Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes

2012 ◽  
Vol 447 (2) ◽  
pp. 301-311 ◽  
Author(s):  
Ivana Campia ◽  
Valentina Sala ◽  
Joanna Kopecka ◽  
Christian Leo ◽  
Nico Mitro ◽  
...  
Keyword(s):  
Density Lipoprotein ◽  
Mitochondrial Respiratory Chain ◽  
Liver X Receptor ◽  
Target Cells ◽  
Human Hepatoma Cells ◽  
Inotropic Effects ◽  
Reverse Transport ◽  
Cardioactive Glycosides ◽  
Independent Effects ◽  
Coa Reductase

Cardioactive glycosides exert positive inotropic effects on cardiomyocytes through the inhibition of Na+/K+-ATPase. We showed previously that in human hepatoma cells, digoxin and ouabain increase the rate of the mevalonate cascade and therefore have Na+/K+-ATPase-independent effects. In the present study we found that they increase the expression and activity of 3-hydroxy-3 methylglutaryl-CoA reductase and the synthesis of cholesterol in cardiomyocytes, their main target cells. Surprisingly this did not promote intracellular cholesterol accumulation. The glycosides activated the liver X receptor transcription factor and increased the expression of ABCA1 (ATP-binding cassette protein A1) transporter, which mediates the efflux of cholesterol and its delivery to apolipoprotein A-I. By increasing the synthesis of ubiquinone, another derivative of the mevalonate cascade, digoxin and ouabain simultaneously enhanced the rate of electron transport in the mitochondrial respiratory chain and the synthesis of ATP. Mice treated with digoxin showed lower cholesterol and higher ubiquinone content in their hearts, and a small increase in their serum HDL (high-density lipoprotein) cholesterol. The results of the present study suggest that cardioactive glycosides may have a role in the reverse transport of cholesterol and in the energy metabolism of cardiomyocytes.

Glycation and HMG-CoA Reductase Inhibitors: Implication in Diabetes and Associated Complications

2019 ◽  
Vol 15 (3) ◽  
pp. 213-223 ◽  
Author(s):  
Rabia Nabi ◽  
Sahir Sultan Alvi ◽  
Mohd. Saeed ◽  
Saheem Ahmad ◽  
Mohammad Salman Khan
Keyword(s):  
Oxidized Ldl ◽  
Advanced Glycation Endproducts ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Protective Role ◽  
Therapeutic Effects ◽  
Hmg Coa Reductase ◽  
Toxicological Effects ◽  
Coa Reductase

Introduction: Diabetes Mellitus (DM) acts as an absolute mediator of cardiovascular risk, prompting the prolonged occurrence, size and intricacy of atherosclerotic plaques via enhanced Advanced Glycation Endproducts (AGEs) formation. Moreover, hyperglycemia is associated with enhanced glyco-oxidized and oxidized Low-Density Lipoprotein (LDL) possessing greater atherogenicity and decreased the ability to regulate HMG-CoA reductase (HMG-R). Although aminoguanidine (AG) prevents the AGE-induced protein cross-linking due to its anti-glycation potential, it exerts several unusual pharmaco-toxicological effects thus restraining its desirable therapeutic effects. HMG-R inhibitors/statins exhibit a variety of beneficial impacts in addition to the cholesterol-lowering effects. Objective: Inhibition of AGEs interaction with receptor for AGEs (RAGE) and glyco-oxidized-LDL by HMG-R inhibitors could decrease LDL uptake by LDL-receptor (LDL-R), regulate cholesterol synthesis via HMG-R, decrease oxidative and inflammatory stress to improve the diabetes-associated complications. Conclusion: Current article appraises the pathological AGE-RAGE concerns in diabetes and its associated complications, mainly focusing on the phenomenon of both circulatory AGEs and those accumulating in tissues in diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy, discussing the potential protective role of HMG-R inhibitors against diabetic complications.

scholarly journals The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1828
Author(s):  
Jared Kirui ◽  
Yara Abidine ◽  
Annasara Lenman ◽  
Koushikul Islam ◽  
Yong-Dae Gwon ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Molecular Mechanisms ◽  
Rna Virus ◽  
Ectopic Expression ◽  
Point Mutations ◽  
Cell Entry ◽  
Target Cells ◽  
Human Hepatoma Cells ◽  
Chikv Infection ◽  
Phosphatidylserine Receptor

Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain poorly understood. The phosphatidylserine-dependent receptors, T-cell immunoglobulin and mucin domain 1 (TIM-1) and Axl receptor tyrosine kinase (Axl), are transmembrane proteins that can serve as entry factors for enveloped viruses. Previous studies used pseudoviruses to delineate the role of TIM-1 and Axl in CHIKV entry. Conversely, here, we use the authentic CHIKV and cells ectopically expressing TIM-1 or Axl and demonstrate a role for TIM-1 in CHIKV infection. To further characterize TIM-1-dependent CHIKV infection, we generated cells expressing domain mutants of TIM-1. We show that point mutations in the phosphatidylserine binding site of TIM-1 lead to reduced binding, entry, and infection of CHIKV. Ectopic expression of TIM-1 renders immortalized keratinocytes permissive to CHIKV, whereas silencing of endogenously expressed TIM-1 in human hepatoma cells reduces CHIKV infection. Altogether, our findings indicate that, unlike Axl, TIM-1 readily promotes the productive entry of authentic CHIKV into target cells.

scholarly journals Role of Baicalin and Liver X Receptor Alpha in the Formation of Cholesterol Gallstones in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Geng Chen ◽  
Shuodong Wu
Keyword(s):  
Oxidative Stress ◽  
Bile Acid ◽  
Cholesterol Metabolism ◽  
Density Lipoprotein ◽  
Liver X Receptor ◽  
Cholesterol Gallstones ◽  
Receptor Alpha ◽  
Lithogenic Diet ◽  
Liver X Receptor Alpha ◽  
And Oxidative Stress

This study was aimed at investigating the effect of baicalin on experimental cholesterol gallstones in mice. The mouse gallstone model was induced by feeding with a lithogenic diet, and cholesterol stones were found in the gallbladder. The lithogenic diet caused elevation of triglycerides, cholesterol, and low-density lipoprotein concentrations and descent of high-density lipoprotein concentration in serum. Hyperplasia and inflammatory infiltration were observed in the gallbladder wall of lithogenic diet-fed mice. We also found the increase of cholesterol content and the decrease of bile acid in bile. Real-time PCR and western blot results demonstrated that the expression levels of two enzymes (cholesterol 7α-hydroxylase (CYP7a1) and sterol 12α-hydroxylase (CYP8b1)) to catalyze the synthesis of bile acid from cholesterol were decreased and that two cholesterol transporters (ATP-binding cassette transporter G5/G8 (ABCG5/8)) were increased in the liver of lithogenic diet-fed mice. The lithogenic diet also led to enhanced activity of alanine aminotransferase and aspartate aminotransferase in serum; increased concentrations of tumor necrosis factor-α, interleukin- (IL-) 1β, IL-6, and malondialdehyde; and decreased superoxide dismutase activity in the liver, suggesting inflammatory and oxidative stress. In addition, liver X receptor alpha (LXRα) was increased in the liver. After gavage of baicalin, the lithogenic diet-induced gallstones, hyperlipidemia, gallbladder hyperplasia, inflammation, and oxidative stress in liver and cholesterol metabolism disorders were all alleviated to some degree. The expression of LXRα in the liver was inhibited by baicalin. In addition, the LXRα agonist T0901317 aggravated lithogenic diet-induced harmful symptoms in mice, including the increase of gallstone formation, hyperlipidemia, hepatic injury, inflammation, and oxidative stress. In conclusion, we demonstrated that baicalin played a protective role in a lithogenic diet-induced gallstone mouse model, which may be mediated by inhibition of LXRα activity. These findings may provide novel insights for prevention and therapy of gallstones in the clinic.

scholarly journals Ribavirin and Alpha Interferon Enhance Death Receptor-Mediated Apoptosis and Caspase Activation in Human Hepatoma Cells

2003 ◽  
Vol 47 (6) ◽  
pp. 1912-1921 ◽  
Author(s):  
Stephan F. Schlosser ◽  
Markus Schuler ◽  
Christoph P. Berg ◽  
Kirsten Lauber ◽  
Klaus Schulze-Osthoff ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Death Receptor ◽  
Alpha Interferon ◽  
Target Cells ◽  
Clinical Effects ◽  
Caspase Activation ◽  
Human Hepatoma Cells ◽  
Promoting Effect

ABSTRACT The molecular mechanisms underlying the clinical effects of alpha interferon (IFN) and ribavirin are not understood. Elimination of infected cells occurs in part by cytotoxic T lymphocytes (CTLs) expressing CD95 ligand and thereby attacking target cells which are positive for the death receptor CD95. Since many viruses have evolved mechanisms to inhibit apoptosis, the opposite, namely, promotion of apoptosis, could be a strategy to strengthen the host antiviral response. In the present study, we have asked whether the antiviral substances IFN and ribavirin could support CD95-mediated apoptosis by interfering with the activation of caspases, a family of proteases known for their essential role in apoptosis. HepG2 cells, stimulated with the agonistic anti-CD95 antibody, served as a minimal model to mimic the CD95 stimulation ocurring during a CTL attack of target cells in vivo. Apoptosis was quantitated by flow cytometric detection of hypodiploid nuclei. Caspase activity was measured by cytofluorometry, immunocytochemistry, and immunoblot analysis. IFN and ribavirin sensitized HepG2 cells for CD95-mediated apoptosis. This effect was correlated with an increase in CD95-mediated caspase activation and enhanced cleavage of the caspase substrate poly(ADP-ribose) polymerase. Furthermore, the positive effect on CD95-mediated caspase activation by IFN and ribavirin was confirmed by immunocytochemistry for activated caspase-3 and by immunoblot detection of activated caspase-3, caspase-7, and caspase-8. Our data demonstrate that the antiviral substances IFN and ribavirin are able to sensitize for CD95-mediated apoptosis. IFN and ribavirin also enhance CD95-mediated caspase activation, which might in part be responsible for the apoptosis-promoting effect of these antiviral compounds.

scholarly journals The absolute rate of cholesterol biosynthesis in monocyte-macrophages from normal and familial hypercholesterolaemic subjects

1984 ◽  
Vol 219 (2) ◽  
pp. 461-470 ◽  
Author(s):  
D D Patel ◽  
C R Pullinger ◽  
B L Knight
Keyword(s):  
Cholesterol Synthesis ◽  
Reductase Activity ◽  
Cholesterol Biosynthesis ◽  
Specific Radioactivity ◽  
Density Lipoprotein ◽  
Cellular Protein ◽  
True Rate ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
In Cells

The true rate of cholesterogenesis in cultured monocyte-macrophages was determined from the incorporation of [2-14C]acetate into cholesterol, using the desmosterol (cholesta-5,24-dien-3 beta-ol) that accumulated in the presence of the drug triparanol to estimate the specific radioactivity of the newly formed sterols. It was shown that this procedure could be successfully adapted for use with cultured monocytes despite the accumulation of other unidentified biosynthetic intermediates. In cells maintained in 20% (v/v) whole serum approx. 25% of the sterol carbon was derived from exogenous acetate. Cholesterol synthesis was as high in normal cells as in cells from homozygous familial hypercholesterolaemic (FH) subjects and accounted for 50% of the increase in cellular cholesterol. The addition of extra low-density lipoprotein (LDL) reduced cholesterol synthesis, apparently through a decrease in the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). When incubated in lipoprotein-deficient serum some cells did not survive, but those that remained showed a normal increase in protein content; the amount of cellular protein and cholesterol in each well did not increase and cholesterol synthesis was reduced by over 80%. HMG-CoA reductase activity fell less dramatically and the proportion of sterol carbon derived from exogenous acetate increased, suggesting that the low rate of cholesterogenesis with lipoprotein-deficient serum was due to a shortage of substrate. The results indicate that under normal conditions monocyte-macrophages obtain cholesterol from endogenous synthesis rather than through receptor-mediated uptake of LDL, and that synthesis together with non-saturable uptake of LDL provides the majority of the cholesterol required to support growth.

Abstract 1927: High-dose Simvastatin Alone Inhibits Rho Kinase and Improves Flow-mediated Vasodilatation to a Greater Extent than Combination of Low-dose Simvastatin and Ezetimibe, Despite Comparable Lipid-Lowering

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ping-Yen Liu ◽  
Ping-Yen Liu ◽  
Yen-Wen Liu ◽  
Li-Jen Lin ◽  
Jyh-Hong Chen ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Low Dose ◽  
Cholesterol Biosynthesis ◽  
Rho Kinase ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Lipid Lowering ◽  
High Dose ◽  
Independent Effects ◽  
Rock Activity

Background: By inhibiting HMG-CoA reductase, statins not only inhibit cholesterol biosynthesis, but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho/Rho kinase (ROCK) pathway. In animal studies, inhibition of ROCK by statins improves endothelial function, decreases inflammation, and prevents atherosclerosis. These so-called cholesterol-independent effects of statins are dose-related and may contribute to some of their clinical benefits. We hypothesize that ezetimibe, which inhibits cholesterol absorption, does not exert these cholesterol-independent effects in humans. Methods and Results: We studied 60 dyslipidemia subjects (n=20 in each arm) in a prospective, randomized, observer-blinded study comparing treatment with simvastatin 40 mg/d or simvastatin/ezetimibe 10/10 mg/d to corresponding placebo tablets for 28 days. Prior statin usage was comparable between the groups and a washout period of 2 weeks was instituted before enrollment. Blood samples for fasting lipids, leukocyte ROCK activity and C-reactive protein (CRP) were collected at days 0 and 28. Baseline demographics, lipid levels, ROCK activity and CRP were not different between the 3 groups. Compared to placebo group, both treatment regimens decreased low-density lipoprotein cholesterol (LDL-C) by 38% and CRP by 32– 42% after 28 days (p<0.001 for both compared to placebo). Although LDL-C and CRP were reduced to comparable levels by either lipid-lowering regimen (p>0.05 between the groups), only simvastatin 40 mg reduced ROCK activity and improved forearm flow-mediated vasodilatation (FMD) (p<0.01 for both compared to baseline). The reduction of ROCK activity with simvastatin 40 mg remained significant even after controlling for changes in LDL-C (p=0.01) and correlated with improvement in FMD (R 2 =0.78, p<0.01). However, there was no correlation between changes in FMD with changes in LDL-C or CRP. Conclusions: These findings suggest that despite comparable decrease in LDL-C and CRP, high-dose statin monotherapy has greater effects on both ROCK activity and endothelial function than low-dose statin and ezetimibe. These findings provide additional evidence of potential statin benefits beyond cholesterol lowering.

scholarly journals Modulation of hepatic apolipoprotein B, 3-hydroxy-3-methylglutaryl-CoA reductase and low-density lipoprotein receptor mRNA and plasma lipoprotein concentrations by defined dietary fats. Comparison of trimyristin, tripalmitin, tristearin and triolein

1995 ◽  
Vol 311 (1) ◽  
pp. 167-173 ◽  
Author(s):  
A J Bennett ◽  
M A Billett ◽  
A M Salter ◽  
E H Mangiapane ◽  
J S Bruce ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Plasma Lipids ◽  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Dietary Fats ◽  
Low Density ◽  
Mrna Levels ◽  
Expression Of Genes ◽  
Coa Reductase

Different dietary fatty acids exert specific effects on plasma lipids but the mechanism by which this occurs is unknown. Hamsters were fed on low-cholesterol diets containing triacylglycerols enriched in specific saturated fatty acids, and effects on plasma lipids and the expression of genes involved in hepatic lipoprotein metabolism were measured. Trimyristin and tripalmitin caused significant rises in low-density lipoprotein (LDL) cholesterol which were accompanied by significant reductions in hepatic LDL receptor mRNA levels. Tripalmitin also increased hepatic expression of the apolipoprotein B gene, implying an increased production of LDL via very-low-density lipoprotein (VLDL) and decreased removal of LDL in animals fed this fat. Hepatic levels of 3-hydroxy-3-methylglutaryl-CoA reductase mRNA did not vary significantly between the groups. Compared with triolein, tristearin had little effect on hepatic gene expression or total plasma cholesterol. However, it caused a marked decrease in VLDL cholesterol and a rise in LDL cholesterol such that overall it appeared to be neutral. Lipid analysis suggested a rapid desaturation of much of the dietary stearate. The differential changes in plasma lipids and hepatic mRNA levels induced by specific dietary fats suggests a role for fatty acids or a metabolite thereof in the regulation of the expression of genes involved in lipoprotein metabolism.

Abstract 476: Attenuated Activities of Mitochondria in Vascular Endothelial Cells Exposed to Oxidized or Glycated Low Density Lipoprotein

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Garry X Shen ◽  
Subir K Roy Chowdhury
Keyword(s):  
Endothelial Cells ◽  
Respiratory Chain ◽  
Complex I ◽  
Vascular Endothelial Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Mitochondrial Respiratory Chain ◽  
Low Density ◽  
Vascular Endothelial ◽  
Glycated Ldl

Hyperglycemia and dyslipoproteinemia are two major biochemical markers of diabetes. Elevated low density lipoprotein (LDL) is a classical risk factor for atherosclerotic cardiovascular disease. Our previous studies demonstrated that oxidized LDL (ox-LDL) and glycated LDL (gly-LDL) increased the generation of reactive oxygen species (ROS) in vascular endothelial cells. ROS is implicated in endothelial dysfunction and diabetic vascular complications. Mitochondria are an important source of ROS in the body. We hypothesize that ox-LDL or gly-LDL might affect the activity of mitochondrial respiratory chain. We evaluated the activities of mitochondrial respiratory chain complexes in porcine aortic endothelial cells (PAEC) using OROBORS oxygraph. The oxygraph was used as a highly sensitive tool to evaluate mitochondrial complex activity in freshly harvested and digitonin-permeabilized PAEC (for Complex I, the rotenone-sensitive oxidation of glutamate + malate in the presence of ADP; Complex II, antimycin A-sensitive oxidation of succinate; Complex IV, potassium cyanide-sensitive oxidation of ascorbate + TMPD). The oxygen consumption in Complex I, II and IV of PAEC was significantly decreased by >12 h of incubation with LDL, ox-LDL or gly-LDL compared to control cultures. Attenuated activity of succinate cytochrome C reductase was detected in EC treated with LDL, ox-LDL or gly-LDL for 24 h. Decreased levels of respiratory control ratio were detected in EC treated with LDL or ox-LDL for 6 h, but not for 2 h, compared to control. Impaired activity of mitochondrial complexes can cause electron leakage in the respiratory chain and substantially increase ROS formation. The findings suggest that oxidized or glycated LDL attenuates mitochondrial activities in vascular EC, which may contribute to increased ROS generation and endothelial dysfunction induced by the atherogenic lipoproteins (supported by operating grants from Canadian Institute of Health Research and Canadian Diabetes Association).

scholarly journals Effect of dietary eicosapentaenoic and docosahexaenoic acid on expression of rat liver genes controlling cholesterol homeostasis and on plasma cholesterol level

2014 ◽  
Vol 59 (No. 9) ◽  
pp. 391-398 ◽  
Author(s):  
T. Komprda ◽  
G. Zorníková ◽  
A. Knoll ◽  
Z. Vykoukalová ◽  
V. Rozíková ◽  
...  
Keyword(s):  
Docosahexaenoic Acid ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Ldlr Gene ◽  
Expression Of Genes ◽  
Density Lipoprotein Receptor ◽  
Lower Plasma Cholesterol ◽  
Coa Reductase

A hypothesis that eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) lower plasma cholesterol via increased expression of the Insig-1 gene with ensuing decrease of expression of genes coding for 3-hydroxy-3-methyl-glutaryl-CoA reductase (Hmgcr) and low density lipoprotein receptor (Ldlr) was tested in rats fed a diet with 3% of fish oil (FO). Expression of the Insig-1 gene in the liver of the FO-fed rats was 730% (P &lt; 0.05) of the control. However, contrary to the hypothesis, expression of the Hmgcr gene and Ldlr gene was 165% and 210% of the control (P &gt; 0.05). Nevertheless, FO in the diet decreased (P &lt; 0.05) plasma cholesterol of rats by 10% (from 1.19 to 1.07 mmol/l); it was therefore concluded that the cholesterol-lowering effect of EPA+DHA is at least partly based on mechanisms other than tested in the present experiment. &nbsp;

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