Naturally occurring and bioengineered apoA-I mutations that inhibit the conversion of discoidal to spherical HDL: the abnormal HDL phenotypes can be corrected by treatment with LCAT

In the present study we have used adenovirus-mediated gene transfer of apoA-I (apolipoprotein A-I) mutants in apoA-I−/− mice to investigate how structural mutations in apoA-I affect the biogenesis and the plasma levels of HDL (high-density lipoprotein). The natural mutants apoA-I(R151C)Paris, apoA-I(R160L)Oslo and the bioengineered mutant apoA-I(R149A) were secreted efficiently from cells in culture. Their capacity to activate LCAT (lecithin:cholesterol acyltransferase) in vitro was greatly reduced, and their ability to promote ABCA1 (ATP-binding cassette transporter A1)-mediated cholesterol efflux was similar to that of WT (wild-type) apoA-I. Gene transfer of the three mutants in apoA-I−/− mice generated aberrant HDL phenotypes. The total plasma cholesterol of mice expressing the apoA-I(R160L)Oslo, apoA-I(R149A) and apoA-I(R151C)Paris mutants was reduced by 78, 59 and 61% and the apoA-I levels were reduced by 68, 64 and 55% respectively, as compared with mice expressing the WT apoA-I. The CE (cholesteryl ester)/TC (total cholesterol) ratio of HDL was decreased and the apoA-I was distributed in the HDL3 region. apoA-I(R160L)Oslo and apoA-I(R149A) promoted the formation of preβ1 and α4-HDL subpopulations and gave a mixture of discoidal and spherical particles. apoA-I(R151C)Paris generated subpopulations of different sizes that migrate between preβ and α-HDL and formed mostly spherical and a few discoidal particles. Simultaneous treatment of mice with adenovirus expressing any of the three mutants and human LCAT normalized plasma apoA-I, HDL cholesterol levels and the CE/TC ratio. It also led to the formation of spherical HDL particles consisting mostly of α-HDL subpopulations of larger size. The correction of the aberrant HDL phenotypes by treatment with LCAT suggests a potential therapeutic intervention for HDL abnormalities that result from specific mutations in apoA-I.

Download Full-text

Effects of retinoid therapy on insulin sensitivity, lipid profile and circulating adipocytokines

Acta Endocrinologica ◽

10.1530/eje.1.02057 ◽

2006 ◽

Vol 154 (1) ◽

pp. 83-86 ◽

Cited By ~ 47

Author(s):

S Corbetta ◽

R Angioni ◽

A Cattaneo ◽

P Beck-Peccoz ◽

A Spada

Keyword(s):

Insulin Sensitivity ◽

Glucose Metabolism ◽

Lipid Profile ◽

Oral Treatment ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Glucose And Lipid Metabolism ◽

Cholesterol Levels

Objective: In vitro and in vivo models indicate that all-trans retinoic acids influence glucose and lipid metabolism. We aimed to evaluate the effects of chronic treatment with acitretin, an all-trans retinoic acid, on glucose metabolism, lipid profile and adiponectin and resistin levels. Design: Ten normoglycemic, normolipemic patients affected with psoriasis vulgaris were studied before and after 1 and 3 months of oral treatment with 35 μg of acitretin. Methods: Glucose metabolism, lipid profile, and adiponectin and resistin levels were evaluated in basal conditions and after acitretin treatment. Ten healthy subjects matched for age, body mass index (BMI) and insulin sensitivity were studied as controls. Results: One-month acitretin treatment reduced psoriasis activity, insulin sensitivity, evaluated as QUICKI values (0.364 ± 0.034 versus 0.329 ± 0.051; P < 0.05) and HOMA-IR index (1.53 ± 0.73 versus 2.59 ± 1.41; P < 0.05), and high-density lipoprotein (HDL)-cholesterol levels (45.2 ± 11.7 versus 39.4 ± 10.4 mg/dl; P = 0.01). The impairment in glucose and lipid homeostasis was transient and not associated to BMI variations. Adiponectin levels did not change during the treatment, while resistin levels, which were higher in untreated patients than in controls (9.4 ± 4.4 versus 6.2 ± 2.1 ng/ml; P = 0.05), fell within the normal range after 1 and 3 months of therapy. The normalization of resistin levels occurred without significant changes in circulating tumor necrosis factor α (TNFα) levels, which persisted elevated throughout the treatment. Conclusions: Treatment with a low dose of acitretin induced a mild, transient reduction of insulin sensitivity and HDL-cholesterol levels that was not related to modifications of adiponectin, resistin and TNFα levels. Although the role of resistin in humans remains elusive, the levels of this adipocytokine seem to be affected, at least in part, by retinoids.

Download Full-text

The effect of daily baked bean (Phaseolus vulgaris) consumption on the plasma lipid levels of young, normo-cholesterolaemic men

British Journal Of Nutrition ◽

10.1079/bjn19890114 ◽

1989 ◽

Vol 61 (2) ◽

pp. 257-265 ◽

Cited By ~ 42

Author(s):

Susan M. Shutler ◽

Gemma M. Bircher ◽

Jacki A. Tredger ◽

Linda M. Morgan ◽

Ann F. Walker ◽

...

Keyword(s):

Phaseolus Vulgaris ◽

Plasma Cholesterol ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Normal Diet ◽

Male Students ◽

C Peptide ◽

Tomato Sauce ◽

Cholesterol Ratio

1. Thirteen normo-cholesterolaemic male students consumed one 450 g can of baked beans (Phaseolus vulgaris) in tomato sauce, daily, for 14 d as part of their normal diet. After a 14 d washout period, eleven of the students went on to consume one 440 g can of spaghetti in tomato sauce, daily, for 14 d.2. Fasting blood samples were taken frequently for measurement of plasma cholesterol, high-density lipoprotein (HDL)-cholesterol, triacylglycerols, glucose, insulin and C-peptide. Diet diaries (3 d) were completed by the subjects during each period.3. Consumption of beans and spaghetti led to a significant reduction in the amount of fat eaten daily (P< 0.05). Bean consumption also resulted in significant increases in protein, fibre and sugar intakes (P< 0.02,P< 0.001 andP< 0.05 respectively).4. During the bean-eating period the mean total plasma cholesterol level of the students fell significantly from 5.1 to 4.5 mmol/l (P< 0.02). No reduction in plasma cholesterol occurred during the spaghetti-eating period.5. HDL-cholesterol levels fell significantly during both periods (P< 0.001), but HDL:total cholesterol ratio was significantly reduced only during the spaghetti-eating period (P< 0.001). Neither beans nor spaghetti affected triacylglycerol, insulin or C-peptide levels.6. The benefits of a legume-rich diet are discussed.

Download Full-text

Uremic serum-induced calcification of human aortic smooth muscle cells is a regulated process involving Klotho and RUNX2

Bioscience Reports ◽

10.1042/bsr20190599 ◽

2019 ◽

Vol 39 (10) ◽

Author(s):

Ashish Patidar ◽

Dhruv K. Singh ◽

Shori Thakur ◽

Ken Farrington ◽

Anwar R. Baydoun

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Muscle Cells ◽

Runx2 Expression ◽

Cholesterol Ratio ◽

Ckd Stage ◽

Related Transcription Factor

Abstract Vascular calcification (VC) is common in subjects with chronic kidney disease (CKD) and is associated with increased cardiovascular risk. It is an active process involving transdifferentiation of arterial smooth muscle cells (SMCs) into osteogenic phenotype. We investigated the ability of serum from CKD subjects to induce calcification in human SMCs in vitro (calcific potential of sera: CP), and associated changes in expression of Runt-related transcription factor 2 (RUNX2), SM22α, and Klotho. Sera from subjects with CKD (18 stage 3, 17 stage 4/5, and 29 stage 5D) and 20 controls were added to human cultured SMCs and CP quantified. The CP of CKD sera was greater (P<0.01) than that of controls, though not influenced by CKD stage. Modification of diet in renal disease estimated glomerular filtration rate (MDRD-4 eGFR) (P<0.001), serum phosphate (P=0.042), receptor activator of nuclear factor κappa-B ligand (RANKL) (P=0.001), parathyroid hormone (PTH) (P=0.014), and high-density lipoprotein (HDL)/cholesterol ratio (P=0.026) were independent predictors of CP accounting for 45% of variation. Adding calcification buffer (CB: calcium chloride [7 mM] and β-glycerophosphate [7 mM]) increased the CP of control sera to approximate that of CKD sera. CP of CKD sera was unchanged. CKD sera increased RUNX2 expression (P<0.01) in human SMCs and decreased SM22α expression (P<0.05). Co-incubating control but not CKD serum with CB further increased RUNX2 expression (P<0.01). Both SM22α and Klotho expression decreased significantly (P<0.01) in the presence of CKD serum, and were virtually abolished with stage 5D sera. These findings support active regulation by CKD serum of in vitro VC by induction of RUNX2 and suppression of SM22α and Klotho.

Download Full-text

Loss of TIMP4 (Tissue Inhibitor of Metalloproteinase 4) Promotes Atherosclerotic Plaque Deposition in the Abdominal Aorta Despite Suppressed Plasma Cholesterol Levels

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.315522 ◽

2021 ◽

Author(s):

Mei Hu ◽

Sayantan Jana ◽

Tolga Kilic ◽

Faqi Wang ◽

Mengcheng Shen ◽

...

Keyword(s):

Extracellular Matrix ◽

Thoracic Aorta ◽

Abdominal Aorta ◽

Plasma Cholesterol ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Plaque Deposition ◽

Cholesterol Levels

Objective: Atherosclerosis is accumulation of lipids and extracellular matrix in the arterial wall. TIMPs (tissue inhibitor of metalloproteinases) can impact plaque deposition by regulating ECM (extracellular matrix) turnover. TIMP4 also influences lipid metabolism and smooth muscle cell (SMC) proliferation. We investigated the role of TIMP4 in atherosclerosis. Approach and Results: Mice lacking low-density lipoprotein receptor ( Ldlr −/− ) and Timp4 ( Timp4 −/− / Ldlr −/− ) were fed high-fat diet (HFD) or regular laboratory diet. After 3 or 6 months, HFD-fed male and female Timp4 −/− / Ldlr −/− mice exhibited higher plaque density in the abdominal aorta (but not in aortic valves, arch, thoracic aorta) compared with Ldlr −/− mice. Although plasma lipid and cholesterol levels were lower in Timp4 −/− / Ldlr −/− -HFD, cholesterol content in the abdominal aorta was higher along with elevated inflammatory cytokines, MMP (matrix metalloproteinase) activities, CD68 + /calponin + macrophage-like SMCs in Timp4 −/− / Ldlr −/− -HFD compared with Ldlr −/− -HFD mice. In vitro, oxidized LDL (low-density lipoprotein) markedly increased CD68 expression, reduced SMC markers, increased lipid uptake, and reduced cholesterol efflux protein ABCA1 (ATP-binding cassette transporter A1) in Timp4 −/− / Ldlr −/− compared with Ldlr −/− primary SMCs from abdominal, but not thoracic aorta. TIMP4 expression in the abdominal aorta (in vivo) and its corresponding SMCs (in vitro) was ≈2-fold higher than in the thoracic aorta and SMCs; TIMP4 levels decreased following HFD. Timp4 -deficiency in bone marrow–derived macrophages did not alter their foam cell formation capacity. Conclusions: TIMP4 protects against plaque deposition in the abdominal aorta independent of plasma cholesterol levels. TIMP4 prevents proteolytic degradation of ABCA1 in SMCs, hindering cholesterol accumulation and transdifferentiation to macrophage-like foam cells, representing a novel negative regulator of atherosclerosis.

Download Full-text

High Triglyceride/HDL Cholesterol Ratio is Associated with Silent Brain Infarcts in a Healthy Population

10.21203/rs.2.9432/v2 ◽

2019 ◽

Author(s):

Ki-Woong Nam(Former Corresponding Author) ◽

Hyung-Min Kwon(New Corresponding Author) ◽

Han-Yeong Jeong ◽

Jin-Ho Park ◽

Hyuktae Kwon ◽

...

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Vascular Diseases ◽

Hdl Cholesterol ◽

Cerebrovascular Diseases ◽

Healthy Population ◽

Cholesterol Ratio ◽

Silent Brain Infarct ◽

Cholesterol Levels

Abstract Background: Triglycerides (TG)/high-density lipoprotein (HDL) cholesterol ratio is a marker of small/dense low-density lipoprotein particles, which are closely associated with various metabolic and vascular diseases. However, the role of TG/HDL cholesterol ratio in cerebrovascular diseases has not been well studied. In this study, we evaluated the relationship between TG/HDL cholesterol ratio and the presence of silent brain infarct (SBI) in a neurologically healthy population. Methods: We retrospectively evaluated consecutive participants in health check-ups between January 2006 and December 2013. SBI was defined as an asymptomatic, well-defined lesion with a diameter of ≥ 3 mm on T1- or T2-weighted images. TG/HDL cholesterol ratio was calculated after dividing absolute TG levels by absolute HDL cholesterol levels. Results: Of 3,172 healthy participants, 263 (8.3%) had SBI lesions. In multivariate analysis, TG/HDL cholesterol ratio was independently associated with SBI (adjusted odds ratio [aOR] = 1.16, 95% confidence interval [CI] = 1.00 to 1.34, P = 0.047). This association was prominent in males (aOR = 1.23, 95% CI = 1.03 to 1.48, P = 0.021), but not in females. In the analyses of the relationships between lipid parameters and SBI lesion burden, TG/HDL cholesterol ratio was positively correlated, and total cholesterol/TG ratio was negatively correlated with SBI lesion burden, in dose-response manners (P for trend = 0.015 and 0.002, respectively). Conclusions: The TG/HDL cholesterol ratio was positively associated with the prevalence of SBI in a neurologically healthy population.

Download Full-text

GH002: A Novel and Potent Agents for Elevating HDL-Cholesterol

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.340.337 ◽

2011 ◽

Vol 340 ◽

pp. 337-343

Author(s):

Guo Lei

Keyword(s):

Hepg2 Cells ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Control Group ◽

Vitro Assay ◽

Cholesterol Levels ◽

Promoter Effects ◽

Positive Effect

The aim of this study was to evaluate whether the positive effect of GH002 on high-density lipoprotein (HDL) cholesterol in vitro and in vivo. In vitro assay, effects of GH002 on apolipoprotein (apo) A-I was studied using stable-transfected HepG2 cells with recombinant vector including apoA-I promoter; Effects of GH002 on apoA-I, apoA-II and apoC-III production were determined using HepG2 cells. In vivo assay, Effects of GH002 on lipid profile were investigated in hyperlipidemic rats. The results showed that GH002 can effectively activate apoA-I promoter, enhance apoA-I and apoA-II secretion in vitro, whereas reduce apoC-III production significantly. Furthermore, after in vivo study that the hyperlipidemic rats were treated with GH002, HDL-cholesterol levels were increased significantly (P<0.01) at 2 weeks (100 mg/kg, 28.8%) and 3 weeks (30mg/kg, 19.8% and 100mg/kg, 36.4%, respectively) compared with control group. Triglyceride levels were reduced significantly at 2 and 3 weeks (19.5%, P<0.05 and 28.1%, P<0.01 respectively). Total cholesterol levels also were reduced at 3 weeks (19.1%, P<0.05) after 100mg/kg GH002 administration, but GH002 didn’t increase the ratio of liver/body weight compared with the control group at the end of the experiments. It is therefore reasonable to assume that GH002 is an effectively HDL-cholesterol enhancer by regulating apoA-I gene expression, consequently enhancing apoA-I, apoA-II secretion and reducing apoC-III production.

Download Full-text

High Triglyceride/HDL Cholesterol Ratio is Associated with Silent Brain Infarcts in a Healthy Population

10.21203/rs.2.9432/v3 ◽

2019 ◽

Author(s):

Ki-Woong Nam ◽

Hyung-Min Kwon(Former Corresponding Author) ◽

Han-Yeong Jeong ◽

Jin-Ho Park(New Corresponding Author) ◽

Hyuktae Kwon ◽

...

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Vascular Diseases ◽

Hdl Cholesterol ◽

Cerebrovascular Diseases ◽

Healthy Population ◽

Cholesterol Ratio ◽

Silent Brain Infarct ◽

Cholesterol Levels

Download Full-text

Abstract 1392: Increased High Density Lipoprotein Cholesterol induced by Human Apolipoprotein A-I Gene Transfer increases Adiponectin Expression in abdominal Adipose Tissue

Circulation ◽

10.1161/circ.116.suppl_16.ii_286 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Sophie Van Linthout ◽

Frank Spillmann ◽

Anna Foryst-Ludwig ◽

Carola Bücker-Gärtner ◽

Marco Meloni ◽

...

Keyword(s):

Gene Transfer ◽

High Density Lipoprotein ◽

Plasma Concentrations ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

High Density ◽

Dependent Manner ◽

Human Apolipoprotein ◽

Protein Levels

Introduction: High density lipoprotein (HDL) cholesterol (C) levels positively correlate with plasma adiponectin levels. However, the role of HDL on adiponectin expression is unkown. To investigate the effect of increased HDL levels on adiponectin expression, 1) gene transfer with human apolipoprotein (apo) A-I, the main apo of HDL, was performed in control mice and in lipopolysaccharide (LPS)-injected mice, associated with decreased adiponectin levels and 2) HDL was supplemented in vitro on (pre)-adipocytes. Methods: Eight weeks old male C57BL/6 mice were i.v. injected with 5 × 10e10 total particles of the E1E3E4-deleted adenoviral vector Ad.hapoA-I, expressing human apo A-I or with the same dose of Ad.Null, containing no expression cassette. Fourteen days hereafter, mice were i.p. injected with LPS from Escherichia coli at a dose of 80 mg/kg or with saline. Mice were sacrificed 12 hours after LPS or saline injection. Human apo A-I and mouse adiponectin plasma concentrations were determined by ELISA. Abdominal fat phospho (p) and total (tot.) Akt protein levels were determined by Western Blot; adiponectin mRNA expression of (pre)-adipocytes by real-time PCR. Results: Ad.hapoA-I GT resulted in human apo A-I expression levels of 83Â27>4.6 mg/dl at day 14, which was associated with 1.8-fold (p<0.05) and 1.5-fold (p<0.05) higher HDL-C and adiponectin levels compared to Ad.Null mice, respectively. After LPS-injection, human apo A-I levels decreased by 1.7-fold (p<0.001), leading to 1.7-fold lower adiponectin levels compared to Ad.hapoA-I control mice, but still 1.5-fold (p<0.01) higher compared to LPS-Ad.Null mice. The increased adiponectin levels in Ad.hapoA-I versus Ad.Null LPS-injected mice were associated with a 1.7-fold (p<0.05) increase in p-Akt/tot.Akt ratio. In vitro, LPS administration decreased adiponectin expression by 2.1-fold (p<0.01), which was normalized to control levels by HDL supplementation in a phosphatidylinositol-3-kinase (PI3K)-dependent manner, since Ly 294002 reversed the HDL-mediated increase in adiponectin expression. Conclusion: HDL increases adiponectin expression via the PI3K-Akt pathway, which may contribute to some of the pleiotropic actions of HDL such as its well-known anti-inflammatory effects.

Download Full-text

ABCA1/ApoE/HDL Signaling Pathway Facilitates Myelination and Oligodendrogenesis after Stroke

International Journal of Molecular Sciences ◽

10.3390/ijms21124369 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4369 ◽

Cited By ~ 2

Author(s):

Li Li ◽

Rongwen Li ◽

Alex Zacharek ◽

Fengjie Wang ◽

Julie Landschoot-Ward ◽

...

Keyword(s):

Signaling Pathway ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Artery Occlusion ◽

Mammalian Brain ◽

Ischemic Brain ◽

Atp Binding Cassette Transporter ◽

Cerebral Artery Occlusion ◽

Apoe Expression

ATP-binding cassette transporter A1 (ABCA1) plays an important role in the regulation of apolipoprotein E (ApoE) and the biogenesis of high-density lipoprotein (HDL) cholesterol in the mammalian brain. Cholesterol is a major source for myelination. Here, we investigate whether ABCA1/ApoE/HDL contribute to myelin repair and oligodendrogenesis in the ischemic brain after stroke. Specific brain ABCA1-deficient (ABCA1-B/-B) and ABCA1-floxed (ABCA1fl/fl) control mice were subjected to permanent distal middle-cerebral-artery occlusion (dMCAo) and were intracerebrally administered (1) artificial mouse cerebrospinal fluid (CSF) as vehicle control, (2) human plasma HDL3, and (3) recombined human ApoE2 starting 24 h after dMCAo for 14 days. All stroke mice were sacrificed 21 days after dMCAo. The ABCA1-B/-B–dMCAo mice exhibit significantly reduced myelination and oligodendrogenesis in the ischemic brain as well as decreased functional outcome 21 days after stroke compared with ABCA1fl/fl mice; administration of human ApoE2 or HDL3 in the ischemic brain significantly attenuates the deficits in myelination and oligodendrogenesis in ABCA1-B/-B–dMCAo mice ( p < 0.05, n = 9/group). In vitro, ABCA1-B/-B reduces ApoE expression and decreases primary oligodendrocyte progenitor cell (OPC) migration and oligodendrocyte maturation; HDL3 and ApoE2 treatment significantly reverses ABCA1-B/-B-induced reduction in OPC migration and oligodendrocyte maturation. Our data indicate that the ABCA1/ApoE/HDL signaling pathway contributes to myelination and oligodendrogenesis in the ischemic brain after stroke.

Download Full-text

Maternal Quercetin Consumption during Pregnancy May Help Regulate Total Cholesterol/HDL-Cholesterol Ratio without Effect on Cholesterol Levels in Male Progeny Consuming High-Fat Diet

Nutrients ◽

10.3390/nu13041242 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1242

Author(s):

Masakatsu Takashima ◽

Wataru Tanaka ◽

Hiroki Matsuyama ◽

Hayato Tajiri ◽

Hiroyuki Sakakibara

Keyword(s):

Total Cholesterol ◽

High Fat Diet ◽

Control Diet ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Blood Cholesterol ◽

High Fat ◽

Cholesterol Ratio ◽

Male Progeny ◽

Cholesterol Levels

Quercetin has been shown to have anti-obesity effects, but it is unknown whether these effects can be transmitted from mothers to their progeny. In this study, we investigated whether maternal quercetin consumption during pregnancy has a protective effect on high-fat diet–induced hyper lipid levels and overweight in progeny. Female mice consumed a control diet or a diet containing 1.0% quercetin during breeding. The male progeny were then divided into four groups that were (1) sacrificed at postnatal day 3; (2) born to dams fed the control diet and also fed the control diet (C-C), (3) born to dams fed the control diet and then fed a 30% high-fat diet (C-HF), or (4) born to dams fed the Q-diet and then fed the HF diet (Q-HF). Maternal consumption of quercetin did not affect body weight or blood lipid parameters in either dams or neonates at postnatal day 3. After 13 weeks, the Q-HF group exhibited greater body and liver weights, and higher blood cholesterol levels than the C-HF group. However, the total cholesterol/ high density lipoprotein (HDL)-cholesterol ratios in the Q-HF and C-C groups remained similar. In conclusion, maternal quercetin consumption does not appear to protect the next generation from high-fat diet–induced hyper cholesterol level in the blood and liver, and consequently overweight, but may help regulate the total cholesterol/HDL-cholesterol ratio.

Download Full-text