低氧诱导因子1α在高脂饮食诱导肥胖小鼠前列腺组织中的表达
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摘要
目的:观察低氧诱导因子1α(HIF-1α)在高脂饮食诱导C57BL/6J小鼠前列腺组织中的表达,以探讨缺氧对肥胖小鼠前列腺增生的作用。方法:将20只小鼠随机分为对照组(普通饮食)和高脂饮食组,各10只。高脂饮食组高脂饮食干预17周,测量小鼠体重,解剖取材测量前列腺重量,排水法测量前列腺体积,ELISA法检测血清甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、游离脂肪酸(FFA)的含量;HE染色观察前列腺组织形态并测量其腺腔面积,免疫组化检测前列腺组织HIF-1α的表达。结果:①高脂饮食组小鼠体重为(42.55±3.01) g、前列腺重量(0.13±0.03)g、前列腺体积(0.14±0.03)ml、TG(179.29±65.19) mmol/L、LDL(66.88±1.93)g/L,均显著高于对照组[(28.94±2.17) g、(0.05±0.03) g、(0.05±0.02) ml、(115.77±25.25) mmol/L,(44.16±7.24)g/L](P<0.01或<0.05)。②组织病理学结果显示,对照组小鼠前列腺上皮表现为单层立方上皮和单层柱状上皮,高脂饮食组则主要表现为不规则上皮结构;高脂饮食组小鼠前列腺腺腔面积显著大于对照组[(18 453±7 311)μm~2vs(12 390±8 587)μm~2,P<0.01]。③高脂饮食组前列腺组织HIF-1α积分光密度值明显高于对照组[(9.1±6.9)×10~6vs(2.0±3.6)×10~6,P<0.01]。④相关性分析表明,前列腺体积与体脂肪重量(r=0.887,P<0.01)、TG(r=0. 520,P=0.047)、LDL(r=0.772,P=0.010)呈正相关。结论:肥胖小鼠脂代谢异常使前列腺组织出现局部低氧从而引发BPH。
Objective: To investigate the expression of hypoxia-inducible factor-1α(HIF-1α) in the prostatic tissue of mice with high-fat diet-induced obesity and to explore the effect of hypoxia on BPH in obese male mice. Methods: We randomly divided 20 C57 BL/6 J male mice into two groups of equal number and fed them on a high-fat diet(HFD group) or a normal diet(control group) for 17 weeks. Then, we measured the body weight, prostate weight, prostate volume and levels of serum triglycerides(TG), high-density lipoprotein(HDL), low-density lipoprotein(LDL) and free fatty acids(FFA) by ELISA, observed the morphology of the prostate by HE staining, calculated the area of the prostatic glandular cavity, and determined the expression of HIF-1α in the prostatic tissue by immunohistochemistry. Results: Compared with the controls, the mice fed on the HFD showed significant increases in the body weight([28.94 ± 2.17] vs [42.55 ± 3.01] g, P < 0.01), prostate weight([0.05 ± 0.03] vs [0.13 ± 0.03] g, P < 0.01), prostate volume([0.05 ± 0.02] vs [0.14 ± 0.03] ml, P < 0.01), and the levels of TG([115.77 ± 25.25] vs [179.29 ± 65.19] mmol/L, P = 0.022), HDL([67.14 ± 3.10] vs [72.84 ± 1.91] g/L, P < 0.01) and LDL([44.16 ± 7.24] vs [66.88 ± 1.93] g/L, P < 0.01) at 17 weeks. Histopathological examination exhibited single-layer cuboidal or columnar prostatic epithelium in the controls but an irregular epithelial structure and a larger area of the prostatic glandular cavity in the HFD group([12 390 ± 8 587] vs [18 453 ± 7 311] μm~2, P < 0.01). The integrated optical density(IOD) of HIF-1α was markedly higher in the HFD group([9.1 ± 6.9] × 10~6) than in the control([2.0 ± 3.6] ×10~6)(P < 0.01). The prostate volume was positively correlated with the body fat weight(r = 0.887, P = 0.01), TG(r = 0.520, P = 0.047) and LDL(r = 0.772, P = 0.010). Conclusion: Abnormal lipid metabolism may induce local hypoxia in the prostate tissue and lead to BPH in obese mice. Natl J Androl, 2019, 25(6): 483-488
Objective: To investigate the expression of hypoxia-inducible factor-1α(HIF-1α) in the prostatic tissue of mice with high-fat diet-induced obesity and to explore the effect of hypoxia on BPH in obese male mice. Methods: We randomly divided 20 C57 BL/6 J male mice into two groups of equal number and fed them on a high-fat diet(HFD group) or a normal diet(control group) for 17 weeks. Then, we measured the body weight, prostate weight, prostate volume and levels of serum triglycerides(TG), high-density lipoprotein(HDL), low-density lipoprotein(LDL) and free fatty acids(FFA) by ELISA, observed the morphology of the prostate by HE staining, calculated the area of the prostatic glandular cavity, and determined the expression of HIF-1α in the prostatic tissue by immunohistochemistry. Results: Compared with the controls, the mice fed on the HFD showed significant increases in the body weight([28.94 ± 2.17] vs [42.55 ± 3.01] g, P < 0.01), prostate weight([0.05 ± 0.03] vs [0.13 ± 0.03] g, P < 0.01), prostate volume([0.05 ± 0.02] vs [0.14 ± 0.03] ml, P < 0.01), and the levels of TG([115.77 ± 25.25] vs [179.29 ± 65.19] mmol/L, P = 0.022), HDL([67.14 ± 3.10] vs [72.84 ± 1.91] g/L, P < 0.01) and LDL([44.16 ± 7.24] vs [66.88 ± 1.93] g/L, P < 0.01) at 17 weeks. Histopathological examination exhibited single-layer cuboidal or columnar prostatic epithelium in the controls but an irregular epithelial structure and a larger area of the prostatic glandular cavity in the HFD group([12 390 ± 8 587] vs [18 453 ± 7 311] μm~2, P < 0.01). The integrated optical density(IOD) of HIF-1α was markedly higher in the HFD group([9.1 ± 6.9] × 10~6) than in the control([2.0 ± 3.6] ×10~6)(P < 0.01). The prostate volume was positively correlated with the body fat weight(r = 0.887, P = 0.01), TG(r = 0.520, P = 0.047) and LDL(r = 0.772, P = 0.010). Conclusion: Abnormal lipid metabolism may induce local hypoxia in the prostate tissue and lead to BPH in obese mice. Natl J Androl, 2019, 25(6): 483-488
引文
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[14] Vikram A,Jena GB,Ramarao P.Increased cell proliferation and contractility of prostate in insulin resistant rats:Linking hyperinsulinemia with benign prostate hyperplasia.Prostate,2010,70(1):79-89.
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[17] 王国增,杨望萍,张爱华.乌鲁木齐地区汉族和维吾尔族人群中前列腺增生患病情况比较.实用老年医学,2000,14(3):160.
[18] Ribeiro R,Monteiro C,Catalán V,et al.Obesity and prostate cancer:Gene expression signature of human periprostatic adipose tissue.BMC Med,2012,10:108.
[19] Rahman NU,Phonsombat S,Bochinski D,et al.An animal model to study lower urinary tract symptoms and erectile dysfunction:The hyperlipidaemic rat.BJU Int,2007,100(3):658-663.
[20] Nandeesha H,Koner BC,Dorairajan LN,et al.Hyperinsulinemia and dyslipidemia in non-diabetic benign prostatic hyperplasia.Clin Chim Acta,2006,370(1-2):89-93.
[21] Bergers G,Hanahan D.Modes of resistance to anti-angiogenic therapy.Nat Rev Cancer,2008,8(8):592-603.
[22] Berger AP,Horninger W,Bektic J,et al.Vascular resistance in the prostate evaluated by colour Doppler ultrasonography:Is benign prostatic hyperplasia a vascular disease?BJU Int,2006,98(3):587-590.
[23] Kim JW,Tchernyshyov I,Semenza GL,et al.HIF-1-mediated expression of pyruvate dehydrogenase kinase:A metabolic switch required for cellular adaptation to hypoxia.Cell Metab,2006,3(3):177-185.
[24] 鲍永霞,吕福祯,马迎军.低氧对小鼠低氧诱导因子-1α和血管内皮生长因子表达的影响.中国实用内科杂志,2006,26(14):1066-1068.
[25] Doerks T,Copley RR,Schultz J,et al.Systematic identification of novel protein domain families associated with nuclear functions.Genome Res,2002,12(1):47-56.
[26] Li SH,Ryu JH,Park SE,et al.Vitamin C supplementation prevents testosterone-induced hyperplasia of rat prostate by down-regulating HIF-1alpha.J Nutr Biochem,2010,21(9):801-808.
[27] Rudolfsson SH,Bergh A.Testosterone-stimulated growth of the rat prostate may be driven by tissue hypoxia and hypoxia-inducible factor-1alpha.J Endocrinol,2008,196(1):11-19.
[2] 杨丽睿,张慧敏.肥胖高血压发病机制研究现状.心血管病学进展,2013,34(2):182-185.
[3] Hosogai N,Fukuhara A,Oshima K,et al.Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation.Diabetes,2007,56(4):901-911.
[4] West JB.Physiological effects of chronic hypoxia.N Engl J Med,2017,376(20):1965-1971.
[5] Shih HJ,Huang CJ,Lin JA,et al.Hyperlipidemia is associated with an increased risk of clinical benign prostatic hyperplasia.Prostate,2018,78(2):113-120.
[6] 甘发连,朱璞太,祁生福.血糖、血脂代谢与良性前列腺增生相关性分析.中国医学前沿杂志(电子版),2014,6(11):77-79.
[7] 王毅,邵继春,张蜀武.雄激素致去势大鼠前列腺增生的组织形态学研究.中华男科学,2002,8(3):190-193.
[8] Chandler PC,Viana JB,Oswald KD,et al.Feeding response to melanocortin agonist predicts preference for and obesity from a high-fat diet.Physiol Behav,2005,85(2):221-230.
[9] 胡晓东,李鸿炎.饮食诱导小鼠肥胖疾病模型的建立.南昌大学学报(医学版),2012,52(8):6-9.
[10] 于金慧,王瑜,彭振英,等.裂壶藻油 DHA 对高脂饮食诱导肥胖小鼠的影响.微生物学通报,2017,44(11):2679-2688.
[11] 张祥华,王行环,王刚,等.良性前列腺增生诊断治疗指南(2006年试行版).贵州:贵州省医学会泌尿外科分会2006年学术年会,2006.
[12] Ozden C,Ozdal OL,Urgancioglu G,et al.The correlation between metabolic syndrome and prostatic growth in patients with benign prostatic hyperplasia.Eur Urol,2007,51(1):199-203.
[13] Jung JH,Ahn SV,Song JM,et al.Obesity as a risk factor for prostatic enlargement:A retrospective cohort study in Korea.Int Neurourol J,2016,20(4):321-328.
[14] Vikram A,Jena GB,Ramarao P.Increased cell proliferation and contractility of prostate in insulin resistant rats:Linking hyperinsulinemia with benign prostate hyperplasia.Prostate,2010,70(1):79-89.
[15] Parsons JK,Sarma AV,McVary K,et al.Obesity and benign prostatic hyperplasia:Clinical connections,emerging etiological paradigms and future directions.J Urol,2013,189(1 Suppl):S102-S106.
[16] DiBello JR,Ioannou C,Rees J,et al.Prevalence of metabolic syndrome and its components among men with and without clinical benign prostatic hyperplasia:A large,cross-sectional,UK epidemiological study.BJU Int,2016,117(5):801-808.
[17] 王国增,杨望萍,张爱华.乌鲁木齐地区汉族和维吾尔族人群中前列腺增生患病情况比较.实用老年医学,2000,14(3):160.
[18] Ribeiro R,Monteiro C,Catalán V,et al.Obesity and prostate cancer:Gene expression signature of human periprostatic adipose tissue.BMC Med,2012,10:108.
[19] Rahman NU,Phonsombat S,Bochinski D,et al.An animal model to study lower urinary tract symptoms and erectile dysfunction:The hyperlipidaemic rat.BJU Int,2007,100(3):658-663.
[20] Nandeesha H,Koner BC,Dorairajan LN,et al.Hyperinsulinemia and dyslipidemia in non-diabetic benign prostatic hyperplasia.Clin Chim Acta,2006,370(1-2):89-93.
[21] Bergers G,Hanahan D.Modes of resistance to anti-angiogenic therapy.Nat Rev Cancer,2008,8(8):592-603.
[22] Berger AP,Horninger W,Bektic J,et al.Vascular resistance in the prostate evaluated by colour Doppler ultrasonography:Is benign prostatic hyperplasia a vascular disease?BJU Int,2006,98(3):587-590.
[23] Kim JW,Tchernyshyov I,Semenza GL,et al.HIF-1-mediated expression of pyruvate dehydrogenase kinase:A metabolic switch required for cellular adaptation to hypoxia.Cell Metab,2006,3(3):177-185.
[24] 鲍永霞,吕福祯,马迎军.低氧对小鼠低氧诱导因子-1α和血管内皮生长因子表达的影响.中国实用内科杂志,2006,26(14):1066-1068.
[25] Doerks T,Copley RR,Schultz J,et al.Systematic identification of novel protein domain families associated with nuclear functions.Genome Res,2002,12(1):47-56.
[26] Li SH,Ryu JH,Park SE,et al.Vitamin C supplementation prevents testosterone-induced hyperplasia of rat prostate by down-regulating HIF-1alpha.J Nutr Biochem,2010,21(9):801-808.
[27] Rudolfsson SH,Bergh A.Testosterone-stimulated growth of the rat prostate may be driven by tissue hypoxia and hypoxia-inducible factor-1alpha.J Endocrinol,2008,196(1):11-19.
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