脂肪细胞胆固醇稳态与动脉粥样硬化

肥胖是动脉粥样硬化发展的重要危险因素。肥胖的发生伴随着脂肪细胞内胆固醇含量与分布的改变。胆固醇是细胞膜脂筏区的重要组成成分与调节因子。而且,它本身还是信号分子,可直接调控脂肪细胞的代谢与功能。脂肪细胞自身合成胆固醇的能力极其有限,因此主要依赖摄取与流出来调控胆固醇稳态。最新研究更发现阻断脂肪细胞上胆固醇的主动流出可抑制肥胖的发生。本文将详细介绍脂肪细胞摄取与外排胆固醇的通路,并讨论胆固醇稳态对脂肪细胞的重要性及脂肪细胞胆固醇稳态在动脉粥样硬化发展中的作用。     

复合膳食纤维对高胆固醇血症大鼠胆固醇代谢的长期作用

健康、断乳SD大鼠 84只 ,经高脂饲料诱导形成高脂血症模型后按体重及血胆固醇均衡的原则分为 7组 ,分别以基础饲料及高脂饲料作为对照组 ,其余 5组饲以不同水平的复合膳食纤维配方B(可溶性纤维 不可溶性纤维 =2 .0 ) ,实验期为 3个月 ,观察配方B对大鼠血浆胆固醇代谢的长期作用。结果表明 :与高脂组相比 ,高胆固醇血症大鼠的血总胆固醇、低密度脂蛋白胆固醇在不同水平的复合膳食纤维配方B组均显著降低 (P <0 .0 5 ) ,而高密度脂蛋白胆固醇水平及高密度脂蛋白胆固醇 低密度脂蛋白胆固醇比值显著升高 (P <0 .0 5 ) ;复合膳食纤维配方B在降低大鼠血总胆固醇浓度的作用上 ,存在明显的剂量反应关系。以上结果提示 :以燕麦麸、沙棘皮、瓜儿豆胶为主要原料研制成的复合膳食纤维确能长期有效地降低血浆胆固醇水平 ,可用于动脉粥样硬化和冠心病的防治。     

降低胆固醇在冠心病防治中的作用

降低胆固醇作为冠心病一级预防和二级预防措施，对其临床效益曾引起争议。只是在最近的两年里，几个大规模的研究结果春有益作用。降低ＴＣ不仅能稳定动脉粥样硬化斑块，而且对内皮功能及凝血纤溶系统均产生积极的影响。     

昼夜节律对肝脏胆固醇代谢的影响

目的:分析昼夜节律对肝脏脂代谢相关基因表达谱的影响,研究胆固醇代谢相关基因的昼夜节律性,以及高脂饮食、节律调节因子的缺失等因素对节律的影响。方法:选取小鼠肝脏组织昼夜节律表达谱的相关数据,利用CirGRDB数据库Lomb-Scargle周期表算法预测时间序列的周期,分析基因表达的昼夜节律性,并分析胆固醇代谢通路中具有昼夜节律性的基因,分析肝脏胆固醇代谢基因的昼夜节律变化。结果:小鼠肝脏中具有昼夜节律性的胆固醇代谢基因主要功能在于胆固醇合成、胆固醇排泄、胆汁酸的排泄、脂蛋白脂解酶的抑制,可能与动脉粥样硬化相关,高脂饮食对节律性影响较少,节律控制因子影响相关胆固醇代谢基因的节律。结论:肝脏中部分胆固醇代谢通路基因具有昼夜节律性,其节律性不受高脂饮食影响,节律紊乱可干扰肝脏胆固醇代谢的节律性。     

肝脏移植治疗纯合型家族性高胆固醇血症的研究进展

家族性高胆固醇血症(FH)是一种常染色体遗传代谢性疾病,患者血清中低密度脂蛋白胆固醇(LDLC)水平显著升高,导致早发动脉粥样硬化性心血管疾病(ASCVD).未经治疗的纯合型家族性高胆固醇血症(HoFH)患者多因动脉粥样硬化性心血管疾病于30岁前死亡.HoFH的降胆固醇治疗包括治疗性生活方式改变、降脂药物治疗、血脂净化...     

miRNA 调控脂质代谢的相关研究进展

miRNA是一种能负性调节基因表达非蛋白编码单链RNA,能够特异性结合到对应的mRNA上并使其翻译受到抑制。目前已发现一些miRNA与脂质代谢密切相关,特别是miR-122和miR-33对脂质谢的稳态有重要影响,甚至可成为治疗脂代谢与动脉粥样硬化相关疾病的潜在靶标。本文总结近期有关miRNA在调节脂代谢方面的研究,旨在为其相关机制更进一步的研究提供参考。     

胆固醇调节元件结合蛋白基因及其与脂质代谢的关系

近年来，心脑血管疾病在我国死亡顺因中居首位，其中又以发病率逐年上升的动脉粥样硬化最为关键。有证据表明高胆固醇血症、高血压、吸烟和糖尿病等多种危险因素在动脉粥样硬化的发病中起重要作用，其中高胆固醇血症影响最大。而血脂水平受遗传和环境因素的双重调节，胆固醇调节元件结合蛋白（sterol regulatory element binding protein，SREBP）是其中一个重要的调节因子。SREBP属于核转录因子家族，是脂肪合成基因转录的重要调节因子，它不但介导胆固醇生物合成的反馈调节，而且在脂肪酸合成中起重要的调节作用。有文献报道，由于SREBP在脂质代谢中的重要调控作用，当编码SREBP的基因发生突变时，会导致脂质的代谢紊乱。本文综述SREBP基因及其与脂质代谢关系的研究进展。     

银杏叶提取物及其合剂对饲胆固醇兔动脉粥样硬化的作用

目的：研究银杏叶提取物和银杏叶提取物合剂（银杏叶提取物＋维生素Ｅ＋Ｌ－精氨酸＋牛磺酸,２：１：２：２．５）对饲胆固醇兔动脉粥样硬化的防治作用。方法采用饲１％胆固醇兔形成动脉粥样硬化为模型,观察银杏叶提取物和银杏叶提取物合剂对饲胆固醇兔胸主动脉动脉粥样硬化斑块面积百分比及对血浆丙二醛和一氧化氮含量的影响。结果银杏叶提取物合剂（１－３ｍｇ／ｋｇｐｅｒｄａｙ）和银杏叶提取物（０．５ｍｇ／ｋｇｐｅｒｄａｙ     

高胆固醇血症治疗前后血小板立体计量学参数的变化

为研究高胆固醇血症对血小板超微结构及97立体计量学参数的影响及调脂药普伐他汀干预后的变化,选择高胆固醇血症患者20例,口服普伐他汀10－20mg/d,疗程4－8周,治疗前后在透射电镜下观察血小板的超微结构并进行立体计量分析。结果发现,治疗后高胆固醇血症患者血清总胆固醇和低密度脂蛋白水平及血小板聚集功能均明显下降,同时血小板形态结构的立体计量学参数得以改善。结果提示,高胆固醇血症患者血小板功能及立体计量学参数的可逆性变化可能与普伐他汀促进动脉粥样斑块消退的机制有关。     

NPY modulates PYY function in the regulation of energy balance and glucose homeostasis

Aims: Both the neuronal‐derived neuropeptide Y (NPY) and the gut hormone peptide YY (PYY) have been implicated in the regulation of energy balance and glucose homeostasis. However, despite similar affinities for the same Y receptors, the co‐ordinated actions of these two peptides in energy and glucose homeostasis remain largely unknown. Methods: To investigate the mechanisms and possible interactions between PYY with NPY in the regulation of these processes, we utilized NPY/PYY single and double mutant mouse models and examined parameters of energy balance and glucose homeostasis. Results: PYY^?/? mice exhibited increased fasting‐induced food intake, enhanced fasting and oral glucose‐induced serum insulin levels, and an impaired insulin tolerance, ? changes not observed in NPY^?/? mice. Interestingly, whereas PYY deficiency‐induced impairment in insulin tolerance remained in NPY^?/?PYY^?/? mice, effects of PYY deficiency on fasting‐induced food intake and serum insulin concentrations at baseline and after the oral glucose bolus were absent in NPY^?/?PYY^?/? mice, suggesting that NPY signalling may be required for PYY's action on insulin secretion and fasting‐induced hyperphagia. Moreover, NPY^?/?PYY^?/?, but not NPY^?/? or PYY^?/? mice had significantly decreased daily food intake, indicating interactive control by NPY and PYY on spontaneous food intake. Furthermore, both NPY^?/? and PYY^?/? mice showed significantly reduced respiratory exchange ratio during the light phase, with no additive effects observed in NPY^?/?PYY^?/? mice, indicating that NPY and PYY may regulate oxidative fuel selection via partly shared mechanisms. Overall, physical activity and energy expenditure, however, are not significantly altered by NPY and PYY single or double deficiencies. Conclusions: These findings show significant and diverse interactions between NPY and PYY signalling in the regulation of different aspects of energy balance and glucose homeostasis.     

Lipid rafts and redox regulation of cellular signaling in cholesterol induced atherosclerosis

Redox mediated signaling mechanisms play crucial roles in the pathogenesis of several cardiovascular diseases. Atherosclerosis is one of the most important disorders induced mainly by hypercholesterolemia. Oxidation products and related signaling mechanisms are found within the characteristic biomarkers of atherosclerosis. Several studies have shown that redox signaling via lipid rafts play a significant role in the regulation of pathogenesis of many diseases including atherosclerosis. This review attempts to summarize redox signaling and lipid rafts in hypercholesterolemia induced atherosclerosis.     

新HOMA稳态模型在临床中的应用

目的研究利用新HOMA稳态模型HOMA2计算的胰岛素敏感性指数（ISI）和分泌功能指数在临床的应用价值。方法选取80名志愿者，其中正常糖耐量（NGT）31人、糖调节异常（IGR）26人，2型糖尿病（T2DM）23人；抽取空腹血测定血糖、胰岛素（Ins）、真胰岛素（TI）和C肽水平，利用HOMA2计算器分别计算三种ISI（HOMA2-％S-Ins、HOMA2-％S-TI和HOMA2-％S-C）和三种胰岛素分泌功能指数（HOMA2-％B-Ins、HOMA2-％B-TI和HOMA2-％B-C），比较上述指数区分不同糖耐量组的胰岛素敏感性和分泌功能变化的能力。结果在三种ISI中，利用空腹TI计算的HOMA2-％S-TI区分三组的胰岛素敏感性的能力相对最强（F=4．888，P〈0．01），利用空腹Ins计算的HOMA2-％S-Ins次之（F=3．397，P〈0．05），利用空腹C肽计算的HOMA2-％S-C不能区分三组的胰岛素敏感性（F=1．042，P〉0．05）。利用HOMA2-％S-TI调整后，三种胰岛素分泌功能指数区分三组胰岛素分泌功能的能力非常接近（F值分别为60．323、58．203和58．179，P〈0．01），且均可很好区分IGR组和DM组的胰岛素分泌功能，其中只有HOMA2-％B-C可较好区分NGT组和IGR组的胰岛素分泌功能（t=2．2709，P〈0．05）。结论利用新HOMA稳态模型计算的HOMA2-％S-TI是一个相对较好的计算ISI的公式，HOMA2-％B-C是一个相对较好的计算胰岛素分泌功能指数的公式。     

原发性高血压患者胰岛素抵抗与非高密度脂蛋白胆固醇的关系

目的探讨壮族原发性高血压患者胰岛素抵抗(IR)与非HDL-C的关系,为壮族高血压综合治疗提供参考。方法选取壮族高血压患者200例,以是否合并糖尿病分为合并组80例和未合并组120例;另选健康体检者60例为对照组。各组均测定TC、TG、LDL-C、HDL-C、空腹血糖和空腹胰岛素,计算IR指数(HOMA-IR)和非HDL-C,分析非HDL-C与IR等指标的关系。以非HDL-C水平进行四分位,分为上四分位组51例和下四分位组48例,并分析HOMA IR等指标间的关系。结果与对照组比较,合并组和未合并组患者空腹血糖、空腹胰岛素、TC、TG、IDL C、非HDL C和HOMA IR明显升高,HDLC明显降低(P<0.05,P<0.01);与未合并组比较,合并组患者空腹胰岛素、非HDL-C和HOMA IR明显升高,HDLC明显降低(P<0.05)。与下四分位组比较,上四分位组患者收缩压、舒张压、空腹血糖、TC、TG、LDL-C和HOMA-IR明显升高,HDL-C明显降低(P<0.05,P<0.01)。结论不同糖代谢状态下壮族高血压患者均存在脂代谢紊乱和IR。非HDL-C与IR密切相关,是临床上评估糖、脂代谢异常的良好指标。     

Effect of lifibrol on the metabolism of low density lipoproteins and cholesterol

Lifibrol is a powerful cholesterol-lowering drug of unknown mechanism of action. This investigation was carried out to determine whether the major action of lifibrol is to enhance clearance of low density lipoproteins (LDL) through the LDL-receptor pathway, and if so, whether the drug exerts its action by altering the excretion of bile acids (acidic steroids), the absorption of cholesterol, or the synthesis of cholesterol. In a first study, in two patients with complete absence of LDL receptors, lifibrol therapy had essentially no effect on plasma LDL concentrations; in two others who had a marked reduction in LDL-receptor activity, response to the drug was attenuated. These findings suggest that lifibrol requires an intact LDL-receptor pathway to exert its action. In a second study, in patients with primary moderate hypercholesterolemia, isotope kinetic studies showed that lifibrol enhanced the fractional catabolic rate of LDL-apolipoprotein B (apo B), but had no effect on transport rates of LDL; these observations likewise support the probability that lifibrol acts mainly to increase the activity of the LDL-receptor pathway. However, in a third study in hypercholesterolemic patients, lifibrol therapy failed to increase acidic steroid excretion, inhibit cholesterol absorption, or reduce net cholesterol balance. Furthermore, lifibrol treatment did not significantly reduce urinary excretion of mevalonic acid. In contrast, in a parallel study, simvastatin therapy, which is known to inhibit cholesterol synthesis, gave the expected decrease in net cholesterol balance and reduction in urinary excretion of mevalonic acid. Thus, lifibrol, like statins, appears to increase the activity of LDL receptors; but in contrast to findings with statins, it was not possible to detect a significant decreased synthesis of cholesterol, either from balance studies or from urinary excretion of mevalonic acid. This finding raises the possibility that lifibrol activates the LDL-receptor pathway through a different mechanisms which remains to be determined.     

Apolipoprotein E Polymorphism in Alagille Syndrome and Progressive Familial Intrahepatic Cholestasis

The aim of the study was to assess the apolipoprotein E polymorphism (apoE) in two familial cholestatic diseases—Alagille syndrome (AS) and progressive familial intrahepatic cholestasis (PFIC)—and to estimate its association with gallstone formation, cholesterol levels, and response to UDCA treatment. We investigated 16 children with AS age 8.8 ± 5.7 years (mean ± sd) and 18 children with PFIC age 6.3 ± 4.6 years. The frequency of the -2 allele in AS and PFIC was higher and the frequency of the -3 allele was lower than in controls. Gallstones were diagnosed in nine children with PFIC and different apoE phenotypes. No association between phenotype and cholesterol levels or response to UDCA therapy was observed in the patients studied. In conclusion, the allele -2 is overrepresented in AS and PFIC, similar to primary biliary cirrhosis, although this does not seem to contribute to different cholesterol levels, gallstones, and response to UDCA therapy.     

Sex differences in hepatic regulation of cholesterol homeostasis

Physiological sex differences may influence metabolic status and then alter the onset of some diseases. According to recent studies, it is now well established that females are more protected from hypercholesterolemia-related diseases, such as cardiovascular diseases until menopause. Female protection from hypercholesterolemia is mediated by the hypolipidemic properties of estrogens, even if mechanisms underlying this protection remain still debated. Even though the regulatory mechanisms of cholesterol homeostasis maintenance are well known, few data are available on the supposed differences between male and female in these processes. So, the aim of this work was to define, through an in vivo study, the putative sex-dependent regulation of the processes underlying cholesterol homeostasis maintenance. We examined 3-hydroxy 3-methylglutaryl coenzyme A reductase and its regulatory protein network as well as the amount of low-density lipoprotein receptor and cholesterol. The study was conducted in the liver and plasma of male and female rats, on adults and during postnatal development, and on 17-beta-estradiol-treated male rats. Our data support that physiological differences in proteins involved in cholesterol balance are present between the sexes and, in particular, 3-hydroxy 3-methylglutaryl coenzyme A reductase shows lower activity and expression in female and 17-beta-estradiol-treated male rats than in adult untreated male. Our data suggest that sex differences in enzyme expression depend on variation in regulatory proteins and seem to be related to estrogen presence. This work adds new evidence in the complicated picture of sex-dependent cellular physiology and establishes a new role for reductase regulatory proteins as a link between estrogen protective effects and cholesterol homeostasis.     

Management of high cholesterol levels in older people

The management of hypercholesterolemia in older adults still represents a challenge in clinical medicine. The pathophysiological alterations of cholesterol metabolism associated with aging are still incompletely understood, even if epidemiological evidence suggests that serum cholesterol levels increase with ongoing age, possibly with a plateau after the age of 80 years. Age is also one of the main determinants of cardiovascular disease, according to all cardiovascular risk estimate tools. Cholesterol‐lowering treatment, therefore, would be expected to bring significant protection, even in these patients. Unfortunately, direct experimental evidence is extremely limited, particularly in the very old age strata of the population; a clinical benefit still seems to be present, but the risk for drug‐related adverse events is clearly higher. At any rate, at the present time, definite guidelines for the correct management of hypercholesterolemia in older patients are not available. Therefore, the decision whether or not a pharmacological treatment should be set up, and the choice of the drug, need to be tailored to the individual patient, and requires accurate clinical judgment. The specific aspects of frailty and disability, along with the actual age of the patients, have to be considered together, with a comprehensive assessment approach. The present review summarizes the evidence regarding the modifications of cholesterol metabolism in older patients, the impact of lipid‐lowering drugs on cardiovascular outcomes and focuses on the considerations that can help to define the most appropriate treatment strategy, in view of the individual functional profile. Geriatr Gerontol Int 2019; 19: 375–383 .     

Structural basis of antizyme-mediated regulation of polyamine homeostasis

Polyamines are organic polycations essential for cell growth and differentiation; their aberrant accumulation is often associated with diseases, including many types of cancer. To maintain polyamine homeostasis, the catalytic activity and protein abundance of ornithine decarboxylase (ODC), the committed enzyme for polyamine biosynthesis, are reciprocally controlled by the regulatory proteins antizyme isoform 1 (Az₁) and antizyme inhibitor (AzIN). Az₁ suppresses polyamine production by inhibiting the assembly of the functional ODC homodimer and, most uniquely, by targeting ODC for ubiquitin-independent proteolytic destruction by the 26S proteasome. In contrast, AzIN positively regulates polyamine levels by competing with ODC for Az₁ binding. The structural basis of the Az₁-mediated regulation of polyamine homeostasis has remained elusive. Here we report crystal structures of human Az₁ complexed with either ODC or AzIN. Structural analysis revealed that Az₁ sterically blocks ODC homodimerization. Moreover, Az₁ binding triggers ODC degradation by inducing the exposure of a cryptic proteasome-interacting surface of ODC, which illustrates how a substrate protein may be primed upon association with Az₁ for ubiquitin-independent proteasome recognition. Dynamic and functional analyses further indicated that the Az₁-induced binding and degradation of ODC by proteasome can be decoupled, with the intrinsically disordered C-terminal tail fragment of ODC being required only for degradation but not binding. Finally, the AzIN–Az₁ structure suggests how AzIN may effectively compete with ODC for Az₁ to restore polyamine production. Taken together, our findings offer structural insights into the Az-mediated regulation of polyamine homeostasis and proteasomal degradation.Polyamines are multivalent organic cations that are ubiquitous and essential in eukaryotes (1). With their polycationic characteristics, these compounds are known to modulate the structural and functional properties of nucleic acids and proteins via electrostatic interactions, in turn affecting cell growth and differentiation by influencing the underlying cellular processes (1, 2). Consistent with their crucial regulatory roles, fluctuations in intracellular polyamine levels are rigorously controlled during cell growth and differentiation via fine-tuning the balance between the biosynthesis, degradation, and uptake of polyamines. Aberrant accumulation of polyamines is associated with pathological consequences, including many types of cancer (3–5).Regulation of polyamine homeostasis is achieved mainly by adjusting the catalytic activity and protein abundance of ornithine decarboxylase (ODC), a homodimeric and pyridoxal 5ʹ-phosphate-dependent enzyme that catalyzes the committed and rate-limiting step in polyamine biosynthesis, through the actions of the regulatory proteins antizyme isoform 1 (Az₁) and antizyme inhibitor (AzIN) (3, 6). Elevation of cellular polyamine levels induces the translation of the full-length Az₁, an intracellular ODC inhibitory protein, by stimulating the bypassing of an in-frame stop codon on Az₁ mRNA (7, 8) and by relieving the translational repression effect mediated through the N-terminal fragment of Az₁ (9). The formation of the ODC–Az₁ heterodimer blocks the assembly of the functional ODC homodimer to inhibit polyamine production (10). Moreover, Az₁ can completely shut down the polyamine biosynthetic pathway by targeting ODC for proteolytic destruction via the 26S proteasome (11). Although ubiquitylation is a predominant pathway that channels proteins for proteasomal degradation, Az-induced ODC degradation is unique in its ubiquitin-independent nature. The identification of antizyme isoform 2 (Az₂) and antizyme isoform 3 (Az₃) (12, 13), the tissue and development-specific Az isoforms, further underscores the physiological significance of keeping the cellular polyamine concentrations under tight control. Unlike Az₁, however, Az₂ and Az₃ simply inhibit the catalytic activity of ODC without promoting its degradation, which allows a protein synthesis-independent restoration of ODC activity (6).Replenishment of the intracellular polyamine pool requires the expression of AzIN, an enzymatically inactive ODC homolog, which effectively restores ODC activity by competing with ODC for Az₁ binding (6, 14). Together, ODC, AzIN, and the various Az isoforms form a delicate regulatory circuit to coordinate polyamine biosynthesis, in which ODC and AzIN serve as positive regulators and are considered oncogenic because they promote cell growth and transformation (15). In contrast, Az isoforms are tumor suppressors whose ectopic expression inhibits cell proliferation and tumorigenesis (16).Although the Az₁-mediated regulation of polyamine homeostasis bears high biological and medical significance, our understanding of the underlying molecular basis has remained incomplete due to the lack of structural information about the ODC–Az₁ and AzIN–Az₁ complexes. This study fills in this gap by providing for the first time, to our knowledge, the crystal structures of the two complexes. Moreover, the accompanying solution NMR and biochemical analysis revealed previously unidentified insights into the Az₁-mediated recognition and degradation of ODC by the 26S proteasome.