Increased atherosclerosis in diabetic dyslipidemic swine: protection by atorvastatin involves decreased VLDL triglycerides but minimal effects on the lipoprotein profile

Male Yucatan swine were allocated to four groups (n = 5-6 pigs per group): low fat (3%) fed control, high fat/2% cholesterol (CH) fed (HF), high fat/CH fed with alloxan-induced diabetes (DF) and DF pigs that were treated with atorvastatin (80 mg/day; DF+A). Pigs were fed two meals per day and daily insulin injections were used in diabetic pigs to maintain plasma glucose between 250 and 350 mg/dl. Diabetic dyslipidemic (DF) pigs exhibited greater coronary atherosclerosis and increased collagen deposition in internal mammary artery compared with normoglycemic hyperlipidemic pigs. Although total and LDL CH concentrations did not differ, triglyceride (TG) were increased in DF pigs and FPLC analysis indicated that the LDL/HDL CH ratio was significantly increased in DF compared with HF pigs. The LDL fraction of DF pigs contained larger, lipid enriched particles resembling IDL. Consumption of the high fat/CH diet caused a moderate increase in the percentage of 14:0 fatty acids in plasma lipids and this was compensated by small-moderate declines in several unsaturated fatty acids. There was a significant increase in phospholipid arachidonic acid in DF compared with HF pigs. Atorvastatin protected diabetic pigs from atherosclerosis and decreased total and VLDL TG, but exerted minimal effects on the FPLC lipoprotein and plasma fatty acid profiles and plasma concentrations of total and LDL CH, vitamin A, vitamin E, and lysophosphatidylcholine. Across all groups the plasma CH concentration was positively correlated with hepatic CH concentration. These findings suggest that atorvastatin's protection against coronary artery atherosclerosis in diabetes may involve effects on plasma VLDL TG concentration. Lack of major effects on other lipid parameters, including the LDL/HDL ratio, suggests that atorvastatin may have yet other anti-atherogenic effects, possibly directly in the vessel wall.     

Apolipoprotein E polymorphism alters the association between body fatness and plasma lipoproteins in women

The aim of the present study was to investigate the associations between total adiposity, body fat distribution, and plasma lipoprotein levels within groups of women defined on the basis of apolipoprotein E phenotypes, in order to verify whether apoE polymorphism could modify these associations. In women having only apolipoprotein E3 isoforms (n = 24), body fat mass, the waist: hip circumference ratio, and computed tomography-derived total and intra-abdominal fat areas were all positively correlated with very low density lipoprotein (VLDL) and low density lipoprotein (LDL) lipids and apolipoprotein B concentrations. These body fatness variables were also negatively correlated with plasma high density lipoprotein (HDL) cholesterol concentration. These associations were, however, altered in the groups of women carrying either apoE2 or E4 isoforms. Indeed, in women carrying the apoE2 isoform (n = 22), body fatness variables were predominantly associated with VLDL components concentration (0.05 greater than P less than 0.01) and with LDL triglyceride content. No association was found between adiposity and LDL cholesterol or apolipoprotein B levels in these women. In contrast, no relationship was found between total adiposity, regional fat accumulation, and VLDL fraction in women carrying the apolipoprotein E4 isoform (n = 17). In this latter group, computed tomography-measured total abdominal fat accumulation was positively correlated with LDL apolipoprotein B (r = 0.58, P less than 0.05) concentration, whereas intra-abdominal fat accumulation was positively correlated with both LDL cholesterol and apolipoprotein B concentrations (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Postabsorptive VLDL‐TG Fatty Acid Storage in Adipose Tissue in Lean and Obese Women

Adipose tissue lipoprotein lipase (LPL) is a necessary enzyme for storage of very‐low‐density lipoprotein–triglyceride (VLDL‐TG), but whether it is a rate‐determining step is unknown. To test this hypothesis we included 10 upper‐body obese (UBO), 11 lower‐body obese (LBO), and 8 lean women. We infused ex vivo‐labeled VLDL‐¹⁴C‐TG and then performed adipose tissue biopsies to understand the relationship between VLDL‐TG storage and LPL activity in femoral and upper‐body subcutaneous fat. Both fractional tracer storage and rate of storage of the VLDL‐TG tracer were evaluated. VLDL‐TG storage was also examined as a function of regional adipose tissue blood flow (ATBF), insulin, VLDL‐TG turnover, regional fat mass, fat‐free mass (FFM), and fat cell size. LPL activity per adipocyte was significantly greater in obese than lean women but not significantly different per gram lipid. Both VLDL‐TG fractional tracer storage per kg lipid and VLDL‐TG storage rate per kg lipid were similar in abdominal and femoral fat in all three groups and were not significantly different between groups. Multiple regression analysis identified FFM and femoral fat mass as significant independent predictors of VLDL‐TG fractional tracer storage and insulin as a significant predictor of VLDL‐TG fatty acid storage rate. LPL activity, ATBF, and VLDL‐TG turnover did not predict VLDL‐TG storage. We conclude that lower FFM and greater plasma insulin are associated with greater VLDL‐TG deposition in abdominal subcutaneous and femoral fat. Greater femoral fat mass signals greater femoral VLDL‐TG storage. We suggest that the differences in VLDL‐TG storage in abdominal and femoral fat that occur with progressive obesity are regulated through mechanisms other than LPL activity.     

The composition, structural properties and binding of very-low-density and low-density lipoproteins to the LDL receptor in normo- and hypertriglyceridemia: relation to the apolipoprotein E phenotype

The composition, apolipoprotein structure and lipoprotein binding to the LDL receptor were studied for very-low-density (VLDL) and low-density lipoprotein (LDL) particles isolated from subjects with apoE phenotype E3/3 (E3), E2/2 or E2/3 (E2+) and E3/4 or E4/4 (E4+) and a wide range of plasma triglyceride (TG) contents. The data combined for all three phenotype groups can be summarized as follows. (i) A decrease in accessibility of VLDL tryptophan residues to I- anions with a decrease in tryptophan surface density, concomitant with an increase in VLDL dimensions, reflects the increased efficiency of protein-protein interactions. (ii) A gradual increase in the quenching constant for LDL apoB fluorescence with an increase in TG/cholesterol (Chol) ratio reflects the 'freezing' effect of Chol molecules on apoB dynamics. (iii) Different mechanisms specific for a particular lipoprotein from E3/3 or E2/3 subjects are responsible for apoE-mediated VLDL binding and apoB-mediated LDL binding to the LDL receptor in a solid-phase binding assay. (iv) The 'spacing' effect of apoC-III molecules on apoE-mediated VLDL binding results in a decrease in the number of binding sites. (v) The maximum of the dependence of the LDL binding affinity constant on relative tryptophan density corresponds to LDL intermediate size. VLDL particles from hypertriglyceridemic E2/3 heterozygotic individuals had remnant-like properties (increased cholesterol, apoE and decreased apoC-III content) while their binding efficiency was unchanged. Based on the affinity constant value and LDL-Chol content, increased competition between VLDL and LDL for the binding to the LDL receptor upon increase in plasma TG is suggested, and LDL from hypertriglyceridemic E3/3 homozygotic individuals is the most efficient competitor.     

Glycosylphosphatidylinositol-specific phospholipase D influences triglyceride-rich lipoprotein metabolism

Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is a minor HDL-associated protein. Because many minor HDL-associated proteins exchange between different lipoprotein classes during the postprandial state and are also involved in triglyceride (TG) metabolism, we hypothesized that GPI-PLD may play a role in the metabolism of TG-rich lipoproteins. To test this hypothesis, we examined the distribution of GPI-PLD among lipoprotein classes during a fat tolerance test in C57BL/6 and LDL receptor-deficient (LDLR(-/-)) mice fed either a chow or high-fructose diet. In the fasting state in wild-type mice fed a chow diet, GPI-PLD was only present in HDL, whereas in LDLR(-/-) mice GPI-PLD was present in HDL and intermediate-density lipoproteins (IDL)/LDL. During the fat tolerance test, there was no change in total serum GPI-PLD levels in either model; however, a significant amount of GPI-PLD appeared in both VLDL (0.5-1% of total GPI-PLD) and IDL/LDL (5-10% of total GPI-PLD) in both models. The high-fructose diet increased both fasting and postprandial TG and serum GPI-PLD levels in both strains as well as the amount of GPI-PLD in VLDL. To determine whether GPI-PLD plays a direct role in TG metabolism, we increased liver GPI-PLD expression in C57BL/6 mice by adenovirus-mediated gene transfer, which resulted in a sevenfold increase in serum GPI-PLD levels. This change was associated with an increase in fasting (30%) and postprandial TG (50%) and a twofold reduction in TG-rich lipoprotein catabolism compared with saline or control adenovirus-treated mice. These studies demonstrate that GPI-PLD affects serum TG levels by altering catabolism of TG-rich lipoproteins.     

9758 例健康体检者血糖与血脂的关系分析

目的:探讨健康体检人群血糖与血脂现况及两者之间的相关性。方法:采集我院9758例健康体检者的空腹静脉血,检测其空腹血糖(FPG)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL-C)和低密度脂蛋白(LDL-C)水平,比较不同FPG水平组间各血脂水平,分析FPG水平与血脂的相关性。结果:各年龄组FPG、TC、TG、HDL-C和LDL-C水平差异均具有统计学意义(P0.05);FPG均与TC、TG和LDL-C水平呈现正相关(r=0.127,0.189,0.141,P0.005),而与HDL-C呈现负相关(r=-0.112,P0.005);根据FPG水平由高到低分为糖尿病(DM)组,血糖调节受损(IFG)组及血糖正常组,其中对TC和LDL-C水平异常率而言,IFG组DM组血糖正常组;对TG、HDL-C水平异常率而言,DM组IFG组血糖正常组。结论:健康人群中血糖和血脂水平呈现一定的相关性,两者的水平异常会增加慢性疾病的发生风险。     

Structural peculiarities of the binding of very low density lipoproteins and low density lipoproteins to the LDL receptor in hypertriglyceridemia: role of apolipoprotein E

Very low (VLDL) and low density lipoproteins (LDL) were isolated from plasma of patients with the E3/3 phenotype which were divided into three groups based on their plasma triglyceride content: low (TG<200 mg/dl, TG(l)), intermediate (200<300 mg/dl, TG(i)300 mg/dl, TG(h)). The protein density (PD) on the VLDL and LDL surface was calculated from lipoprotein composition and protein location was studied by tryptophan fluorescence quenching by I(-) anions at 25 degrees C and 40 degrees C. A comparison of the TG(h) with the TG(l) group revealed a significant (<0.05) increase of the PD parameter as much as 21% for VLDL, but not for LDL where this parameter did not change for any group; generally, PD(LDL) values were 3.2-3.8-fold lower than PD(VLDL). In accordance with this difference, the tryptophan accessibility f in VLDL vs. LDL was lower at both temperatures. There were temperature-induced changes of the f parameter in opposite directions for these lipoproteins. The difference in f value gradually decreased for VLDL in the direction TG(l)TG(i)TG(h) while for LDL there was a U-shaped dependence for these groups. The Stern-Volmer quenching constant K(S-V) which is sensitive to both temperature and viscosity, did not change for VLDL, but K(S-V)(LDL) was 2-3-fold higher for the TG(i) group compared to the other two. The efficiencies of VLDL and LDL binding to the LDL receptor (LDLr) in vitro were compared by solid-phase assay free of steric hindrance observed in cell binding. The maximal number of binding sites did not change for either type of particles and between groups. The association constant K(a) and apolipoprotein (apo) E/apoB mole ratio values all increased significantly for VLDL, but not for LDL, in comparison of the TG(i+h) with the TG(l) group. Based on VLDL and LDL concentrations in serum and on the affinity constant values obtained in an in vitro assay, VLDL concentrations corresponding to 50% inhibition of LDL binding (IC(50)) were calculated in an assumption of the competition of both ligands for LDLr in vivo; the mean values of IC(50) decreased 2-fold when plasma TG exceeded 200 mg/dl. The functional dependences of K(a)(VLDL), IC(50) and apoE content in VLDL (both fractional and absolute) and in serum on TG content in the whole concentration range studied were fitted to a saturation model. For all five parameters, the mean half-maximum values TG(1/2) were in the range 52-103 mg/dl. The efficiency of protein-protein interactions is suggested to differ in normolipidemic vs. HTG-VLDL and apoE content and/or protein density on VLDL surface may be the primary determinant(s) of the increased binding of HTG-VLDL to the LDL receptor. ApoCs may compete with apoE for the binding to the VLDL lipid surface as plasma triglyceride content increases. The possible competition of VLDL with LDL for the catabolism site(s) in vivo, when plasma TG increases, could explain the atherogenic action of TG-rich lipoproteins. Moreover, the 'dual action' hypothesis on anti-atherogenic action of apoE-containing high density lipoproteins (HDL) in vivo is suggested: besides the well-known effect of HDL as cholesteryl ester catabolic outway, the formation of a transient complex of apoE-containing discs appearing at the site of VLDL TG hydrolysis by lipoprotein lipase with VLDL particles proposed in our preceding paper promotes the efficient uptake of TG-rich particles; in hypertriglyceridemia due to the diminished HDL content this uptake seems to be impaired which results in the increased accumulation of the remnants of TG-rich particles. This explains the observed increase in cholesterol and triglyceride content in VLDL and LDL, respectively, due to the CETP-mediated exchange of cholesteryl ester and triglyceride molecules between these particles.     

A rapid single-step centrifugation method for determination of HDL, LDL, and VLDL cholesterol, and TG, and identification of predominant LDL subclass

Determination of the circulating levels of plasma lipoproteins HDL, LDL, and VLDL is critical in the assessment of risk of coronary heart disease. More recently it has become apparent that the LDL subclass pattern is a further important diagnostic parameter. The reference method for separation of plasma lipoproteins is ultracentrifugation. However, current methods often involve prolonged centrifugation steps and use high salt concentrations, which can modify the lipoprotein structure and must be removed before further analysis. To overcome these problems we have now investigated the use of rapid self-generating gradients of iodixanol for separation and analysis of plasma lipoproteins. A protocol is presented in which HDL, LDL, and VLDL, characterized by electron microscopy and agarose gel electophoresis, separate in three bands in a 2.5 h centrifugation step. Recoveries of cholesterol and TG from the gradients were close to 100%. The distribution profiles of cholesterol and TG in the gradient were used to calculate the concentrations of individual lipoprotein classes. The values correlated with those obtained using commercial kits for HDL and LDL cholesterol. The position of the LDL peak in the gradient and its shape varied between plasma samples and was indicative of the density of the predominant LDL class. The novel protocol offers a rapid, reproducible and accurate single-step centrifugation method for the determination of HDL, LDL, and VLDL cholesterol, and TG, and identification of LDL subclass pattern.     

肥胖2型糖尿病患者神经肽Y水平与糖脂代谢的相关性分析

目的:探讨肥胖2型糖尿病患者神经肽Y(NPY)水平与糖脂代谢的相关性。方法:选择2017年7月至2019年7月我院接诊的134例肥胖2型糖尿病患者为本研究对象,设为观察组,并选择我院收治的2型糖尿病非肥胖患者100例作为对照组,分析腰围、腹围、臀围、BMI、腰臀比(WHR)、血清NPY、空腹血糖(FPG)、糖化血红蛋白(Hb Alc)、空腹胰岛素(FINS)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)水平变化情况,及其之间的相关性分析。结果:观察组腹围、腰围、臀围、腰臀比及BMI水平均显著高于对照组,差异显著(P0.05);观察组患者血清NPY、FPG、Hb Alc水平显著高于对照组,FINS水平显著低于对照组,差异显著(P0.05);观察组患者血清TC、TG、LDL-C水平显著高于对照组,HDL-C水平显著低于对照组,差异显著(P0.05);将FPG、Hb Alc、FINS、TC、TG、LDL-C、HDL-C作为因变量,将血清NPY作为自变量,在相关性分析结果中显示,血清NPY和FPG、Hb Alc、TC、TG、LDL-C之间均呈正相关(r=0.399,0.173,0.435,0.451,0.376,P均0.05),血清NPY和FINS、HDL-C之间均呈负相关(r=-0.566,-0.223,P均0.05)。结论:在肥胖2型糖尿病患者中NPY水平显著升高,且与腹部脂肪增加、糖脂代谢显著相关。     

Assembly and secretion of chylomicrons by differentiated Caco-2 cells. Nascent triglycerides and preformed phospholipids are preferentially used for lipoprotein assembly.

To develop a cell culture model for chyclomicron (CM) assembly, the apical media of differentiated Caco-2 cells were supplemented with oleic acid (OA) together with either albumin or taurocholate (TC). The basolateral media were subjected to sequential density gradient ultracentrifugations to obtain large CM, small CM, and very low density lipoproteins (VLDL), and the distribution of apoB in these fractions was quantified. In the absence of OA, apoB was secreted as VLDL/LDL size particles. Addition of OA (>/=0.8 mM) with TC, but not with albumin, resulted in the secretion of one-third of apoB as CM. Lipid analysis revealed that half of the secreted phospholipids (PL) and triglycerides (TG) were associated with CM. In CM, TG were 7-11-fold higher than PL indicating that CM were TG-rich particles. Secreted CM contained apoB100, apoB48, and other apolipoproteins. Secretion of large CM was specifically inhibited by Pluronic L81, a detergent known to inhibit CM secretion in animals. These studies demonstrate that differentiated Caco-2 cells assemble and secrete CM in a manner similar to enterocytes in vivo. Next, experiments were performed to identify the sources of lipids used for lipoprotein assembly. Cells were labeled with [3H]glycerol for 12 h, washed, and supplemented with OA, TC, and [14C] glycerol for various times to induce CM assembly and to radiolabel nascent lipids. TG and PL were extracted from cells and media and the association of preformed and nascent lipids with lipoproteins was determined. All the lipoproteins contained higher amounts of preformed PL compared with nascent PL. VLDL contained equal amounts of nascent and preformed TG, whereas CM contained higher amounts of nascent TG even when nascent TG constituted a small fraction of the total cellular pool. These studies indicate that nascent TG and preformed PL are preferentially used for CM assembly and provide a molecular explanation for the in vivo observations that the fatty acid composition of TG, but not PL, of secreted CM reflects the composition of dietary fat. It is proposed that in the intestinal cells the preformed PL from the endoplasmic reticulum bud off with apoB as primordial particles and the assembly of larger lipoproteins is dependent on the synthesis and delivery of nascent TG to these particles.     

Increased concentration of plasma cholesteryl ester transfer protein in nephrotic syndrome: role in dyslipidemia.

Hyperlipidemia is a prominent feature of the nephrotic syndrome. Lipoprotein abnormalities include increased very low and low density lipoprotein (VLDL and LDL) cholesterol and variable reductions in high density lipoprotein (HDL) cholesterol. We hypothesized that plasma cholesteryl ester transfer protein (CETP), which influences the distribution of cholesteryl esters among the lipoproteins, might contribute to lipoprotein abnormalities in nephrotic syndrome. Plasma CETP, apolipoprotein and lipoprotein concentrations were measured in 14 consecutive untreated and 7 treated nephrotic patients, 5 patients with primary hypertriglyceridemia, and 18 normolipidemic controls. Patients with nephrotic syndrome displayed increased plasma concentrations of apoB, VLDL, and LDL cholesterol. The VLDL was enriched with cholesteryl ester (CE), shown by a CE/triglyceride (TG) ratio approximately twice that in normolipidemic or hypertriglyceridemic controls (P < 0.001). Plasma CETP concentration was increased in patients with untreated nephrotic syndrome compared to controls (3.6 vs. 2.3 mg/l, P < 0.001), and was positively correlated with the CE concentration in VLDL (r = 0.69, P = 0.004) and with plasma apoB concentration (r = 0.68, P = 0.007). Treatment with corticosteroids resulted in normalization of plasma CETP and of the CE/TG ratio in VLDL. An inverse correlation between plasma CETP and HDL cholesterol was observed in hypertriglyceridemic nephrotic syndrome patients (r = -0.67, P = 0.03). The dyslipidemia of nephrotic syndrome includes increased levels of apoB-lipoproteins and VLDL that are unusually enriched in CE and likely to be atherogenic. Increased plasma CETP probably plays a significant role in the enrichment of VLDL with CE, and may also contribute to increased concentrations of apoB-lipoproteins and decreased HDL cholesterol in some patients.     

腹部脂肪分布与2型糖尿病合并肥胖患者胰岛素抵抗和骨密度的关系研究

目的:探讨腹部脂肪分布与2型糖尿病合并肥胖患者胰岛素抵抗和骨密度的相关性。方法:选择2017年2月至2019年7月青岛大学附属医院内分泌与代谢病科收治的159例肥胖合并2型糖尿病患者(观察组)和同期100例单纯性肥胖且口服葡萄糖糖耐量试验(OGTT)正常者(对照组)。采用多层螺旋CT(MSCT)测量腹腔内脂肪面积(VFA)、腹内脂肪体积(IAFV)、全腹脂肪体积(TAV),并计算IAFV/TAV;采用全自动生化分析仪检测受试者血脂、空腹血糖(FPG)、空腹胰岛素(FINS)水平,并计算胰岛素抵抗指数(HOMA-IR);采用骨密度仪测量腰椎骨密度、股骨骨密度、髋骨骨密度。分析VFA、IAFV、TAV、IAFV/TAV与胰岛素抵抗和骨密度之间相关性。结果:观察组VFA、IAFV、IAFV/TAV、FPG、HOMA-IR、FINS、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)高于对照组(P0.05),高密度脂蛋白胆固醇(HDL-C)、腰椎骨密度、股骨骨密度、髋骨骨密度低于对照组(P0.05),TAV与对照组比较差异无统计学意义(P0.05)。Pearson相关分析结果示VFA、IAFV、IAFV/TAV与FPG、HOMA-IR、FINS、TC、TG、LDL-C呈正相关(P0.05),与腰椎、股骨、髋骨骨密度、HDL-C呈负相关(P0.05),偏相关分析结果显示,VFA、IAFV、IAFV/TAV与HOMA-IR呈正相关(P0.05),与腰椎、股骨、髋骨骨密度呈负相关(P0.05)。结论:腹内脂肪异常堆积与2型糖尿病合并肥胖患者胰岛素抵抗和骨密度具有显著相关性,临床可通过检测腹内脂肪分布情况预估2型糖尿病合并肥胖患者发生胰岛素抵抗和骨质疏松的风险。     

Induction and evaluation of atherosclerosis in New Zealand white rabbits

Atherosclerosis was experimentally induced in New Zealand white rabbits by feeding a high cholesterol diet for 12 weeks for screening of drugs against atherosclerosis. After 12 weeks, blood was collected from ear vein for evaluation of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and very low density lipoprotein (VLDL) levels, then the animals were sacrificed to collect the livers for estimation of cholesterol, and aorta for gross and histopathological evaluations. The elevated levels of serum and liver parameters accompanied by gross and histopathological changes like accumulation of foam cells, atheromatous plaque formation and replacement fibrosis supported the successful induction of atherosclerosis in New Zealand white rabbits.     

兰州地区健康体检者血脂水平分析

目的:通过检测兰州地区健康体检者空腹血脂水平了解本地区人群血脂水平现状及血脂异常情况,建立本地区血脂参考值。方法:采用全自动生化分析仪检测兰州市2328名健康体检者,血清胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)。比较不同年龄、性别血脂水平差异。结果:本地区2328名被检者,女性TC平均(4.54±0.94)mmol/L,TG中位数1.24mmol/L、HDL-C平均(1.34±0.26)mmol/L、LDL-C平均(2.61±0.76)mmol/L;男性TC平均(4.52±0.84)mmol/L、TG中位数1.56mmol/L mmol/L、HDL-C平均(1.20±0.23)mmol/L LDL-C平均(2.76±0.72)mmol/L,血脂水平随年龄增加逐渐升高(P<0.05)。血脂参考范围为女性TC:2.70~6.38 mmol/L、TG:0.52~3.66 mmol/L、HDL-C:0.83~1.85 mmol/L、LDL-C:1.12~4.10 mmol/L男性:TG:2.87~6.17 mmol/L、0.65~4.00 mmol/L、0.75~1.65 mmol/L、1.35~4.17 mmol/L。男性高TC、高TG、低HDL-C和高LDL-C患病率为18.2%、42.8%、19.6%和28%,女性高TC、高TG、低HDL和高LDL的患病率分别为22.1%、25.5%、2.7%和23.5%。结论:兰州地区血脂水平随年龄、性别、地区不同存在较大差异,临床上不能采用统一标准衡量,而应根据本地区建立的参考值诊断高脂血症。积极控制血脂水平、降低高脂血症患病率预防心脑血管疾病发生。     

Metabolomic analysis of polar metabolites in lipoprotein fractions identifies lipoprotein-specific metabolic profiles and their association with insulin resistance

While the molecular lipid composition of lipoproteins has been investigated in detail, little is known about associations of small polar metabolites with specific lipoproteins. The aim of the present study was to investigate the profiles of polar metabolites in different lipoprotein fractions, i.e., very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and two sub-fractions of the high-density lipoprotein (HDL). The VLDL, IDL, LDL, HDL(2), and HDL(3) fractions were isolated from serum of sixteen individuals having a broad range of insulin sensitivity and characterized using comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC×GC-TOFMS). The lipoprotein fractions had clearly different metabolite profiles, which correlated with the particle size and surface charge. Lipoprotein-specific associations of individual metabolites with insulin resistance were identified, particularly in VLDL and IDL fractions, even in the absence of such associations in serum. The results indicate that the polar molecules are strongly attached to the surface of the lipoproteins. Furthermore, strong lipoprotein-specific associations of metabolites with insulin resistance, as compared to their serum profiles, indicate that lipoproteins may be a rich source of tissue-specific metabolic biomarkers.     

Heparin binding triggers human VLDL remodeling by circulating lipoprotein lipase: Relevance to VLDL functionality in health and disease

Hydrolysis of VLDL triacylglycerol (TG) by lipoprotein lipase (LpL) is a major step in energy metabolism and VLDL-to-LDL maturation. Most functional LpL is anchored to the vascular endothelium, yet a small amount circulates on TG-rich lipoproteins. As circulating LpL has low catalytic activity, its role in VLDL remodeling is unclear. We use pre-heparin plasma and heparin-sepharose affinity chromatography to isolate VLDL fractions from normolipidemic, hypertriglyceridemic, or type-2 diabetic subjects. LpL is detected only in the heparin-bound fraction. Transient binding to heparin activates this VLDL-associated LpL, which hydrolyses TG, leading to gradual VLDL remodeling into IDL/LDL and HDL-size particles. The products and the timeframe of this remodeling closely resemble VLDL-to-LDL maturation in vivo. Importantly, the VLDL fraction that does not bind heparin is not remodeled. This relatively inert LpL-free VLDL is rich in TG and apoC-III, poor in apoE and apoC-II, shows impaired functionality as a substrate for the exogenous LpL or CETP, and likely has prolonged residence time in blood, which is expected to promote atherogenesis. This non-bound VLDL fraction increases in hypertriglyceridemia and in type-2 diabetes but decreases upon diabetes treatment that restores the glycemic control. In stark contrast, heparin binding by LDL increases in type-2 diabetes triggering pro-atherogenic LDL modifications. Therefore, the effects of heparin binding are associated negatively with atherogenesis for VLDL but positively for LDL. Collectively, the results reveal that binding to glycosaminoglycans initiates VLDL remodeling by circulating LpL, and suggest heparin binding as a marker of VLDL functionality and a readout for treatment of metabolic disorders.     

Ethnic differences in body composition and obesity related risk factors: study in Chinese and white males living in China

The purpose of this cross-sectional observational study was to identify ethnic differences in body composition and obesity-related risk factors between Chinese and white males living in China. 115 Chinese and 114 white male pilots aged 28-63 years were recruited. Fasting body weight, height and blood pressure were measured following standard procedures. Whole-body and segmental body composition were measured using an 8-contact electrode bioimpedance analysis (BIA) system. Fasting serum glucose, fasting plasma total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglycerides (TG) were assessed using automatic biochemistry analyzer. After adjusting for age and body mass index (BMI), Chinese males had significantly higher percentage of body fat (PBF) both with respect to whole body (Chinese: 23.7%±0.2% vs. Whites: 22.4%±0.2%) and the trunk area (Chinese: 25.0%±0.3% vs. Whites: 23.2%±0.3%) compared to their white counterparts. At all BMIs, Chinese males had significantly higher fasting glucose levels (Chinese: 5.7±1.0 mmol/L vs. Whites: 5.2±1.0 mmol/L) but lower high-density lipoprotein levels (Chinese: 0.8±1.0 mmol/L vs. Whites: 1.0±1.0 mmol/L) than white males. In addition, a marginally significantly higher diastolic blood pressure was found among Chinese men than that among white men (Chinese: 80±1.0 mmHg vs. Whites: 77±1.0 mmHg). Chinese males had more body fat and a greater degree of central fat deposition pattern than that seen in white males in the present study. Furthermore, data on blood pressure, fasting glucose and blood lipids suggest that Chinese men may be more prone to obesity-related risk factors than white men.     

强化阿托伐他汀治疗对ACS患者血脂水平的短期影响

目的:观察强化阿托伐他汀治疗对急性冠脉综合征(ACS)患者血脂水平的短期影响。方法:收集100例ACS患者,入院当天(the day of admission,D0)、入院第一天(the first day,D1)及入院第二天(The Second Day,D2)分别给予阿托伐他汀80mg治疗,入院D0立即采血化验血脂参数包括总胆固醇(total cholesterol,TC)、低度脂蛋白(LDL-cholesterol,LDL-C)、高密度脂蛋白(HDL-cholesterol,HDL-C)、甘油三酯(triglycerides,TG),分别在D1和D2晨起空腹复查。结果:总胆固醇的平均基线水平为5.24±0.07(D0),低密度脂蛋白为3.26±0.07,高密度脂蛋白胆固醇为1.07±0.07,甘油三酯为1.31±0.07。口服阿托伐他汀80毫克后第一天早晨,TC水平下降6.1%(D1)(与D0相比P0.001),第二日下降13.2%(D2)(与D0相比P0.001),LDL-C下降5.8%(D1)(DO与D1相比,P0.001)和15.6%(D2)(DO与D2相比,P0.001);HDL-C下降7.5%(D1)(DO与D1相比,P0.001)和12.1(D2)(DO与D2相比,P0.001);相反TG水平升高20.6%(D1)(DO与D1相比,P0.001)和25.5%(D2)(DO与D2相比,P0.001)。结论:强化他汀治疗对ACS患者血脂短期的影响与长期的影响是不同的,TC,LDL和HDL在短期内是下降的,而TG是升高的。     

In vivo evidence of a role for hepatic lipase in human apoB-containing lipoprotein metabolism, independent of its lipolytic activity

Hepatic lipase (HL) is a key player in lipoprotein metabolism by modulating, through its lipolytic activity, the triglyceride (TG) and phospholipid content of apolipoprotein B (apoB)-containing lipoproteins and of high density lipoproteins (HDL), thereby affecting their size and density. A new and separate role has been suggested for HL in cellular lipoprotein metabolism, in which it serves as a ligand promoting cellular uptake of apoB-containing remnant lipoproteins and HDL. We tested the hypothesis that HL has both a lipolytic and a nonlipolytic role in human lipoprotein metabolism, by measuring lipid plasma concentrations, lipoprotein density distribution by density gradient ultracentrifugation, and lipoprotein composition, in three subjects with HL deficiency: two of the patients (S-1 and S-3) were characterized as having neither plasma HL activity nor detectable HL protein; the third subject (S-2) had no plasma HL activity but a detectable amount (35.5 ng/ml) of HL protein. All HL-deficient subjects showed a severalfold increase in lipoprotein TG content across the lipoprotein density spectrum [very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), and HDL] as compared with control subjects. They also had remarkably more buoyant LDL particles (LDL-R(f) = 0.342;-0.394) as compared with the control subjects (LDL-R(f) = 0.303). Subjects S-1 and S-3 (no HL activity or protein) presented with a distinct increase in cholesterol and apoB levels in the IDL and VLDL density range as compared with patient S-2, with detectable HL protein, and the control subjects.This study provides evidence in humans that HL indeed plays an important role in lipoprotein metabolism independent of its enzymatic activity: in particular, inactive HL protein appears to affect VLDL and IDL particle concentration, whereas HL enzymatic activity seems to influence VLDL-, IDL-, LDL-, and HDL-TG content and their physical properties.     

Oxidative modification of lipoproteins in hypertriglyceridemic patients and hypercholesterolemic rabbits in vivo

Many lines of evidence suggest that LDL is oxidized in vivo and that Ox-LDL is present in the artery wall. But the oxidation of VLDL and HDL in vivo has not yet been reported. In this study, the oxidative modification of serum LDL, VLDL, and HDL in patients with endogenous hypertriglyceridemia (HTG) and in serum of rabbits fed on high cholesterol diet were made. The serum LDL, VLDL and HDL were isolated by the density gradient ultracentrifugation. The oxidative modification of LDL, VLDL and HDL were identified by agarose eletrophoresis, absorbance at 234 nm and fluorescence of TBARS. The results showed that serum TC, TG and TBARS in the HTG group (n= 25) and in rabbits fed with a high fat diet (for 12 weeks, n = 8) were significantly higher than those of the corresponding control groups (normal subjects, n = 25; rabbits fed with a normal diet, n = 8; p < 0.01). The electrophoretic mobilities of LDL, VLDL and HDL were increased when compared with the controls, and absorbance at 234 nm and TBARS of LDL, VLDL and HDL in the HTG group and in the high fat diet rabbits were significantly higher than those of the controls (p < 0.01). These results suggest that not only LDL but also VLDL and HDL were oxidatively modified in vivo in the patients with HTG and in the rabbits fed with a high cholesterol diet.