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Apolipoprotein M and Obesity-related Metabolic Abnormalities and Intervention Study

Author: YangLiu
Tutor: ZhaoShuiPing
School: Central South University
Course: Internal Medicine
Keywords: Apolipoprotein M Obesity Adiponectin Inflammatory cytokines Simvastatin Fenofibrate
CLC: R589.2
Type: PhD thesis
Year: 2010
Downloads: 264
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Abstract

The background of a large number of studies have shown that high-density lipoprotein cholesterol (HDL-C) levels and coronary heart disease incidence was negatively correlated. Increase HDL-C levels can delay or prevent the occurrence of atherosclerosis. HDL-C anti-atherosclerosis mainly with HDL-C in the reverse cholesterol transport (RCT) play a key role. With the living environment and dietary changes in the structure, the incidence of obesity is rising rapidly on a global scale, obesity is a common disease caused by the decrease of HDL-C. Statins and fibrates is a common clinical lipid-lowering drugs, studies have shown that statins and fibrates increase HDL-C level and improve RCT. Apolipoprotein M (apoM) is a recently discovered major apolipoprotein associated with HDL-C, HDL-C metabolism plays an important role, it is mainly generated by the former p-HDL regulation to affect human RCT process . apoM in HDL-C generates and RCT process can not be replaced. Hepatocyte nuclear factor-1α (HNF-1α), forkhead transcription factor A2 (FoxA2) and liver X receptor the a (LXRa) three key nuclear receptors regulating apoM expression. Among them, the former two raised apoM the expression, the expression of the latter downward apoM. It is not clear statins and fibrates increase HDL-C and improve RCT whether apoM; the obese state I do not know whether low HDL-C viremia apoM related. The study confirmed that obesity is a chronic inflammatory disease, and is often accompanied by hypoadiponectinemia no obese state, of apoM with inflammatory factors and adiponectin prime relations research. Objective To observe the changes in obese mice apolipoprotein M, and to explore the obese state download lipoprotein M adiponectin relationship, and reveals the mechanism; apolipoprotein M levels observed in obese patients and to explore its relationship with inflammatory factors; explore simvastatin and fenofibrate combination apolipoprotein M expression and its mechanism. Method, changes in obese mice apolipoprotein M relationship with adiponectin investigate animal experiments 32 3-week-old male C57BL / 6 N mice were randomly divided into four groups (n = 8 / group): (1) control group: an ordinary diet, fed for 12 weeks; (2) obesity groups: high fat diet fed for 12 weeks; (3) obesity intervention groups: high fat diet for 12 weeks feeding adiponectin intervention 7 days. (4) Common intervention groups: normal diet, fed for 12 weeks adiponectin intervention 7 days. Body weight, plasma adiponectin, blood glucose, plasma insulin were measured experimental week 0, week 12, and adiponectin. Saying check the weight at the end of the experiment, mice visceral fat mouse liver tissue samples using real-time quantitative reverse transcription polymerase chain reaction (real-time RT-PCR) and Western blot (Western Blot) to detect the mouse liver apolipoprotein M, of FoxA2 the mRNA and protein expression. 2 cell experiments high concentrations of insulin-induced HepG2 cells build hepatocyte model of insulin resistance (IR), using real-time RT-PCR and Western Blot insulin resistance state of liver cells in the apoM gene and protein expression changes. Adiponectin intervention in insulin resistance in HepG2 cells, HepG2 cells 24h, using real-time RT-PCR and Western Blot to detect the expression of apolipoprotein M FoxA2 mRNA and protein expression. Apolipoprotein M and its relationship with inflammatory factors in obese patients enrolled 58 healthy and 40 obese patients as research subjects, routine measurement of blood pressure, weight, height, body mass index, fasting blood test their blood sugar , blood lipids, fasting insulin, plasma apoM, interleukin -6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), plasma lipid adiponectin and detection of brachial artery endothelial diastolic functions (FMD). Simvastatin and fenofibrate on apolipoprotein M expression and regulation mechanisms animal experiments 32 8-week-old male C57BL/6N mice were randomly divided into four groups (n = 8 / group) : (1) control group: normal ordinary diet; (2) (3) the Bethe group: fenofibrate (100mg/kg / day of atorvastatin group: intervention simvastatin (10mg/kg / day) for 4 weeks;) intervention for four weeks; (4) joint groups: simvastatin (10mg/kg / day) and fenofibrate (100mg/kg / day) intervention to four weeks; Experiment 4 weeks before the experiment (week 0), fasting lipid levels. After 4 weeks the animal liver tissue samples using real-time RT-PCR and immunoblotting (Western Blot) determination of the liver the apoM the gene and protein expression, while using real-time RT-PCR and Western Blot determination of the liver HNF-1α and LXRa genes and protein expressed. 2 cell experiments with different concentrations of simvastatin respectively the (0,1,5,10,25 μmol / L) and fenofibrate (0,50,100 mmol / L) and simvastatin (5.0μmol / L) non- fenofibrate (50mmol / L), simvastatin (25μmol / L) of HNF-1α inhibitor, simvastatin (25μmol / L) LXRα agonist, fenofibrate (100mmol / L) HNF-1α inhibitor, The fenofibrate (100mmol / L) LXRa inhibitor intervention HepG2 cells 24h. Extract groups total cellular RNA and protein, respectively, by real-time RT-PCR and Western Blot. ApoM mRNA and protein expression. HNF-1α and LXRα gene and protein expression using real-time RT-PCR and Western Blot. The result of a change in obese mice apolipoprotein M, and explore the relationship between adiponectin. Compared with the control group, the obese group, obesity intervention body weight of mice was significantly higher than that in the control group (P lt; 0.05), obese group visceral fat weight, fasting glucose, fasting insulin, insulin resistance index (HOMA-IR) was significantly higher (P lt; 0.05); compared with the control group, the obese group, plasma adiponectin levels significantly decreased (P lt; 0.05); the obesity intervention group, blood glucose, plasma insulin, insulin resistance index was significantly lower than the obese group (P lt; 0.05), obesity intervention group, plasma adiponectin levels were significantly higher than the obese group (P lt; 0.05), obesity intervention group no statistically significant difference in visceral fat weight and obese group. 2. Comparison with the control group, the mRNA and protein expression of liver apolipoprotein M in the obese group decreased significantly (P lt; 0.05). 3 compared with control group the obese group liver the FoxA2 the mRNA and protein expression was significantly decreased (P lt; 0.05). 4. Adiponectin obesity intervention group mice apolipoprotein M mRNA and protein expression was significantly higher than that of the obese group (P lt; 0.05), of mouse apolipoprotein M mRNA adiponectin acting on ordinary intervention group and protein expression in the control group showed no significant difference (P gt; 0.05). 5 the mouse FoxA2 the obesity intervention group adiponectin mRNA and protein expression, plasma adiponectin levels were significantly higher than the obese group (P lt; 0.05); fasting glucose, fasting insulin, HOMA-IR were significantly lower than obese group (P lt; 0.05). The role of adiponectin was no significant difference in the the the ordinary intervention mice FoxA2 mRNA and protein expression and control group (P gt; 0.05). 6. Insulin resistance HepG2 cells than HepG2 cell apolipoprotein M, the FoxA2 the mRNA and protein expression were significantly decreased (P lt; 0.05). 7 after adiponectin intervention, insulin resistance HepG2 cell apolipoprotein M, FoxA2 mRNA and protein expression was significantly increased (P lt; 0.05). Adiponectin HepG2 cell apolipoprotein M, FoxA2 mRNA and protein expression was no significant change (P gt; 0.05). Apolipoprotein M in obese patients and its relationship with inflammatory factors research. Compared with the control group, the plasma of obese patients The copies of apoM, HDL-C, plasma adiponectin, FMD level was significantly lower (P lt; 0.05) fasting insulin, IL-6, TNF-α, hs-CRP levels (P lt; 0.05). Obese patients plasma apoM with HDL-C are related (P lt; 0.05), plasma apoM with BMI, insulin, insulin resistance index (HOMA-IR) of IL-6, of TNF-α, CRP levels significantly negatively correlated ( all P lt; 0.05), plasma of apoM and plasma lipid adiponectin, LDL-C, TC, of ??TG, blood pressure, blood glucose, FMD was no significant correlation (P gt; 0.05). Control group apoM with HDL-C significantly positive related (P lt; 0.05), plasma apoM with BMI significantly with negative related (P lt; 0.05), plasma apoM with insulin, insulin resistance index (HOMA-IR), of IL-6 and of TNF -α, CRP plasma adiponectin, LDL-C, TC, TG, blood pressure, blood sugar, FMD was no significant correlation (P gt; 0.05). Simvastatin and fenofibrate on apolipoprotein M expression and regulation mechanism in comparison with the control group, HDL-C of the drug treatment group were significantly higher combined group increased higher than the statin group and shellfish special group (P lt; 0.05); the apoM gene and protein of the drug treatment group were significantly higher in the combination group increased higher than the statin group and fibrate group (P lt; 0.05): cell experiments showed that simvastatin and fenofibrate dose-dependent upregulation of expression of apoM combination group increased higher than the statin group and the Bethe group (P lt; 0.05). HNF-1α inhibitor simvastatin group, the simvastatin LXRα agonist group apoM the gene and protein on average significantly lower than the same concentration of simvastatin group (P lt; 0.05); fenofibrate HNF-1α inhibitor group of apoM the genes and protein levels were significantly lower than the same concentration of fenofibrate group (P lt; 0.05), the average of fenofibrate LXRα inhibitor group apoM gene and protein was significantly higher than the same concentration in the fenofibrate group ( P lt; 0.05). 2. Compared with the control group, the HNF-1α gene and protein in the drug treatment group were significantly higher, the combined group increased higher than the statin group and fibrate group (P lt; 0.05); cells experiments showed simvastatin and fenofibrate showed a dose-dependent increase of HNF-1α gene and protein expression, the combined group increased higher than the statin group and the Bethe group (P lt; 0.05). 3 He statin group LXRα the gene and protein expression reduce (P lt; 0.05), Beit group LXRα the gene and protein expression was significantly increased (P lt; 0.05), joint group LXRα the gene and protein expression and the control group. no significant difference (P lt; 0.05); cells experiments showed simvastatin in a dose-dependent down the LXRα the gene and protein expression (P lt; 0.05), fenofibrate dose-dependent upregulation of LXRα gene and protein expression (P lt; 0.05), the joint group of the LXRα the gene and protein expression control group had no significant difference (P lt; 0.05). Conclusions obese mice apolipoprotein M FOXA2 gene and protein expression decreased apolipoprotein M decline may be reduced FOXA2 expression. Obese mice plasma adiponectin levels decreased significantly, visceral fat weight, fasting blood glucose, fasting insulin, HOMA-IR increased significantly. Adiponectin may raise obese mice apolipoprotein M expression, the mechanism may improve insulin resistance and adiponectin, and further up FOXA2 expression. Adiponectin may raise insulin resistance apolipoprotein M expression in HepG2 cells Quedui HepG2 cell apolipoprotein M expression had no effect, suggesting that adiponectin regulation of apolipoprotein M may indirectly by affecting insulin resistance 's. 5. Obese patients plasma apoM significantly reduce the ApoM and apoM reduce the level may be one of the potential mechanism of obesity HDL-C in patients with decreased. 6. Obese patients apoM levels of hs-CRP, TNF-α, IL-6 levels are closely related to the regulation of these inflammatory cytokines, apoM may be affected, the mechanism may promote insulin resistance and inflammatory factors. ApoM level of obese patients with FMD without significantly related, suggesting apoM also can not be used as early artery atherosclerosis predictors. Simvastatin and fenofibrate increased HDL-C may be related with the raised apoM expression, a combination of both a more pronounced effect. 9 mechanism with both simvastatin and fenofibrate raised apoM expression regulation HNF-1α and LXRa, the two drugs are complementary: the former raised HNF-1α suppression LXRa, latter raised the HNF-1α and LXRa, this interpretable combination therapy is better than single drug significantly increased HDL-C and The copies of apoM.

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