成纤维细胞生长因子21对糖脂代谢调控的研究进展

成纤维细胞生长因子21(FGF21)是成纤维细胞生长因子(FGF)家族中的一员。由于它在改善能量代谢方面的积极作用,近年来获得了广泛的关注。FGF21可作用于多个组织参与调控糖脂代谢:减轻体重,改善肥胖、糖尿病等病理情况下的高血糖及高血脂;此外,FGF21在调节饥饿等特殊生理状态的能量代谢中也起着重要的作用。本文就FGF21调控糖脂代谢的研究进展作一综述,以便更好地理解其作用机制,为慢性代谢性疾病的防治提供依据。     

Dual Effect of Phosphate Transport on Mitochondrial Ca2+ Dynamics

The large inner membrane electrochemical driving force and restricted volume of the matrix confer unique constraints on mitochondrial ion transport. Cation uptake along with anion and water movement induces swelling if not compensated by other processes. For mitochondrial Ca²⁺ uptake, these include activation of countertransporters (Na⁺/Ca²⁺ exchanger and Na⁺/H⁺ exchanger) coupled to the proton gradient, ultimately maintained by the proton pumps of the respiratory chain, and Ca²⁺ binding to matrix buffers. Inorganic phosphate (P_i) is known to affect both the Ca²⁺ uptake rate and the buffering reaction, but the role of anion transport in determining mitochondrial Ca²⁺ dynamics is poorly understood. Here we simultaneously monitor extra- and intra-mitochondrial Ca²⁺ and mitochondrial membrane potential (ΔΨ_m) to examine the effects of anion transport on mitochondrial Ca²⁺ flux and buffering in P_i-depleted guinea pig cardiac mitochondria. Mitochondrial Ca²⁺ uptake proceeded slowly in the absence of P_i but matrix free Ca²⁺ ([Ca²⁺]_mito) still rose to ∼50 μm. P_i (0.001–1 mm) accelerated Ca²⁺ uptake but decreased [Ca²⁺]_mito by almost 50% while restoring ΔΨ_m. P_i-dependent effects on Ca²⁺ were blocked by inhibiting the phosphate carrier. Mitochondrial Ca²⁺ uptake rate was also increased by vanadate (V_i), acetate, ATP, or a non-hydrolyzable ATP analog (AMP-PNP), with differential effects on matrix Ca²⁺ buffering and ΔΨ_m recovery. Interestingly, ATP or AMP-PNP prevented the effects of P_i on Ca²⁺ uptake. The results show that anion transport imposes an upper limit on mitochondrial Ca²⁺ uptake and modifies the [Ca²⁺]_mito response in a complex manner.     

The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase

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Metabolic adaptation to the chronic loss of Ca2+ signaling induced by KO of IP3 receptors or the mitochondrial Ca2+ uniporter

Calcium signaling is essential for regulating many biological processes. Endoplasmic reticulum inositol trisphosphate receptors (IP₃Rs) and the mitochondrial Ca²⁺ uniporter (MCU) are key proteins that regulate intracellular Ca²⁺ concentration. Mitochondrial Ca²⁺ accumulation activates Ca²⁺-sensitive dehydrogenases of the tricarboxylic acid (TCA) cycle that maintain the biosynthetic and bioenergetic needs of both normal and cancer cells. However, the interplay between calcium signaling and metabolism is not well understood. In this study, we used human cancer cell lines (HEK293 and HeLa) with stable KOs of all three IP₃R isoforms (triple KO [TKO]) or MCU to examine metabolic and bioenergetic responses to the chronic loss of cytosolic and/or mitochondrial Ca²⁺ signaling. Our results show that TKO cells (exhibiting total loss of Ca²⁺ signaling) are viable, displaying a lower proliferation and oxygen consumption rate, with no significant changes in ATP levels, even when made to rely solely on the TCA cycle for energy production. MCU KO cells also maintained normal ATP levels but showed increased proliferation, oxygen consumption, and metabolism of both glucose and glutamine. However, MCU KO cells were unable to maintain ATP levels and died when relying solely on the TCA cycle for energy. We conclude that constitutive Ca²⁺ signaling is dispensable for the bioenergetic needs of both IP₃R TKO and MCU KO human cancer cells, likely because of adequate basal glycolytic and TCA cycle flux. However, in MCU KO cells, the higher energy expenditure associated with increased proliferation and oxygen consumption makes these cells more prone to bioenergetic failure under conditions of metabolic stress.     

A Novel Phosphorylated Lipid Counteracts Activation of the Renal Plasma Membrane (Ca2+ + Mg2+)ATPase by Endogenous Phosphatidylinositol-4-Phosphate

The plasma membrane (Ca²⁺ + Mg²⁺)ATPase is activated by acidic phospholipids in reconstituted systems. In this report it is shown that reversible phosphorylation of endogenous phosphatidylinositol regulates the renal plasma membrane (Ca²⁺ + Mg²⁺)ATPase, and that a novel phosphorylated lipid that can be isolated from the same membrane strongly counteracts the stimulatory effect of phosphatidylinositol-4-phosphate.     

Molecular Tuning of the Axonal Mitochondrial Ca2+ Uniporter Ensures Metabolic Flexibility of Neurotransmission

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利拉鲁肽联合二甲双胍对肥胖2型糖尿病患者糖脂代谢、血管内皮功能及微炎症状态的影响

目的:探讨利拉鲁肽联合二甲双胍对肥胖2型糖尿病(T2DM)患者糖脂代谢、血管内皮功能及微炎症状态的影响.方法:选取2016年7月～2019年4月期间我院收治的117例T2DM肥胖患者.根据随机数字表法分为对照组(n=58,二甲双胍治疗)和研究组(n=59,利拉鲁肽联合二甲双胍治疗),比较两组患者体质量指数(BMI)、糖...     

茵陈五苓散联合利拉鲁肽对肥胖型2型糖尿病患者糖脂代谢、胰岛素敏感性和氧化应激的影响

摘要 目的：探讨茵陈五苓散联合利拉鲁肽对肥胖型2型糖尿病（T2DM）患者糖脂代谢、胰岛素敏感性和氧化应激的影响。方法：选取2021年12月~2022年12月期间广州中医药大学附属佛山中医院收治的160例痰湿内蕴型肥胖T2DM患者。根据随机数字表法将患者分为对照组（利拉鲁肽治疗,80例）和研究组（茵陈五苓散联合利拉鲁肽治疗,80例）。对比两组疗效、糖脂代谢指标、肥胖相关指标、胰岛素敏感性、氧化应激和不良反应发生情况。结果：与对照组相比,研究组的临床总有效率更高（P<0.05）。研究组治疗后体质量指数（BMI）、空腹血糖（FBG）、腰臀比（WHR）、餐后2 h血糖（2hPG）、丙二醛（MDA）、糖化血红蛋白（HbAlc）、稳态模型胰岛素抵抗指数（HOMA-IR）、总胆固醇（TC）、黄嘌呤氧化酶（XO）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）较对照组低（P<0.05）。治疗后研究组稳态模型胰岛β细胞功能指数（HOMA-β）、高密度脂蛋白胆固醇（HDL-C）、超氧化物歧化酶（SOD）高于对照组（P<0.05）。两组不良反应发生率组间对比未见差异（P>0.05）。结论：茵陈五苓散联合利拉鲁肽治疗肥胖型T2DM患者疗效确切,可调节糖脂代谢水平,降低胰岛素敏感性,减轻氧化应激,且具有一定安全性,值得临床借鉴应用。     

Ca2+ Binding/Permeation via Calcium Channel,CaV1.1, Regulates the Intracellular Distribution of the Fatty Acid Transport Protein,CD36, and Fatty Acid Metabolism

Ca²⁺ permeation and/or binding to the skeletal muscle L-type Ca²⁺ channel (Ca_V1.1) facilitates activation of Ca²⁺/calmodulin kinase type II (CaMKII) and Ca²⁺ store refilling to reduce muscle fatigue and atrophy (Lee, C. S., Dagnino-Acosta, A., Yarotskyy, V., Hanna, A., Lyfenko, A., Knoblauch, M., Georgiou, D. K., Poché, R. A., Swank, M. W., Long, C., Ismailov, I. I., Lanner, J., Tran, T., Dong, K., Rodney, G. G., Dickinson, M. E., Beeton, C., Zhang, P., Dirksen, R. T., and Hamilton, S. L. (2015) Skelet. Muscle 5, 4). Mice with a mutation (E1014K) in the Cacna1s (α₁ subunit of Ca_V1.1) gene that abolishes Ca²⁺ binding within the Ca_V1.1 pore gain more body weight and fat on a chow diet than control mice, without changes in food intake or activity, suggesting that Ca_V1.1-mediated CaMKII activation impacts muscle energy expenditure. We delineate a pathway (Ca_v1.1→ CaMKII→ NOS) in normal skeletal muscle that regulates the intracellular distribution of the fatty acid transport protein, CD36, altering fatty acid metabolism. The consequences of blocking this pathway are decreased mitochondrial β-oxidation and decreased energy expenditure. This study delineates a previously uncharacterized Ca_V1.1-mediated pathway that regulates energy utilization in skeletal muscle.     

新诊断2型糖尿病患者血清Pannexin-1、Apelin、RBP4、VEGF水平与糖脂代谢和胰岛素抵抗的关系研究

摘要 目的：探讨新诊断2型糖尿病患者血清缝隙连接蛋白-1(Pannexin-1)、爱帕琳肽（Apelin）、视黄醇结合蛋白4(RBP4)、血管内皮生长因子（VEGF）水平与糖脂代谢和胰岛素抵抗的关系。方法：选择2018年2月至2020年2月我院诊治的120例新诊断2型糖尿病患者作为糖尿病组,选择同期在我院进行体检的120例健康者作为对照组。检测所有受试者甘油三酯（TG）、总胆固醇（TC）、谷草转氨酶（AST）、谷丙转氨酶(ALT)、高密度脂蛋白（HDL）和低密度脂蛋白（LDL）水平、空腹血糖（FPG）、空腹胰岛素(FINS)、Pannexin-1、Apelin、RBP4、VEGF水平,计算胰岛素抵抗指数(HOMA-IR)、胰岛素敏感性指数（ISI）和胰岛?茁细胞功能指数(HOMA-β)。分析Pannexin-1、Apelin、RBP4、VEGF水平与糖脂代谢和胰岛素抵抗相关指标的关系,分析影响上述指标表达的相关因素。结果：与对照组相比,糖尿病组体质量指数（BMI）、TG、TC、FPG、FINS、Pannexin-1、Apelin、RBP4、VEGF水平,HOMA-IR明显升高（P<0.05）,ISI和HOMA-β明显下降（P<0.05）。新诊断2型糖尿病患者血清Pannexin-1、Apelin、RBP4、VEGF水平与ISI和HOMA-β均呈负相关（P<0.05）,与BMI、TG、TC、FPG、FINS、HOMA-IR均呈正相关（P<0.05）。TG与Pannexin-1表达联系密切（β=0.006,P<0.05）,ISI和HOMA-IR与Apelin表达联系密切（β=-6.673、0.049,P<0.05）,FPG和TC与RBP4表达联系密切（β=22.309、0.506,P<0.05）,HOMA-IR与VEGF表达联系密切（β=0.574,P<0.05）。结论：新诊断2型糖尿病患者血清Pannexin-1、Apelin、RBP4、VEGF水平异常升高,并参与新诊断2型糖尿病患者的糖脂代谢和胰岛素抵抗,在2型糖尿病的诊断和预防中有一定临床价值。     

八段锦联合抗阻运动对老年2型糖尿病患者糖脂代谢、氧化应激及生活质量的影响

摘要 目的：探讨八段锦联合抗阻运动对老年2型糖尿病（T2DM）患者糖脂代谢、氧化应激及生活质量的影响。方法：选取2021年4月~2022年5月期间在我院接受治疗的老年T2DM患者238例。按照随机数字表法分为对照组（在常规治疗的基础上,接受抗阻运动干预,119例）和联合组（在对照组的基础上,接受八段锦干预,119例）。观察两组糖脂代谢、氧化应激及生活质量的改善情况。结果：干预12周后,联合组体质量指数、腰臀比低于对照组（P<0.05）。干预12周后,联合组空腹血糖（FBG）、餐后2 h血糖（2hPG）、糖化血红蛋白（HbAlc）低于对照组（P<0.05）。干预12周后,联合组高密度脂蛋白胆固醇（HDL-C）高于对照组（P<0.05）,低密度脂蛋白胆固醇（LDL-C）、总胆固醇（TC）、甘油三酯（TG）低于对照组。干预12周后,联合组丙二醛（MDA）低于对照组,超氧化物歧化酶（SOD）、过氧化氢酶（CAT）高于对照组（P<0.05）。干预12周后,联合组的健康调查简表（SF-36）各维度评分均高于对照组（P<0.05）。结论：八段锦联合抗阻运动用于老年T2DM患者中,可有效改善患者的氧化应激、糖脂代谢,并提高患者的生活质量。     

Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress

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间歇性θ脉冲刺激联合有氧运动训练对老年2型糖尿病合并轻度认知功能障碍患者糖脂代谢、认知功能和听觉诱发电位P300的影响

摘要 目的：探讨间歇性θ脉冲刺激（iTBS）联合有氧运动训练对老年2型糖尿病（T2DM）合并轻度认知功能障碍（MCI）患者糖脂代谢、认知功能和听觉诱发电位P300的影响。方法：选取2020年3月~2021年11月期间来我院接受治疗的老年T2DM合并MCI患者117例。按照随机数字表法分为对照组（有氧运动训练,58例）和观察组（iTBS联合有氧运动训练,59例）。观察两组干预前后糖脂代谢、认知功能和听觉诱发电位P300的变化情况。结果：观察组干预后空腹血糖（FBG）、糖化血红蛋白（HbA1c）低于对照组（P<0.05）。两组干预后总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）组间对比,统计学无差异（P>0.05）。观察组干预后蒙特利尔量表（MoCA）各维度及总分高于对照组（P<0.05）。观察组干预后中央区（Cz）潜伏期、组顶区（Pz）潜伏期短于对照组,Cz波幅、Pz波幅高于对照组（P<0.05）。结论：iTBS联合有氧运动训练用于老年T2DM合并MCI患者,可有效降低血糖,改善机体认知功能和听觉诱发电位P300。