.NC group's liver cell has a normal cellular morphology,the nucleus is clearly visible,centered around the central vein into the surrounding are arranged funicular and that is rules,thre occasionally see a small fat drops in the figure.There were not have statistically significant difference in NE and NC group.M group of liver cells markedly swollen and arranged loosely,a large number of vacuoles in liver tissue structure sample cell,there are full of fat drops in the horizon,accidentally see dotted necrosis,vision is full of fatty degeneration of the cells.ME group of liver cell lesion was significantly lighter than M group and there is a small amount of lipid droplets,swelling degree and high fat model group is light,can be found normal liver cells.4.Compared with NC group,M group's m RNA relatively expression of HNF1 alpha and PCSK9 were obviously increased,m RNA relatively expression of LDL receptor were obviously decreased,both of two have statistically significant difference(p<0.05);compared with M group,ME group's m RNA relatively expression of HNF1 alpha and PCSK9 were obviously decreased,and m RNA relatively expression of LDL receptor were increased,all have statistically significant difference(p<0.05);there were not have statistically significant difference in NE and NC group(p>0.05).5.Compared with NC group,M group's protein relative expression of HNF1 alpha and PCSK9 were obviously increased,protein relative expression of LDL receptor were obviously decreased,both of two have statistically significant difference(p<0.05);compared with M group,ME group's protein relative expression of HNF1 alpha and PCSK9 were obviously decreased,and protein relative expression of LDL receptor were increased,all have statistically significant difference(p<0.05);there were not have statistically significant difference in NE and NC group(p>0.05).Conclusion:1 Aerobic exercise can cause hyperlipidemia's development process slow down,it can restore blood lipid levels and the structure of the liver pathology;2 After the intervention of aerobic exercise,hyperlipidemia model mice's expression of HNF1 alpha,PCSK9 in the liver were decreased and expression of LDLreceptor were upregulated;3 HNF1 alpha-PCSK9-LDLR pathway maybe is the one of way for aerobic exercise improve the blood lipid level.