The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia

In the present study, we investigated the effects of xanthine oxidase (XO) inhibition on cholesterol-induced renal dysfunction in chronic kidney disease (CKD) mice, and in low-density lipoprotein (LDL)-treated human kidney proximal tubule epithelial (HK-2) cells. ApoE knockout (KO) mice underwent uninephrectomy to induce CKD, and were fed a normal diet or high-cholesterol (HC) diet along with the XO inhibitor topiroxostat (1 mg/kg/day). HK-2 cells were treated with LDL (200 µg/mL) and topiroxostat (5 µM) or small interfering RNA against xanthine dehydrogenase (siXDH; 20 nM). In uninephrectomized ApoE KO mice, the HC diet increased cholesterol accumulation, oxidative stress, XO activity, and kidney damage, while topiroxostat attenuated the hypercholesterolemia-associated renal dysfunction. The HC diet induced cholesterol accumulation by regulating the expressions of genes involved in cholesterol efflux (Nr1h3 and Abca1) and synthesis (Srebf2 and Hmgcr), which was reversed by topiroxostat. Topiroxostat suppressed the expressions of genes related to hypercholesterolemia-associated inflammation and fibrosis in the unilateral kidney. LDL stimulation evoked changes in the cholesterol metabolism, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and NF-κB pathways in HK-2 cells, which were mitigated by XO inhibition with topiroxostat or siXDH. These findings suggest that XO inhibition exerts renoprotective effects against hypercholesterolemia-associated kidney injury. XO could be a novel therapeutic target for hypercholesterolemia-associated kidney injury in uninephrectomized patients.

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Polyphenols can Potentially Prevent Atherosclerosis and Cardiovascular Disease by Modulating Macrophage Cholesterol Metabolism

Current Molecular Pharmacology ◽

10.2174/1874467213666200320153410 ◽

2020 ◽

Vol 14 (2) ◽

pp. 175-190 ◽

Cited By ~ 3

Author(s):

Fumiaki Ito

Keyword(s):

Cholesterol Efflux ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Arterial Disease ◽

Epidemiological Studies ◽

Cholesterol Homeostasis ◽

Cholesterol Accumulation ◽

Cholesterol Uptake ◽

Patients At Risk

Background: Arterial atherosclerosis is the main pathological cause of coronary artery disease and peripheral arterial disease. Atherosclerosis is a chronic condition characterized by the presence of cholesterol-rich macrophages in the arterial intima. Accumulation of cholesterol in these macrophages is due to increased oxidation of low-density lipoprotein (LDL) and its uptake via scavenger receptors on the macrophages. Cholesterol efflux from the cholesterol-laden macrophages into high-density lipoprotein (HDL) is also a key process in maintaining cholesterol homeostasis and prevention of cholesterol accumulation. Four pathways for the efflux of cholesterol to HDL exist in macrophages, including passive and active pathways. Several HDL characteristics determine cholesterol efflux capacity, namely composition, oxidative status, and HDL size. Oxidation of LDL and HDL as well as any imbalance in cholesterol uptake and efflux could lead to accumulation of cholesterol in macrophages and initiation of atherosclerogenesis. Conclusion: Epidemiological studies have demonstrated that polyphenol-rich foods reduce cardiovascular events in the general population and in patients at risk of cardiovascular diseases. Many studies have reported that polyphenols in polyphenol-rich foods have anti-atherosclerotic properties by preventing cholesterol accumulation in macrophages through the suppression of lipoproteins oxidation and regulation of cholesterol uptake and efflux.

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Gallstone Disease and Cholesterolosis in Monozygotic Twin Sisters

Balkan Journal of Medical Genetics ◽

10.2478/v10034-007-0007-4 ◽

2007 ◽

Vol 10 (1) ◽

pp. 39-42

Author(s):

R Ivanchenkova ◽

N Sharashkina ◽

I Martirosyan ◽

S Limborska ◽

A Ryskov

Keyword(s):

Normal Tissue ◽

Genetic Basis ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Gallstone Disease ◽

Density Lipoprotein ◽

Monozygotic Twin ◽

Gallbladder Wall ◽

Cholesterol Accumulation ◽

Ldl Subfractions

Gallstone Disease and Cholesterolosis in Monozygotic Twin SistersGallstone disease and Cholesterolosis may be independent diseases or forms of the same disease, caused by impairment of cholesterol metabolism. Gallstone disease is characterized by formation of cholesterol concrements in the gallbladder cavity. Cholesterolosis is a hyperplastic cholecistosis, caused by cholesterol accumulation in the gallbladder wall with subsequent proliferation of gallbladder normal tissue elements. We describe monozygotic twin sisters, one of whom developed gallstone disease and the other developed cholesterolosis. Monozygosity was verified by a DNA fingerprinting method. Both had identical heterogeneity of plasma low density lipoprotein (LDL) subfractions, but associated with different functional conditions within the gallbladder. The different manifestations may be due to epigenetic, metabolic or environmental factors, since both had a common genetic basis.

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Efficacy of Bilberry and Grape Seed Extract Supplement Interventions to Improve Glucose and Cholesterol Metabolism and Blood Pressure in Different Populations—A Systematic Review of the Literature

Nutrients ◽

10.3390/nu13051692 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1692

Author(s):

Teresa Grohmann ◽

Caroline Litts ◽

Graham Horgan ◽

Xuguang Zhang ◽

Nigel Hoggard ◽

...

Keyword(s):

Blood Pressure ◽

Metabolic Syndrome ◽

Ldl Cholesterol ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Grape Seed Extract ◽

Grape Seed ◽

Good Evidence ◽

Seed Extract

Intervention with fruit extracts may lower glucose and lipid levels, as well as blood pressure. We reviewed the efficacy of bilberry and grape seed extracts to affect these outcomes across populations with varying health status, age and ethnicity, across intervention doses and durations, in 24 intervention studies with bilberry and blackcurrant (n = 4) and grape seed extract (n = 20). Bilberry and blackcurrant extract lowered average levels of glycated hemoglobin (HbA1c), at least in Chinese subjects, especially in those who were older, who were diagnosed with Type 2 Diabetes Mellitus (T2DM) and who were participating in longer-term studies. We also found good evidence that across studies and in subjects with hypercholesterolemia, T2DM or metabolic syndrome, intervention with bilberry and blackcurrant extract, and to some extent grape seed extract, significantly lowered total and low density lipoprotein (LDL) cholesterol levels after four weeks. Intervention with grape seed extract may reduce systolic and diastolic blood pressure in subjects with hypertension or metabolic syndrome. Differential responsiveness in cholesterol and blood pressure outcomes between stratified populations could not be explained by age, dose or study duration. In conclusion, bilberry and blackcurrant extract appears effective in lowering HbA1c and total and LDL cholesterol, whereas grape seed extract may lower total and LDL cholesterol, and blood pressure, in specific population groups.

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Effect of cell density on binding and uptake of low density lipoprotein by human fibroblasts.

The Journal of Cell Biology ◽

10.1083/jcb.83.3.588 ◽

1979 ◽

Vol 83 (3) ◽

pp. 588-594 ◽

Cited By ~ 54

Author(s):

H S Kruth ◽

J Avigan ◽

W Gamble ◽

M Vaughan

Keyword(s):

Cell Density ◽

Low Density Lipoprotein ◽

Human Fibroblasts ◽

Density Lipoprotein ◽

Low Density ◽

Cellular Lipid ◽

Cholesterol Accumulation ◽

Ldl Receptors ◽

Ldl Binding ◽

In Cells

The effect of cell density on low density lipoprotein (LDL) binding by cultured human skin fibroblasts was investigated. Bound LDL was visualized by indirect immunofluorescence. Cellular lipid and cholesterol were monitored by fluorescence in cells stained with phosphine 3R and filipin, respectively. LDL binding and lipid accumulation were compared in cells in stationary and exponentially growing cultures, in sparsely and densely plated cultures, in wounded and non-wounded areas of stationary cultures, and in stationary cultures with and without the addition of lipoprotein-deficient serum. We conclude that LDL binding and cholesterol accumulation induced by LDL are influenced by cell density. It appears that, compared to rapidly growing cells, quiescent (noncycling) human fibroblasts exhibit fewer functional LDL receptors.

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Emodin alleviated hyperlipidemia and hepatic lipid metabolism in zebrafish larvae fed a high-cholesterol diet via AMPK/SREBP-2/PCSK9/LDLR signaling pathway

10.21203/rs.3.rs-796126/v1 ◽

2021 ◽

Author(s):

Linfeng He ◽

Cheng Wang ◽

Yafang Zhang ◽

Chaocheng Guo ◽

Yan Wan ◽

...

Keyword(s):

Lipid Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

High Cholesterol Diet ◽

Low Density ◽

Cholesterol Diet ◽

High Cholesterol ◽

Cholesterol Accumulation ◽

Hepatic Lipid ◽

Zebrafish Larvae

Abstract BackgroundEmodin (EM) is one of bioactive components extracted from Rheum palmatum L. (Dahuang), which possesses numerous pharmacological activities including hypolipidemic effect. However, the potential action of EM on hyperlipidemia (HLP) remains unclear. Here, the theraputic effect of EM against HLP were investigated.MethodsIn this study, the hypolipidemic properties of EM were evaluated using high-cholesterol diet (HCD)-stimulated zebrafish larvae model. The body weight, body length and body mass index (BMI) was measured. The total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) as well as the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by corresponding assay kits. Tg (flil: eGFP) zebrafish were utilized to observe vascular cholesterol accumulation and Tg (mpx: eGFP) zebrafish to visualize and quantify neutrophil inflammation. The hepatic lipid deposition and hepatic histopathology were analyzed by Oil red O staining and H&E staining, respectively. Finally, the underlying mechanism of EM were investigated using real-time quantitative PCR (RT-qPCR) analysis to assess the gene levels of adenosine monophosphate-activated protein kinase alpha (AMPKα), sterol regulatory element binding protein 2 (SREBP-2), proprotein convertase subtilisin kexin 9 (PCSK9), low-density lipoprotein receptor (LDLR), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), adenosine triphosphate binding cassette transporter A1 (ABCA1) and adenosine triphosphate binding cassette transporter G1 (ABCG1).ResultsOur data indicated that EM reduced obesity of zebrafish as evidenced by the decrease in body weight, body length and BMI. EM significantly reduced TC, TG, and LDL-C, and increased HDL-C contents. Moreover, it displayed a prominent inhibitory effect on blood cholesterol accumulation, hepatic lipid accumulation, and neutrophil inflammation in vascular site. Additionally, EM improved the liver function through decreasing ALT and AST levels of zebrafish with HCD-induced hepatosteatosis. Further investigation showed that EM treatment attenuated lipid accumulation via upregulating the expression of AMPKα, LDLR, ABCA1 and ABCG1, and downregulating the expression of SREBP-2, PCSK9 and HMGCR.ConclusionTo conclude, EM alleviated lipid metabolism disorder symptoms caused by HCD via modulating AMPK/SREBP-2/PCSK9/LDLR pathway in larvae, suggesting that EM may be developed into hypolipidmic agent for treating lipid metabolism related diseases.

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Deleting myeloid IL-10 receptor signalling attenuates atherosclerosis in LDLR-/- mice by altering intestinal cholesterol fluxes

Thrombosis and Haemostasis ◽

10.1160/th16-01-0043 ◽

2016 ◽

Vol 116 (09) ◽

pp. 565-577 ◽

Cited By ~ 6

Author(s):

Gemma Brufau ◽

Marion J. J. Gijbels ◽

Ine M. J. Wolfs ◽

Saskia van der Velden ◽

Chantal C. H. Pöttgens ◽

...

Keyword(s):

Inflammatory Responses ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Homeostasis ◽

Liver Cholesterol ◽

Specific Cell ◽

Low Density ◽

Atherosclerosis Development ◽

Deficient Mice

SummaryInflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleukin (IL)-10 is an important anti-inflammatory cytokine, known to suppress atherosclerosis development. However, the specific cell types responsible for the atheroprotective effects of IL-10 remain to be defined and knowledge on the actions of IL-10 in cholesterol homeostasis is scarce. Here we investigated the functional involvement of myeloid IL-10-mediated atheroprotection. To do so, bone marrow from IL-10 receptor 1 (IL-10R1) wild-type and myeloid IL-10R1-deficient mice was transplanted to lethally irradiated female LDLR-/- mice. Hereafter, mice were given a high cholesterol diet for 10 weeks after which atherosclerosis development and cholesterol metabolism were investigated. In vitro, myeloid IL-10R1 deficiency resulted in a pro-inflammatory macrophage phenotype. However, in vivo significantly reduced lesion size and severity was observed. This phenotype was associated with lower myeloid cell accumulation and more apoptosis in the lesions. Additionally, a profound reduction in plasma and liver cholesterol was observed upon myeloid IL-10R1 deficiency, which was reflected in plaque lipid content. This decreased hypercholesterolaemia was associated with lowered very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels, likely as a response to decreased intestinal cholesterol absorption. In addition, IL-10R1 deficient mice demonstrated substantially higher faecal sterol loss caused by increased non-biliary cholesterol efflux. The induction of this process was linked to impaired ACAT2-mediated esterification of liver and plasma cholesterol. Overall, myeloid cells do not contribute to IL-10-mediated atheroprotection. In addition, this study demonstrates a novel connection between IL-10-mediated inflammation and cholesterol homeostasis in atherosclerosis. These findings make us reconsider IL-10 as a beneficial influence on atherosclerosis.Supplementary Material to this article is available online at www.thrombosis-online.com.

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Bile Acids: The Good, the Bad, and the Ugly

Physiology ◽

10.1152/physiologyonline.1999.14.1.24 ◽

1999 ◽

Vol 14 (1) ◽

pp. 24-29 ◽

Cited By ~ 48

Author(s):

Alan F. Hofmann

Keyword(s):

Bile Acids ◽

Enterohepatic Circulation ◽

Cholesterol Metabolism ◽

Plasma Cholesterol ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipid Absorption ◽

Bile Acid Metabolism ◽

Cholesterol Levels ◽

Density Lipoprotein Receptor

Bile acids, amphipathic end products of cholesterol metabolism, are “good” in the infant because they enhance lipid absorption and thereby promote growth. Bile acids also induce bile flow and biliary lipid secretion. The enterohepatic circulation of bile acids is “bad” in the adult because it downregulates hepatocyte low-density lipoprotein receptor activity and thereby elevates plasma cholesterol levels. Defects in bile acid metabolism such as impaired biosynthesis or transport are “ugly” because they cause morbidity and death. New approaches for treating these defects are being developed.

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Macrophage LRP1 Promotes Diet-Induced Hepatic Inflammation and Metabolic Dysfunction by Modulating Wnt Signaling

Mediators of Inflammation ◽

10.1155/2018/7902841 ◽

2018 ◽

Vol 2018 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Dianaly T. Au ◽

Mary Migliorini ◽

Dudley K. Strickland ◽

Selen C. Muratoglu

Keyword(s):

Insulin Resistance ◽

Wnt Signaling ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Lipoprotein Receptor ◽

Hepatic Inflammation ◽

Low Density Lipoprotein Receptor ◽

Density Lipoprotein Receptor

Hepatic inflammation is associated with the development of insulin resistance, which can perpetuate the disease state and may increase the risk of metabolic syndrome and diabetes. Despite recent advances, mechanisms linking hepatic inflammation and insulin resistance are still unclear. The low-density lipoprotein receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is highly expressed in macrophages, adipocytes, hepatocytes, and vascular smooth muscle cells. To investigate the potential role of macrophage LRP1 in hepatic inflammation and insulin resistance, we conducted experiments using macrophage-specific LRP1-deficient mice (macLRP1−/−) generated on a low-density lipoprotein receptor knockout (LDLR−/−) background and fed a Western diet. LDLR−/−; macLRP1−/− mice gained less body weight and had improved glucose tolerance compared to LDLR−/− mice. Livers from LDLR−/−; macLRP1−/− mice displayed lower levels of gene expression for several inflammatory cytokines, including Ccl3, Ccl4, Ccl8, Ccr1, Ccr2, Cxcl9, and Tnf, and reduced phosphorylation of GSK3α and p38 MAPK proteins. Furthermore, LRP1-deficient peritoneal macrophages displayed altered cholesterol metabolism. Finally, circulating levels of sFRP-5, a potent anti-inflammatory adipokine that functions as a decoy receptor for Wnt5a, were elevated in LDLR−/−; macLRP1−/− mice. Surface plasmon resonance experiments revealed that sFRP-5 is a novel high affinity ligand for LRP1, revealing that LRP1 regulates levels of this inhibitor of Wnt5a-mediated signaling. Collectively, our results suggest that LRP1 expression in macrophages promotes hepatic inflammation and the development of glucose intolerance and insulin resistance by modulating Wnt signaling.

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Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans

PLoS Genetics ◽

10.1371/journal.pgen.1009891 ◽

2021 ◽

Vol 17 (11) ◽

pp. e1009891

Author(s):

Baocai Xie ◽

Xiaochen Shi ◽

Yan Li ◽

Bo Xia ◽

Jia Zhou ◽

...

Keyword(s):

Cardiovascular Disease ◽

De Novo ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Atherogenic Diet ◽

Standard Diet ◽

Low Levels ◽

Reduced Risk

Genetic variants in the asialoglycoprotein receptor 1 (ASGR1) are associated with a reduced risk of cardiovascular disease (CVD) in humans. However, the underlying molecular mechanism remains elusive. Given the cardiovascular similarities between pigs and humans, we generated ASGR1-deficient pigs using the CRISPR/Cas9 system. These pigs show age-dependent low levels of non-HDL-C under standard diet. When received an atherogenic diet for 6 months, ASGR1-deficient pigs show lower levels of non-HDL-C and less atherosclerotic lesions than that of controls. Furthermore, by analysis of hepatic transcriptome and in vivo cholesterol metabolism, we show that ASGR1 deficiency reduces hepatic de novo cholesterol synthesis by downregulating 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and increases cholesterol clearance by upregulating the hepatic low-density lipoprotein receptor (LDLR), which together contribute to the low levels of non-HDL-C. Despite the cardioprotective effect, we unexpectedly observed mild to moderate hepatic injury in ASGR1-deficient pigs, which has not been documented in humans with ASGR1 variants. Thus, targeting ASGR1 might be an effective strategy to reduce hypercholesterolemia and atherosclerosis, whereas further clinical evidence is required to assess its hepatic impact.

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The Bioavailability and Biological Activities of Phytosterols as Modulators of Cholesterol Metabolism

Molecules ◽

10.3390/molecules27020523 ◽

2022 ◽

Vol 27 (2) ◽

pp. 523

Author(s):

Xiang Li ◽

Yan Xin ◽

Yuqian Mo ◽

Pavel Marozik ◽

Taiping He ◽

...

Keyword(s):

Cholesterol Metabolism ◽

Biological Activities ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Absorption ◽

The Body ◽

Research Progress ◽

Intestinal Lumen ◽

Dose Response Relationship ◽

Liver X Receptor Α

Phytosterols are natural sterols widely found in plants that have a variety of physiological functions, and their role in reducing cholesterol absorption has garnered much attention. Although the bioavailability of phytosterols is only 0.5–2%, they can still promote cholesterol balance in the body. A mechanism of phytosterols for lowering cholesterol has now been proposed. They not only reduce the uptake of cholesterol in the intestinal lumen and affect its transport, but also regulate the metabolism of cholesterol in the liver. In addition, phytosterols can significantly reduce the plasma concentration of total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C), with a dose-response relationship. Ingestion of 3 g of phytosterols per day can reach the platform period, and this dose can reduce LDL-C by about 10.7%. On the other hand, phytosterols can also activate the liver X receptor α-CPY7A1 mediated bile acids excretion pathway and accelerate the transformation and metabolism of cholesterol. This article reviews the research progress of phytosterols as a molecular regulator of cholesterol and the mechanism of action for this pharmacological effect.

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