脂蛋白脂酶(LpL)基因敲除对小鼠betatrophin表达的影响
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摘要
目的探讨脂蛋白脂酶(LpL)基因敲除对小鼠betatrophin表达的影响。方法选择正常C57小鼠16周龄(n=6)为对照组,LPL+/-小鼠16周龄(n=6)为实验组,检测2组小鼠血清与肝脏组织中的betatrophin表达水平,同时进行皮下脂肪和内脏脂肪测定。结果实验组血清betatrophin水平显著高于对照组(P<0.05)。实验组小鼠的TC、TG、HDL-C水平显著高于对照组(P<0.05),2组LDL-C水平差异无统计学意义(P>0.05)。实验组小鼠的内脏脂肪质量与含量都高于对照组(P<0.05),2组皮下脂肪质量与含量差异无统计学意义(P>0.05)。Pearson分析显示实验组小鼠的血清与蛋白betatrophin表达水平与TG、内脏脂肪质量、内脏脂肪含量都呈正相关(P<0.05);多元线性回归分析显示TG、内脏脂肪质量为影响血清与蛋白betatrophin表达水平的独立危险因素(P<0.05)。结论 LpL基因敲除能增加小鼠血清与肝脏组织中betatrophin表达水平,从而调节机体内血脂与脂肪水平,作用通路可能与p-Akt有关,可成为一个重要的血脂代谢类调节器。
Objective To investigate the effects of lipoprotein lipase(LpL) gene knockout on the expression of betatrophin in mice.Methods Six normal C57 mice(16 weeks age) were enrolled as control group,and the 6 LPL+/-mice(16 weeks age) were enrolled as experimental group.The expression levels of betatrophin in serum and liver of mice were detected,moreover the contents of subcutaneous fat content and the contents of visceral fat were measured and compared between the two groups.Results The serum levels of betatrophin and the levels of TC,TG and HDLC in experimental group were significantly higher than those in control group(P<0.05),however, there were no significant differences in LDLC levels between the two groups(P>0.05). Moreover, the quality and contents of visceral fat in experimental group were significantly higher than those of control group(P<0.05),but there were no significant differences in the quality and contents of subcutaneous fat between the two groups(P>0.05). In addition, Pearson analysis showed that the expression levels of betatrophin in serum and protein of mice in experimental group were closely positively correlated with those of TG, visceral fat mass and visceral fat contents(P<0.05). Multiple linear regression analysis showed that TG and visceral fat mass were independent risk factors affecting the expression levels of betatrophin in serum and protein of mice(P<0.05).Conclusion LpL gene knockout in mice can increase the expression levels of betatrophin in serum and liver tissues so as to regulate the levels of blood lipid and fat in the body,and its action pathway may be related to pAkt, which can be regarded as an important regulator of lipid metabolism.
Objective To investigate the effects of lipoprotein lipase(LpL) gene knockout on the expression of betatrophin in mice.Methods Six normal C57 mice(16 weeks age) were enrolled as control group,and the 6 LPL+/-mice(16 weeks age) were enrolled as experimental group.The expression levels of betatrophin in serum and liver of mice were detected,moreover the contents of subcutaneous fat content and the contents of visceral fat were measured and compared between the two groups.Results The serum levels of betatrophin and the levels of TC,TG and HDLC in experimental group were significantly higher than those in control group(P<0.05),however, there were no significant differences in LDLC levels between the two groups(P>0.05). Moreover, the quality and contents of visceral fat in experimental group were significantly higher than those of control group(P<0.05),but there were no significant differences in the quality and contents of subcutaneous fat between the two groups(P>0.05). In addition, Pearson analysis showed that the expression levels of betatrophin in serum and protein of mice in experimental group were closely positively correlated with those of TG, visceral fat mass and visceral fat contents(P<0.05). Multiple linear regression analysis showed that TG and visceral fat mass were independent risk factors affecting the expression levels of betatrophin in serum and protein of mice(P<0.05).Conclusion LpL gene knockout in mice can increase the expression levels of betatrophin in serum and liver tissues so as to regulate the levels of blood lipid and fat in the body,and its action pathway may be related to pAkt, which can be regarded as an important regulator of lipid metabolism.
引文
1 Al-Bustan SA,Al-Serri A,Annice BG,et al.A novel LPL intronic variant:g.18704C>A identified by re-sequencing Kuwaiti Arab samples is associated with high-density lipoprotein,very low-density lipoprotein and triglyceride lipid levels.PLoS One,2018,13:e0192617.
2 Zambrano T,Hirata RDC,Hirata MH,et al.Statins differentially modulate microRNAs expression in peripheral cells of hyperlipidemic subjects:A pilot study.Eur J Pharm Sci,2018,7:55-61.
3 杨敏,于菁,马小羽,等.初诊2型糖尿病患者不同尿白蛋白阶段血清betatrophin、脂联素及白细胞介素1β水平的相关性研究.中华内分泌代谢杂志,2017,33:116-119.
4 Chang CK,Lin XR,Lin YL,et al.Magnolol-mediated regulation of plasma triglyceride through affecting lipoprotein lipase activity in apolipoprotein A5 knock-in mice.PLoS One,2018,13:e0192740.
5 Liu L,Yasen M,Tang D,et al.Polyphenol-enriched extract of Rosa rugosa Thunb regulates lipid metabolism in diabetic rats by activation of AMPK pathway.Biomed Pharmacother,2018,5:29-35.
6 Stellavato A,Pirozzi AVA,de Novellis F,et al.In vitro assessment of nutraceutical compounds and novel nutraceutical formulations in a liver-steatosis-based model.Lipids Health Dis,2018,17:24.
7 Tamura S,Koike Y,Takeda H,et al.Ameliorating effects of D-47,a newly developed compound,on lipid metabolism in an animal model of familial hypercholesterolemia (WHHLMI rabbits).Eur J Pharmacol,2018,5:147-153.
8 Kukava NG,Titov BV,Osmak GJ,et al.Multilocus Analysis of Genetic Susceptibility to Myocardial Infarction in Russians:Replication Study.Acta Naturae,2017,9:74-83.
9 Plaza A,Merino B,Cano V,et al.Cholecystokinin is involved in triglyceride fatty acid uptake by rat adipose tissue.J Endocrinol,2018,236:137-150.
10 Grzegorczyk EA,Harasim-Symbor E,Lukaszuk B,et al.Lack of pronounced changes in the expression of fatty acid handling proteins in adipose tissue and plasma of morbidly obese humans.Nutr Diabetes,2018,8:3.
11 Yamada H,Kusaka I,Saikawa R,et al.Relationship Between Angiopoietin-Like Protein 8 and Fasting Serum Triglyceride Level.J Clin Med Res,2018,10:134-136.
12 Su X,Peng DQ.New insights into ANGPLT3 in controlling lipoprotein metabolism and risk of cardiovascular diseases.Lipids Health Dis,2018,17:12.
13 Wu Y,Wang Y,Ji Y,et al.C4orf7 modulates osteogenesis and adipogenesis of human periodontal ligament cells.Am J Transl Res,2017,9:5708-5718.
14 Caddeo A,Mancina RM,Pirazzi C,et al.Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia.Nutr Metab Cardiovasc Dis,2018,28:158-164.
15 田清平,唐朝枢,刘梅林,等.冠状动脉粥样硬化性心脏病患者betatrophin水平及其与三酰甘油和糖化血红蛋白的相关性研究.中国现代医学杂志,2016,26:39-43.
16 Cedó L,Santos D,Roglans N,et al.Human hepatic lipase overexpression in mice induces hepatic steatosis and obesity through promoting hepatic lipogenesis and white adipose tissue lipolysis and fatty acid uptake.PLoS One,2017,12:e0189834.
17 Kowalska K,Olejnik A,Szwajgier D,et al.Inhibitory activity of chokeberry,bilberry,raspberry and cranberry polyphenol-rich extract towards adipogenesis and oxidative stress in differentiated 3T3-L1 adipose cells.PLoS One,2017,12:e0188583.
18 Muraba Y,Koga T,Shimomura Y,et al.The role of plasma lipoprotein lipase,hepatic lipase and GPIHBP1 in the metabolism of remnant lipoproteins and small dense LDL in patients with coronary artery disease.Clin Chim Acta,2018,1:146-153.
19 Shatwan IM,Weech M,Jackson KG,et al.Apolipoprotein E gene polymorphism modifies fasting total cholesterol concentrations in response to replacement of dietary saturated with monounsaturated fatty acids in adults at moderate cardiovascular disease risk.Lipids Health Dis,2017,16:222.
20 杨敏,王秋月.betatrophin与2型糖尿病患者胰岛素抵抗及脂代谢的关系.医学综述,2016,22:2585-2589.
21 Müller C,Hardt M,Schwudke D,et al.Inhibition of Cytosolic Phospholipase A(2)α Impairs an Early Step of Coronavirus Replication in Cell Culture.J Virol,2018,92:e01463-17.
22 Huang H,Zhang Y,Cao M,et al.Effects of fasting on the activities and mRNA expression levels of lipoprotein lipase (LPL),hormone-sensitive lipase (HSL) and fatty acid synthetase (FAS) in spotted seabass Lateolabrax maculatus.Fish Physiol Biochem,2018,44:387-400.
23 Siddiqa A,Cirillo E,Tareen SHK,et al.Visualizing the regulatory role of Angiopoietin-like protein 8 (ANGPTL8) in glucose and lipid metabolic pathways.Genomics,2017,109:408-418.
24 Siddiqa A,Ahmad J,Ali A,et al.Structural characterization of ANGPTL8 (betatrophin) with its interacting partner lipoprotein lipase.Comput Biol Chem,2016,4:210-220.
25 薛灏颖,洪霞飞,王苏,等.2型糖尿病患者血清betatrophin水平与尿白蛋白肌酐比的相关性研究.医学研究生学报,2017,30:389-393.
26 Xu J,Lin Y,Zhou H,et al.The Correlation Between Circulating betatrophin and Insulin Resistance in General Population:A Meta-Analysis.Horm Metab Res,2017,49:760-771.
27 洪霞飞,薛灏颖,王苏,等.短期胰岛素泵强化治疗对初诊2型糖尿病患者血清 betatrophin 的影响.江苏大学学报(医学版),2016,26:504-509.
28 Takebayashi K,Hara K,Terasawa T,et al.Serum betatrophin Levels and Clinical Features in Patients With Poorly Controlled Type 2 Diabetes.J Clin Med Res,2017,9:782-787.
29 Lu P,Chen X,Zhang Z,et al.Insulin upregulates betatrophin expression via PI3K/Akt pathway.Sci Rep,2017,7:5594.
30 翟志红,王忠,李小雷,等.血清 betatrophin 水平与冠状动脉粥样硬化性心脏病的关系.山东医药,2016,56:53-54.
31 Adamska A,Lebkowska A,Jacewicz M,et al.Serum concentrations of betatrophin and its association with indirect indices of insulin resistance and beta cell function in women with polycystic ovary syndrome.Int J Endocrinol,2017,20:2316986.
32 易敏,陈容平,杨锐,等.betatrophin的血脂调节作用.中华糖尿病杂志,2015,7:652-654.
33 Wang Y,Quagliarini F,Gusarova V,et al.Mice lacking ANGPTL8 (betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis.Proc Natl Acad Sci U S A,2013,110:16109-16114.
2 Zambrano T,Hirata RDC,Hirata MH,et al.Statins differentially modulate microRNAs expression in peripheral cells of hyperlipidemic subjects:A pilot study.Eur J Pharm Sci,2018,7:55-61.
3 杨敏,于菁,马小羽,等.初诊2型糖尿病患者不同尿白蛋白阶段血清betatrophin、脂联素及白细胞介素1β水平的相关性研究.中华内分泌代谢杂志,2017,33:116-119.
4 Chang CK,Lin XR,Lin YL,et al.Magnolol-mediated regulation of plasma triglyceride through affecting lipoprotein lipase activity in apolipoprotein A5 knock-in mice.PLoS One,2018,13:e0192740.
5 Liu L,Yasen M,Tang D,et al.Polyphenol-enriched extract of Rosa rugosa Thunb regulates lipid metabolism in diabetic rats by activation of AMPK pathway.Biomed Pharmacother,2018,5:29-35.
6 Stellavato A,Pirozzi AVA,de Novellis F,et al.In vitro assessment of nutraceutical compounds and novel nutraceutical formulations in a liver-steatosis-based model.Lipids Health Dis,2018,17:24.
7 Tamura S,Koike Y,Takeda H,et al.Ameliorating effects of D-47,a newly developed compound,on lipid metabolism in an animal model of familial hypercholesterolemia (WHHLMI rabbits).Eur J Pharmacol,2018,5:147-153.
8 Kukava NG,Titov BV,Osmak GJ,et al.Multilocus Analysis of Genetic Susceptibility to Myocardial Infarction in Russians:Replication Study.Acta Naturae,2017,9:74-83.
9 Plaza A,Merino B,Cano V,et al.Cholecystokinin is involved in triglyceride fatty acid uptake by rat adipose tissue.J Endocrinol,2018,236:137-150.
10 Grzegorczyk EA,Harasim-Symbor E,Lukaszuk B,et al.Lack of pronounced changes in the expression of fatty acid handling proteins in adipose tissue and plasma of morbidly obese humans.Nutr Diabetes,2018,8:3.
11 Yamada H,Kusaka I,Saikawa R,et al.Relationship Between Angiopoietin-Like Protein 8 and Fasting Serum Triglyceride Level.J Clin Med Res,2018,10:134-136.
12 Su X,Peng DQ.New insights into ANGPLT3 in controlling lipoprotein metabolism and risk of cardiovascular diseases.Lipids Health Dis,2018,17:12.
13 Wu Y,Wang Y,Ji Y,et al.C4orf7 modulates osteogenesis and adipogenesis of human periodontal ligament cells.Am J Transl Res,2017,9:5708-5718.
14 Caddeo A,Mancina RM,Pirazzi C,et al.Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia.Nutr Metab Cardiovasc Dis,2018,28:158-164.
15 田清平,唐朝枢,刘梅林,等.冠状动脉粥样硬化性心脏病患者betatrophin水平及其与三酰甘油和糖化血红蛋白的相关性研究.中国现代医学杂志,2016,26:39-43.
16 Cedó L,Santos D,Roglans N,et al.Human hepatic lipase overexpression in mice induces hepatic steatosis and obesity through promoting hepatic lipogenesis and white adipose tissue lipolysis and fatty acid uptake.PLoS One,2017,12:e0189834.
17 Kowalska K,Olejnik A,Szwajgier D,et al.Inhibitory activity of chokeberry,bilberry,raspberry and cranberry polyphenol-rich extract towards adipogenesis and oxidative stress in differentiated 3T3-L1 adipose cells.PLoS One,2017,12:e0188583.
18 Muraba Y,Koga T,Shimomura Y,et al.The role of plasma lipoprotein lipase,hepatic lipase and GPIHBP1 in the metabolism of remnant lipoproteins and small dense LDL in patients with coronary artery disease.Clin Chim Acta,2018,1:146-153.
19 Shatwan IM,Weech M,Jackson KG,et al.Apolipoprotein E gene polymorphism modifies fasting total cholesterol concentrations in response to replacement of dietary saturated with monounsaturated fatty acids in adults at moderate cardiovascular disease risk.Lipids Health Dis,2017,16:222.
20 杨敏,王秋月.betatrophin与2型糖尿病患者胰岛素抵抗及脂代谢的关系.医学综述,2016,22:2585-2589.
21 Müller C,Hardt M,Schwudke D,et al.Inhibition of Cytosolic Phospholipase A(2)α Impairs an Early Step of Coronavirus Replication in Cell Culture.J Virol,2018,92:e01463-17.
22 Huang H,Zhang Y,Cao M,et al.Effects of fasting on the activities and mRNA expression levels of lipoprotein lipase (LPL),hormone-sensitive lipase (HSL) and fatty acid synthetase (FAS) in spotted seabass Lateolabrax maculatus.Fish Physiol Biochem,2018,44:387-400.
23 Siddiqa A,Cirillo E,Tareen SHK,et al.Visualizing the regulatory role of Angiopoietin-like protein 8 (ANGPTL8) in glucose and lipid metabolic pathways.Genomics,2017,109:408-418.
24 Siddiqa A,Ahmad J,Ali A,et al.Structural characterization of ANGPTL8 (betatrophin) with its interacting partner lipoprotein lipase.Comput Biol Chem,2016,4:210-220.
25 薛灏颖,洪霞飞,王苏,等.2型糖尿病患者血清betatrophin水平与尿白蛋白肌酐比的相关性研究.医学研究生学报,2017,30:389-393.
26 Xu J,Lin Y,Zhou H,et al.The Correlation Between Circulating betatrophin and Insulin Resistance in General Population:A Meta-Analysis.Horm Metab Res,2017,49:760-771.
27 洪霞飞,薛灏颖,王苏,等.短期胰岛素泵强化治疗对初诊2型糖尿病患者血清 betatrophin 的影响.江苏大学学报(医学版),2016,26:504-509.
28 Takebayashi K,Hara K,Terasawa T,et al.Serum betatrophin Levels and Clinical Features in Patients With Poorly Controlled Type 2 Diabetes.J Clin Med Res,2017,9:782-787.
29 Lu P,Chen X,Zhang Z,et al.Insulin upregulates betatrophin expression via PI3K/Akt pathway.Sci Rep,2017,7:5594.
30 翟志红,王忠,李小雷,等.血清 betatrophin 水平与冠状动脉粥样硬化性心脏病的关系.山东医药,2016,56:53-54.
31 Adamska A,Lebkowska A,Jacewicz M,et al.Serum concentrations of betatrophin and its association with indirect indices of insulin resistance and beta cell function in women with polycystic ovary syndrome.Int J Endocrinol,2017,20:2316986.
32 易敏,陈容平,杨锐,等.betatrophin的血脂调节作用.中华糖尿病杂志,2015,7:652-654.
33 Wang Y,Quagliarini F,Gusarova V,et al.Mice lacking ANGPTL8 (betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis.Proc Natl Acad Sci U S A,2013,110:16109-16114.
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