Novel P143L polymorphism of the LCAT gene is associated with dyslipidemia in Chinese patients who have coronary atherosclerotic heart disease

Coronary atherosclerotic heart disease (CAD) is a multifactorial disorder resulting from numerous gene-gene and gene-environment interactions. Lecithin:cholesterol acyltransferase (LCAT), a key enzyme in reverse cholesterol transport and the metabolism of high-density lipoprotein (HDL), is thought to be a candidate gene related to dyslipidemia and CAD. Variations in the LCAT gene were investigated in 190 CAD patients and 209 age- and gender-matched controls by denaturing high-performance liquid chromatography, and confirmed by sequencing and RFLP assay. In CAD patients, a novel single-nucleotide polymorphism (P143L) in exon 4 of the LCAT gene was discovered in nine males and two females (frequency of 5.79%), which was found in none of 209 controls. The genotype and allele distribution of P143L is significantly (P<0.04 ) higher in the low HDL-C subgroup than in the normal HDL-C subgroup in both male patients and all CAD patients. P143L was also found to be significantly (P<0.01) associated with the low HDL-C phenotype in both male patients and all CAD patients, with odds-ratios of 7.003 (95% CI 2.243-21.859) and 5.754 (95% CI 1.893-13.785), respectively. Thus, the P143L polymorphism may play a role in causing decreased HDL-C levels, leading to increased risk of dyslipidemia and CAD in Chinese.     

Protective Effects of 7‐Hydroxycoumarin on Dyslipidemia and Cardiac Hypertrophy in Isoproterenol‐Induced Myocardial Infarction in Rats

This study evaluates the protective effects of 7‐hydroxycoumarin (7‐HC) on dyslipidemia and cardiac hypertrophy in isoproterenol (ISO) induced myocardial infarction (MI) in rats. Rats were pre‐ and co treated with 7‐HC (16 mg/kg) daily for 8 days. ISO (100 mg/kg) was subcutaneously injected into rats on seventh and eighth days to induce MI. Increased activity/levels of serum creatine kinase‐MB (CK‐MB), troponin‐T, plasma lipid peroxidation products, and altered levels of lipids in the serum and heart and serum lipoproteins were noted in ISO‐induced rats. ISO‐induced myocardial infarcted rats revealed increased hypertrophy (cardiac and left ventricular) and hepatic 3‐hydroxyl 3‐methylglutaryl‐coenzyme‐A reductase (HMG‐CoA reductase) activity. Pre and cotreatment with 7‐HC revealed significant protective effects on all the biochemical parameters evaluated. The in vitro study demonstrated its free radical scavenging property. Thus, 7‐HC protects ISO‐induced MI in rats by its free radical scavenging and antihyperlipidaemic and antihypertrophic properties.     

Lysosomal acid lipase regulates fatty acid channeling in brown adipose tissue to maintain thermogenesis

Lysosomal acid lipase (LAL) is the only known enzyme, which hydrolyzes cholesteryl esters and triacylglycerols in lysosomes of multiple cells and tissues. Here, we explored the role of LAL in brown adipose tissue (BAT). LAL-deficient (Lal?/?) mice exhibit markedly reduced UCP1 expression in BAT, modified BAT morphology with accumulation of lysosomes, and mitochondrial dysfunction, consequently leading to regular hypothermic events in mice kept at room temperature. Cold exposure resulted in reduced lipid uptake into BAT, thereby aggravating dyslipidemia and causing life threatening hypothermia in Lal?/? mice. Linking LAL as a potential regulator of lipoprotein lipase activity, we found Angptl4 mRNA expression upregulated in BAT. Our data demonstrate that LAL is critical for shuttling fatty acids derived from circulating lipoproteins to BAT during cold exposure. We conclude that inhibited lysosomal lipid hydrolysis in BAT leads to impaired thermogenesis in Lal?/? mice.     

An environment‐friendly approach to isolate and purify glucan from spent cells of recombinant Pichia pastoris and the bioactivity characterization of the purified glucan

While the methylotrophic yeast Pichia pastoris enables the industrial‐scale biosynthesis of many recombinant products, large amount of nutrient‐rich biomass emerged along this process. Polysaccharides, especially glucans that are abundant in the cell wall of P. pastoris, are yet to be better utilized owing to their various biological activities. However, the isolation and purification of cell wall glucan from P. pastoris has not been reported. In this study, we established an environment‐friendly approach, including induced autolysis, hot‐water treatment, ultrasonication, isopropanol extraction, and protease treatment, to isolate and purify glucan from the cell wall of P. pastoris. We achieved a purity of 85.3% and a yield of 11.7% for the purified glucan. Proteins, nucleic acids, lipids, and ash were efficiently removed during the purification. The activities of the purified glucan were investigated in mice fed with a high‐fat diet. The purified glucan decreased the level of total cholesterol and triglycerides by 30.3 and 29.7%, respectively. This result suggested that the cell wall glucan of P. pastoris could be developed to a therapeutic agent for dyslipidemia. Our study proposed an environment‐friendly and effective method to isolate and purify the glucan from P. pastoris, providing solid foundation for the high‐value utilization of this yeast.     

Novel inhibitors of glycation and AGE formation

Accelerated formation of advanced glycation/lipoxidation and endproducts (AGEs/ALEs) has been implicated in the pathogenesis of various diabetic complications. Several natural and synthetic compounds have been proposed and tested as inhibitors of AGE/ALE formation. We have previously reported the therapeutic effects of several new AGE/ALE inhibitors on the prevention of nephropathy and dyslipidemia in streptozotocin (STZ)-induced diabetic rats. In this study, we investigated the effects of various concentrations of a compound, LR-90, on the progression of renal disease and its effects on AGE and receptor for AGE (RAGE) protein expression on the kidneys of diabetic STZ-rats. Diabetic male Sprague–Dawley rats were treated with or without LR-90 (0, 5, 20, 25, and 50 mg/l of drinking water). After 32 weeks, body weight, glycemic status, renal function, and plasma lipids were measured. Kidney histopathology and AGE/ALE accumulation and RAGE protein expression in tissues were also determined. In vitro studies were also performed to determine the possible mechanism of action of LR-90 in inhibiting AGE formation and AGE-protein cross-linking. LR-90 protected the diabetic kidneys by inhibiting the increase in urinary albumin-to-creatinine ratio and ameliorated hyperlipidemia in diabetic rats in a concentration-dependent fashion without any effects on hyperglycemia. LR-90 treatment also reduced kidney AGE/ALE accumulation and RAGE protein expression in a concentration-dependent manner. In vitro, LR-90 exhibited general antioxidant properties by inhibiting metal-catalyzed reactions and reactive oxygen species (^·OH radical) and reactive carbonyl species (methlyglyoxal, glyoxal) generations without any effect on pyridoxal 5′ phosphate. The compound also prevents AGE-protein cross-linking reactions. These findings demonstrate the bioefficacy of LR-90 in treating nephropathy and hyperlipidemia in diabetic animals by inhibiting AGE accumulation, RAGE protein expression, and protein oxidation in the diabetic kidney. Additionally, our study suggests that LR-90 may be useful also to delay the onset and progression of diabetic atherosclerosis as the compound can inhibit the expression of RAGE and inflammation-related pathology, as well as prevent lipid peroxidation reactions.     

苯扎贝特片联合非洛地平缓释片对高血压合并血脂代谢紊乱患者血脂水平、内皮细胞功能及炎性细胞因子的影响

摘要 目的：探讨苯扎贝特片联合非洛地平缓释片对高血压合并血脂代谢紊乱患者血脂水平、内皮细胞功能及炎性细胞因子的影响。方法：选择2018年1月到2020年1月我院收治的105例高血压合并血脂代谢紊乱患者,按随机表字法随机分为观察组（53例）和对照组（52例）。两组均予以调脂饮食,随后对照组给予非洛地平缓释片治疗,观察组给予苯扎贝特片联合非洛地平缓释片治疗。比较两组收缩压（SBP）、舒张压（DBP）、空腹血糖（GLU）、空腹胰岛素（FINS）、胰岛素抵抗指数（HOMA-IR）、总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白（HDL-C）、低密度脂蛋白（LDL-C）、白细胞介素-6（IL-6）、超敏C-反应蛋白（hs-CRP）、一氧化氮（NO）、内皮素（ET）、肿瘤坏死因子α（TNF-α）水平。结果：两组治疗后SBP、DBP、GLU、FINS、血清TG、TC、LDL-C、ET、TNF-α、IL-6、hs-CRP水平及HOMA-IR均明显低于治疗前（P<0.05）,血清HDL-C、NO水平均高于治疗前（P<0.05）,同时观察组治疗后SBP、DBP、GLU、FINS、血清TG、TC、LDL-C、ET、TNF-α、IL-6、hs-CRP水平及HOMA-IR低于对照组（P<0.05）,血清HDL-C、NO水平均高于对照组（P<0.05）。结论：苯扎贝特片联合非洛地平缓释片能够更好地调节高血压合并血脂代谢紊乱患者的血压、血脂水平,改善血管内皮功能和胰岛素抵抗,降低血清炎症因子水平。     

Prevalence and pattern of dyslipidemia in hyperglycemic patients and its associated factors among Pakistani population

In diabetes mellitus dyslipidemia is one of the major risk factors for cardiovascular disease. In type 2 diabetes mellitus early detection and treatment of dyslipidemia can avoid risk for cardiovascular disorder. The present study was carried to determine the prevalence and pattern of hyperlipidemia in patients with hyperglycemia. The cross sectional study was done in different laboratories of Pakistan, the laboratories served patients referred from different government and private hospitals between July 2014 and June 2015. All known cases of diabetes mellitus were evaluated for their lipid profile. Totally 200 diabetic patients were included in the study in which 120 (60%) were males and 80 (40%) were females. Prevalence of dyslipidemia among diabetic males was 97.18% while for females 87.15%. Among dyslipidemic male the proportion with mixed dyslipidemic patients was 17.5%, combined two parameters dyslipidemia was 47.5% and isolated single parameter dyslipidemia was 35%. In females these proportions in mixed, combined two parameters and isolated single parameter were 16.25%, 51.25% and 32.5%, respectively. Majority of hyperglycemic patients were dyslipidemic. The most prevalent pattern among male was combined dyslipidemia with high triglycerides (TG) and low High Density Lipoprotein (HDL) and in female it was high Low Density Lipoprotein (LDL) and low HDL. The most prevalent lipid abnormality in our study was low HDL followed by high TG.     

Synthesis and evaluation of (E)-2-(acrylamido)cyclohex-1-enecarboxylic acid derivatives as HCA1, HCA2, and HCA3 receptor agonists

2-(3-(Naphthalen-2-yl)propanamido)cyclohex-1-enecarboxylic acid and its 6-hydroxynaphthalen-2-yl analogue are well-known hydroxyl-carboxylic acid (HCA) receptor HCA2 agonists. A series of novel aryl derivatives of 2-amidocyclohex-1-ene carboxylic acid that contained rigidity elements, such as an E-double bond, triple bond, and trans or cis-substituted cyclopropane rings, instead of the saturated ethane linker in the amide part of the molecules were designed and synthesized, and the derivatives’ potency for the activation of HCA1, HCA2, and HCA3 receptors by 3′–5′-cyclic adenosine monophosphate (cAMP) assay were evaluated. The SAR studies revealed that the rigidifying of appropriate molecules enabled modulation of the potency and selectivity of the HCA2 receptor activation.     

Hepatic response to aluminum toxicity: dyslipidemia and liver diseases

Aluminum (Al) is a metal toxin that has been implicated in the etiology of a number of diseases including Alzheimer's, Parkinson's, dialysis encephalopathy, and osteomalacia. Al has been shown to exert its effects by disrupting lipid membrane fluidity, perturbing iron (Fe), magnesium, and calcium homeostasis, and causing oxidative stress. However, the exact molecular targets of aluminum's toxicity have remained elusive. In the present review, we describe how the use of a systems biology approach in cultured hepatoblastoma cells (HepG2) allowed the identification of the molecular targets of Al toxicity. Mitochondrial metabolism is the main site of the toxicological action of Al. Fe-dependent and redox sensitive enzymes in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) are dramatically decreased by Al exposure. In an effort to compensate for diminished mitochondrial function, Al-treated cells stabilize hypoxia inducible factor-1α (HIF-1α) to increase ATP production by glycolysis. Additionally, Al toxicity leads to an increase in intracellular lipid accumulation due to enhanced lipogenesis and a decrease in the β-oxidation of fatty acids. Central to these effects is the alteration of α-ketoglutarate (KG) homeostasis. In Al-exposed cells, KG is preferentially used to quench ROS leading to succinate accumulation and HIF-1α stabilization. Moreover, the channeling of KG to combat oxidative stress leads to a reduction of l-carnitine biosynthesis and a concomitant decrease in fatty acid oxidation. The fluidity and interaction of these metabolic modules and the implications of these findings in liver-related disorders are discussed herein.     

High serum concentration of selenium,but not calcium,cobalt, copper,iron, and magnesium,increased the risk of both hyperglycemia and dyslipidemia in adults: A health examination center based cross-sectional study

BackgroundMetabolic disorders of glucose and lipid were associated with some mineral elements, and data were warranted from various contexts to make the association more explicit.ObjectiveTo investigate the relationships between the serum concentrations of six mineral elements (calcium, cobalt, copper, iron, magnesium, and selenium) and the risk of hyperglycemia and dyslipidemia in adults.MethodsThe basic information and the over-night fasting serum samples of adults were randomly collected at a health examination center. The serum concentrations of glucose and lipids were measured with an automatic biochemical analyzer, and the mineral elements were measured with an inductively coupled plasma mass spectrometer. Data were analyzed between the hyperglycemia group (HGg) and the normal glucose group (NGg) as well as between the dyslipidemia group (DLg) and the normal lipid group (NLg).ResultsA total of 1466 adults aged 22–81 years (male/female = 1.8) were included, 110 in the HGg and 1356 in the NGg, or 873 in the DLg and 593 in the NLg. The serum element concentration medians [P50 (P25–P75)] significantly different between the HGg and the NGg were 0.83 (0.75–0.94) vs. 0.76 (0.68–0.87) mg/L for copper and 100 (90–110) vs. 94 (87–103) μg/L for selenium (P < 0.001), while those between the DLg and the NLg were 99 (92–110) vs. 97 (90–106) mg/L for calcium, 0.78 (0.69–0.88) vs. 0.75 (0.66–0.85) mg/L for copper, 1.7 (1.4–2.0) vs. 1.6 (1.3–2.0) mg/L for iron, 24 (22–28) vs. 23 (22–27) mg/L for magnesium, and 97 (89–106) vs. 92 (84–100) μg/L for selenium (P < 0.05). When the copper and selenium between the HGg and the NGg were analyzed by logistic regression with age, gender, body mass index, and mineral elements adjusted, only the highest quartile of selenium concentration had association with the increased risk of hyperglycemia [quartile (Q) 4 against Q1: OR = 2.9, 95 % CI = 1.5–5.5, P < 0.001). When the five differed mineral elements between the DLg and the NLg were similarly analyzed, only iron and selenium had associations with the increased risk of dyslipidemia (e.g., Q4 against Q1: OR = 1.4, 95 % CI = 1.1–2.0 for iron and OR = 2.9, 95 % CI = 2.1–4.0 for selenium, P < 0.05).ConclusionIn contrast to those of calcium, cobalt, copper, iron, and magnesium, the higher serum concentration of selenium increased the risk of both hyperglycemia and dyslipidemia in the study population of adult Chinese.