The Role of Low Density Lipoprotein Apheresis in the Treatment of Familial Hypercholesterolemia

Abstract: The chief indication for low density lipoprotein (LDL) apheresis is the treatment of homozygous familial hypercholesterolemia (FH), a potentially fatal condition that responds poorly to conventional therapy. Dextran sulfate/cellulose adsorption columns (Kaneka) and on-line heparin precipitation (HELP) are the most popular systems used in LDL apheresis. Weekly or biweekly procedures plus concomitant drug therapy enable LDL cholesterol to be maintained at 30–50% of its untreated level, with regression of xanthomas, arrest of progression of coronary atherosclerosis, and improved life expectancy. However, aortic stenosis may progress despite apheresis and necessitate valve replacement. Better control of hypercholesterolemia results from combining apheresis with a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, atorvastatin. LDL apheresis can also be useful in treating drug-resistant FH heterozygotes with coronary disease. However, the FH Regression Study showed no evidence that reduction by apheresis of both LDL and lipoprotein(a), was more advantageous than reduction by combination drug therapy of LDL alone.     

非传统脂质指标与缺血性卒中

缺血性卒中预防和治疗的个性化管理依然是神经病学领域的重中之重。文章旨在阐述非传统脂质谱与传统脂质在急性缺血性卒中发病以及复发中的作用,以期为卒中预防、风险分级和高危人群筛查提供全新指标,并试图探讨非传统脂质指标的潜在预测价值。     

Lysosomal cholesterol accumulation: driver on the road to inflammation during atherosclerosis and non‐alcoholic steatohepatitis

Many studies show an association between the accumulation of cholesterol inside lysosomes and the progression towards inflammatory disease states that are closely related to obesity. While in the past, the knowledge regarding lysosomal cholesterol accumulation was limited to its association with plaque severity during atherosclerosis, recently, a growing body of evidence indicates a causal link between lysosomal cholesterol accumulation and inflammation. These findings make lysosomal cholesterol accumulation an important target for intervention in metabolic diseases that are characterized by the presence of an inflammatory response. In this review, we aim to show the importance of cholesterol trapping inside lysosomes to the development of inflammation by focusing upon cardiovascular disease and non‐alcoholic steatohepatitis (NASH) in particular. We summarize current data supporting the hypothesis that lysosomal cholesterol accumulation plays a key role in the development of inflammation during atherosclerosis and NASH. In addition, potential mechanisms by which disturbed lysosomal function can trigger the inflammatory response, the challenges in improving cholesterol trafficking in macrophages and recent successful research directions will be discussed.     

Obesity and the risk and prognosis of gallstone disease and pancreatitis

Obesity is a risk factor for the formation of cholesterol gallstones and exposes patients to increased risk of gallstone-related complications and cholecystectomy. Rapid weight loss achieved by very low calorie diets or bariatric surgery is also a risk factor for cholelithiasis in obese patients, and therapy should take into account the higher prevalence of gallstones, the possibility of more frequent complications and the need for prophylactic treatment with oral ursodeoxycholic acid during weight loss. Obesity is also frequent in children and adolescents, and the burden of cholesterol cholelithiasis is increasing in this population. The chance to develop acute pancreatitis and the severity of the disease are higher in obese subjects because of specific pathogenic factors, including supersaturated bile and crystal formation, rapid weight loss, and visceral obesity. All health policies aimed at reducing the incidence of obesity worldwide will decrease the incidence of gallstones and gallstone-related complications. The pathophysiological scenarios and the therapeutic implications for obesity, gallstone disease, and pancreatitis are discussed.     

Cholesterol in midlife increases the risk of Alzheimer's disease during an up to 43-year follow-up

PurposeVascular risk factors in midlife may play a role in the development of cognitive decline, dementia and Alzheimer’ disease (AD). The role of serum total cholesterol has yielded inconsistent results in diverse cohorts.ObjectiveTo analyze the relationship between the midlife cholesterol level and AD in late life in a homogenous cohort of Caucasian men.MethodsThe Helsinki Businessmen Study is a cohort of male business executives who have been followed-up since 1964. Midlife cholesterol level was available in 3293 men, of whom 205 developed a register-verified AD. Cognitively intact men in 2007 (n = 844) served as controls, and logistic regression adjusted for age and cardiovascular risk factors was used to investigate the association between cholesterol and AD.ResultsAt baseline, the men with subsequent AD diagnosis had 0.4 mmol/L higher total cholesterol level than controls (6.7 vs 6.3 mmol/L). In adjusted analyses 1 mmol/L rise in total cholesterol was associated with a 22% increased risk of AD (odds ratio [OR] 1.22, 95% confidence interval 1.06 to 1.40, P = 0.005). Risk of AD (OR with 95% CI) also increased in a stepwise manner from the lowest to highest quartile of midlife cholesterol from 1.0 (referent) to 1.6 (1.01–2.6), 1.9 (1.2–3.0), and 2.0 (1.2–3.3), respectively.ConclusionIn this longitudinal study with up to 43 years of follow-up, higher serum total cholesterol in early midlife was clearly associated with a higher risk of AD in late life.     

The effect of corpus luteum on hormonal composition of follicular fluid from different sized follicles and their relationship to serum concentrations in dairy cows

ObjectiveTo investigate the effect of the presence or absence of corpus luteum on hormonal composition of follicular fluid (FF) from different sized follicles and their relationship to serum concentrations in dairy cows.MethodsOvaries were collected from 30 clinically healthy adult female cows (Holstein Friesian) 4–7 years of age with clinically normal reproductive tracts after slaughtering. Blood samples were collected from the jugular vein before slaughter from each cow. The stage of the cycle in the cows was determined postmortem. The ovaries collected from per cow were classified with corpus luteum (CL⁺) and without corpus luteum (CL⁻). FF was aspirated from small (3-5 mm), medium (6-9 mm), and large (10-20 mm) follicles in CL⁺ and CL⁻ ovaries. Serum and FF samples were analyzed for estradiol-17β, progesterone, testosterone, T₃ and T₄ concentrations.ResultsResults demonstrated that the FF concentrations of estradiol-17β, progesterone and testosterone in different sized follicles categories (small, medium and large follicles in CL⁺ and CL⁻ ovaries) were significantly higher (P≤0.05) when compared with the serum. The FF concentrations of estradiol-17β and testosterone in same follicle size categories in CL⁺ and CL⁻ ovaries were also significant (P<0.05). Indeed, concentrations of these hormones in the CL⁻ ovaries were higher than those of the CL⁺ ovaries. However, there was a statistically significant difference between medium and large follicles for progesterone concentration in CL⁺ and CL⁻ ovaries (P<0.05). There was a significant correlation between concentration of hormones in serum and FF with increased follicular diameter.ConclusionsThese results indicated that the levels of hormonal composition in the FF were related to follicular size and interestingly to the presence or absence of a corpus luteum. Indeed, the corpus luteum locally affects neighboring follicular compositions during the luteal phase of the estrous cycle in dairy cows.     

Toll样受体4抑制过氧化物酶体增殖物激活受体γ加重血脂蓄积的分子机制

目的 选取高脂饮食模型大鼠和氧化低密度脂蛋白(oxLDL)暴露下巨噬细胞模型,验证在血脂蓄积过程中Toll样受体4(TLR4)和过氧化物酶体增殖物激活受体γ(PPARγ)的具体干预机制。 方法 健康雄性Wistar大鼠20只,随机分为对照组和高脂组,每组10只。测定各组大鼠总胆固醇、甘油三酯、高密度脂蛋白、低密度脂蛋白水平,采用苏木精-伊红染色检测颈动脉血管内膜中膜厚度比,采用Western blotting法检测TLR4、PPARγ蛋白表达水平。体外培养小鼠巨噬细胞RAW264.7,以oxLDL(50 mg/L)刺激巨噬细胞制备模型,且应用siRNA-TLR4沉默巨噬细胞内的TLR4因子制备TLR4沉默模型,将细胞分为空白组(A组)、oxLDL组(B组)、oxLDL+siRNA组(C组)、oxLDL+siRNA-TLR4组(D组)、oxLDL+siRNA-TLR4+PPARγ激动剂组(E组)、oxLDL+siRNA-TLR4+PPARγ抑制剂组(F组)。采用油红O染色法观察巨噬细胞内血脂蓄积情况,定量检测巨噬细胞内胆固醇含量,采用Western blotting法检测 TLR4、PPARγ蛋白表达水平。 结果 在动物模型实验中,与对照组相比,高脂组总胆固醇、甘油三酯、低密度脂蛋白水平、颈动脉内膜中膜厚度比、TLR4蛋白相对表达含量明显增高(P<0.01),血清高密度脂蛋白水平、PPARγ蛋白相对表达含量明显降低(P<0.01),且TLR4与PPARγ呈负相关性(r=-0.928 1,P<0.001)。在oxLDL暴露巨噬细胞实验中,与A组比较,B、C组巨噬细胞内胆固醇含量、油红O颗粒、光密度值及TLR4蛋白相对表达含量明显增多(P<0.01),PPARγ蛋白相对表达含量明显减少(P<0.05),且B组TLR4与PPARγ呈负相关性(r=-0.986 7,P<0.001)。与B组相比,C组巨噬细胞内胆固醇含量、油红O颗粒、光密度值及TLR4、PPARγ蛋白相对表达含量未见明显改变(P>0.05)。与B组相比,D组巨噬细胞内胆固醇含量、油红O颗粒及光密度值及TLR4蛋白相对表达含量明显减少(P<0.01),PPARγ蛋白相对表达含量明显增多(P<0.05)。与D组相比,E组巨噬细胞内胆固醇含量、油红O颗粒及光密度值明显减少(P<0.01),PPARγ蛋白相对表达含量明显增多(P<0.05),TLR4蛋白相对表达含量未见明显改变(P>0.05)。与D组相比,F组巨噬细胞内胆固醇含量、油红O颗粒及光密度值明显增多(P<0.01),PPARγ蛋白相对表达含量明显减少(P<0.05),TLR4蛋白相对表达含量未见明显改变(P>0.05)。 结论 细胞内的血脂蓄积是动脉粥样硬化形成的机制之一,PPARγ可以抑制巨噬细胞血脂蓄积进而参与动脉粥样硬化调节,是巨噬细胞血脂蓄积过程的保护性因子。而TLR4作为PPARγ上游调控位点,通过抑制PPARγ的表达,加重血脂蓄积的过程,进而干预动脉粥样硬化进程。     

Dialysis Method Alters the Expression of MicroRNA‐33a and Its Target Genes ABCA1, ABCG1 in THP‐1 Macrophages

Atherosclerosis and accompanying cardiovascular disease are the first causes of mortality in patients undergoing maintenance hemodialysis. Anti‐atherosclerotic effects of hemodiafiltration (HDF) have been reported. Our study aimed to investigate the effect of serum derived from a healthy group (n = 23), before and after hemodialysis (HD) therapy (n = 23), and before and after HDF therapy (n = 17) on the expression of microRNA‐33a and its target genes adenosine triphosphate‐binding cassette transporter A1,G1 (ABCA1, ABCG1) in THP‐1 macrophages. Meanwhile, blood lipids and high‐sensitivity C‐reactive protein (hs‐CRP) were measured in these groups. Our data showed that the expression of miRNA‐33a was lower (P < 0.05) and ABCA1 and ABCG1 were higher (P < 0.05) in the healthy group than pre‐HD and pre‐HDF. miR‐33a was significantly decreased (P < 0.05) but ABCA1, ABCG1 was significantly increased (P < 0.05) in post‐HDF compared with pre‐HDF, while these parameters in pre‐ and post‐ HD groups did not show any significant change (P > 0.05). High density lipoprotein cholesterol (HDL‐C) was higher and hs‐CRP was lower in the healthy group than pre‐HD and pre‐HDF groups. Moreover, a significant increase of HDL‐C (P < 0.05) and decrease (P < 0.05) of hs‐CRP was shown in post‐HDF compared with pre‐HDF, but HD appeared to have no significant change in these subjects. HDF therapy can downregulate miR‐33a expression, and then result in ABCA1, ABCG1 upregulation and an increase in circulating HDL‐C, leading to a possible anti‐atherosclerosis effect to some extent.