scholarly journals Downregulation of PTEN promotes podocyte endocytosis of lipids aggravating obesity-related glomerulopathy

2020 ◽  
Vol 318 (3) ◽  
pp. F589-F599 ◽  
Author(s):  
Yuanyuan Shi ◽  
Chen Wang ◽  
Xiaoshuang Zhou ◽  
Yafeng Li ◽  
Yuehong Ma ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Glomerular Sclerosis ◽  
Filamentous Actin ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Stage Renal Disease ◽  
End Stage

With the increasing prevalence of obesity in adults worldwide, the incidence of obesity-related glomerulopathy (ORG) has increased yearly, becoming one of the leading causes of end-stage renal disease. Studies have demonstrated significant correlations between hyperlipidemia and impaired renal function in patients with ORG, indicating that hyperlipidemia causes damage in kidney cells. In podocytes, the endocytosis of lipids triggers an intracellular oxidative stress response that disrupts cellular integrity, resulting in proteinuria and glomerular sclerosis. However, the specific molecular mechanisms through which podocytes endocytose lipids remain unclear. Here, we demonstrated the enhanced endocytosis of lipids by podocytes from patients with ORG. This response was associated with decreased expression of phosphatase and tensin homolog (PTEN). In vitro silencing of PTEN promoted the endocytosis of low-density lipoprotein in mouse podocytes. Conversely, overexpression of PTEN inhibited the endocytosis of lipoproteins in podocytes. PTEN directly dephosphorylates and activates the actin-depolymerizing factor cofilin-1, leading to depolymerization of filamentous actin (F-actin), which is necessary for endocytosis. Notably, inhibition of PTEN resulted in the phosphorylation and inactivation of cofilin-1, leading to F-actin formation that enhanced the endocytosis of lipoproteins in podocytes. When hyperlipidemia was induced in mice with podocyte-specific deletion of PTEN, these mice recapitulated the major pathophysiological features of ORG. Thus, PTEN downregulation in podocytes may contribute to the pathogenesis of ORG.

Therapeutic Application of Diacylglycerol Oil for Obesity: Serotonin Hypothesis

2012 ◽  
Vol 2 (1) ◽  
pp. 1 ◽  
Author(s):  
Hidekatsu Yanai ◽  
Hiroshi Yoshida ◽  
Yuji Hirowatari ◽  
Norio Tada
Keyword(s):  
Energy Expenditure ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serotonin Release ◽  
Intestinal Cell ◽  
Therapeutic Application ◽  
Postprandial Triglyceride

Characteristics for the serum lipid abnormalities in the obesity/metabolic syndrome are elevated fasting, postprandial triglyceride (TG), and decreased high-density lipoprotein-cholesterol (HDL-C). Diacylglycerol (DAG) oil ingestion has been reported to ameliorate postprandial hyperlipidemia and prevent obesity by increasing energy expenditure, due to the intestinal physiochemical dynamics that differ from triacylglycerol (TAG). Our study demonstrated that DAG suppresses postprandial increase in TG-rich lipoprotein, very low-density lipoprotein (VLDL), and insulin, as compared with TAG in young, healthy individuals. Interestingly, our study also presented that DAG significantly increases plasma serotonin, which is mostly present in the intestine, and mediates thermogenesis, proposing a possible mechanism for a postprandial increase in energy expenditure by DAG. Our other study demonstrated that DAG suppresses postprandial increase in TG, VLDL-C, and remnant-like particle-cholesterol, in comparison with TAG in an apolipoprotein C-II deficient subject, suggesting that DAG suppresses postprandial TG-rich lipoprotein independently of lipoprotein lipase. Further, to understand the molecular mechanisms for DAG-mediated increase in serotonin and energy expenditure, we studied the effects of 1-monoacylglycerol and 2-monoacylglycerol, distinct digestive products of DAG and TAG, respectively, on serotonin release from the Caco-2 cells, the human intestinal cell line. We also studied effects of 1- and 2-monoacylglycerol, and serotonin on the expression of mRNA associated with β-oxidation, fatty acids metabolism, and thermogenesis, in the Caco-2 cells. 1-monoacylglycerol significantly increased serotonin release from the Caco-2 cells, compared with 2-monoacylglycerol by approximately 40%. The expression of mRNA of acyl-CoA oxidase (ACO), fatty acid translocase (FAT), and uncoupling protein-2 (UCP-2), was significantly higher in 1-MOG-treated Caco-2 cells, than 2-MOG-treated cells. The expression of mRNA of ACO, medium-chain acyl-CoA dehydrogenase, FAT, and UCP-2, was significantly elevated in serotonin-treated Caco-2 cells, compared to cells incubated without serotonin. In conclusion, our clinical and in vitro studies suggested a possible therapeutic application of DAG for obesity, and obesity-related metabolic disorders.Key words: Diacylglycerol, intestine, obesity, serotonin, thermogenesis

scholarly journals Greater variability in lipid measurements associated with kidney diseases in patients with type 2 diabetes mellitus in a 10-year diabetes cohort study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eric Yuk Fai Wan ◽  
Esther Yee Tak Yu ◽  
Weng Yee Chin ◽  
Christie Sze Ting Lau ◽  
Anna Hoi Ying Mok ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hazard Ratio ◽  
Lipoprotein Cholesterol ◽  
Low Density Lipoprotein Cholesterol ◽  
Cholesterol Ratio ◽  
Stage Renal Disease ◽  
End Stage

AbstractThis study aimed to evaluate the associations between variability of lipid parameters and the risk of kidney disease in patients with type 2 diabetes mellitus. Low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were specifically addressed in this study. This retrospective cohort study included 105,552 patients aged 45–84 with type 2 diabetes mellitus and normal kidney function who were managed under Hong Kong public primary care clinics during 2008–2012. Those with kidney disease (estimated glomerular filtration rate < 60 mL/min/1.73 m2 or urine albumin to creatinine ratio ≥ 3 mg/mmol) were excluded. Variabilities of low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were determined using the standard deviation of the respective parameter obtained from a mixed effects model to minimize regression dilution bias. The associations between lipid variability and renal outcomes including incident kidney disease, renal function decline defined as ≥ 30% reduction in estimated glomerular filtration rate since baseline, and end-stage renal disease (estimated glomerular filtration rate < 15 mL/min/1.73 m2) were evaluated by multivariable Cox regression. After a median follow-up of 66.5 months (0.5 million person-years in total), 49,653 kidney disease, 29,358 renal function decline, and 1765 end-stage renal disease cases were recorded. Positive linear associations between low-density lipoprotein-cholesterol and total cholesterol to high-density lipoprotein-cholesterol ratio variabilities and the risk of all renal outcomes were demonstrated. However, no association between triglyceride variability and any outcome was found. Each mmol/L increase in low-density lipoprotein-cholesterol variability was associated with 20% (Hazard ratio 1.20 [95% CI 1.15–1.25]), 38% (Hazard ratio 1.37 [95% CI 1.30–1.45]), and 108% (Hazard ratio 2.08 [95% CI 1.74–2.50]) higher risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Similarly, each unit increase in total cholesterol to high-density lipoprotein-cholesterol ratio variability was associated with 35% (Hazard ratio 1.15 [95% CI 1.10–1.20]), 33% (Hazard ratio 1.33 [95% CI 1.26–1.40]), and 75% (Hazard ratio 1.75 [95% CI 1.46–2.09]) heightened risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Cholesterol variability may potentially be a useful predictor of kidney diseases in patients with type 2 diabetes mellitus. Attention should be drawn to cholesterol variability when managing diabetic patients and further research is warranted to investigate the modifiable risk factors for lipid variability.

scholarly journals The Protective Role of Adiponectin for Lipoproteins in End-Stage Renal Disease Patients: Relationship with Diabetes and Body Mass Index

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Susana Coimbra ◽  
Flávio Reis ◽  
Sara Nunes ◽  
Sofia Viana ◽  
Maria João Valente ◽  
...  
Keyword(s):  
End Stage Renal Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Obese Patients ◽  
Cvd Risk Factors ◽  
Cvd Risk ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

Cardiovascular disease (CVD) events are the main causes of death in end-stage renal disease (ESRD) patients on dialysis. The number and severity of CVD events remain inappropriate and difficult to explain by considering only the classic CVD risk factors. Our aim was to clarify the changes and the relationship of lipoprotein subfractions with other CVD risk factors, namely, body mass index (BMI) and adipokines, inflammation and low-density lipoprotein (LDL) oxidation, and the burden of the most prevalent comorbidities, diabetes mellitus (DM) and hypertension (HT). We studied 194 ESRD patients on dialysis and 22 controls; lipid profile, including lipoprotein subpopulations and oxidized LDL (oxLDL), C-reactive protein (CRP), adiponectin, leptin, and paraoxonase 1 activity were evaluated. Compared to controls, patients presented significantly lower levels of cholesterol, high-density lipoprotein cholesterol (HDLc), LDLc, oxLDL, and intermediate and small HDL and higher triglycerides, CRP, adiponectin, large HDL, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein- (IDL) B. Adiponectin levels correlated positively with large HDL and negatively with intermediate and small HDL, oxLDL/LDLc, and BMI; patients with DM (n=17) and with DM+HT (n=70), as compared to patients without DM or HT (n=69) or only with HT (n=38), presented significantly higher oxLDL, oxLDL/LDLc, and leptin and lower adiponectin. Obese patients (n=45), as compared to normoponderal patients (n=81), showed lower HDLc, adiponectin, and large HDL and significantly higher leptin, VLDL, and intermediate and small HDL. In ESRD, the higher adiponectin seems to favor atheroprotective HDL modifications and protect LDL particles from oxidative atherogenic changes. However, in diabetic and obese patients, adiponectin presents the lowest values, oxLDL/LDLc present the highest ones, and the HDL profile is the more atherogenic. Our data suggest that the coexistence of DM and adiposity in ESRD patients on dialysis contributes to a higher CVD risk, as showed by their lipid and adipokine profiles.

scholarly journals Functional Comparison Of Immunoglobulin G Versus Oxidized Low-Density Lipoprotien Phagocytic Receptors In Human U937 Macrophages

2021 ◽  
Author(s):  
David T. Vance
Keyword(s):  
Immunoglobulin G ◽  
Kinase Inhibitor ◽  
Ion Trap ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Janus Kinase ◽  
Immunofluorescent Staining ◽  
Low Density ◽  
Filamentous Actin

Phagocytic macrophages bind to solid oxidized low-density lipoprotein (oxLDL) deposited on the arterial intima, differentiate into foam cells and cause atherosclerosis - the largest cause of mortality in Canada. The mechanism of oxLDL internalization was examined in vitro using differentiated U937 cells exposed to latex microbeads coated with oxLDL or Immunoglobulin G (IgG). Bead internalization was quantified using immunofluorescent staining and laser confocal assays. IgG-mediated engulfment was more rapid than oxLDL-mediated engulfment indicating a qualitatively different internalization pathway. The filamentous actin inhibitors Cytochalasin D (10uM) and Latrunculin B (5uM) completely inhibited phagocytosis of both oxLDL-coated and IgG-coated beads. The Src and Spleen tyrosine kinase inhibitor 3,4-methylenedioxy-beta-nitrostyrene (20 uM), the phospholipase C inhibitor U73122 (5 uM), and the Janus kinase inhibitor AG 490 (25 uM) displayed significant inhibitory effects on the phagocytosis of both IgG and oxLDL microbeads. The specific isoforms of oxLDL and IgG receptor associated enzymes were determined by nano LC-ESI-MS/MS with an LTQ ion trap.

scholarly journals Antibody to oxidized low-density lipoprotein and cardiovascular mortality in end-stage renal disease

2002 ◽  
Vol 62 (6) ◽  
pp. 2230-2237 ◽  
Author(s):  
Tetsuo Shoji ◽  
Mariko Fukumoto ◽  
Eiji Kimoto ◽  
Kayo Shinohara ◽  
Masanori Emoto ◽  
...  
Keyword(s):  
Renal Disease ◽  
Cardiovascular Mortality ◽  
End Stage Renal Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Stage Renal Disease ◽  
End Stage

P1581IMPACT OF ACHIEVING LDL CHOLESTEROL LOWER THAN 100 MG/DL WITH STATINS, ON LIPID PROFILE AND INFLAMMATION IN END-STAGE RENAL DISEASE PATIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Susana Coimbra ◽  
Flávio Reis ◽  
Sara Nunes ◽  
Sofia D. Viana ◽  
Maria João Valente ◽  
...  
Keyword(s):  
Lipid Profile ◽  
End Stage Renal Disease ◽  
Inflammatory Markers ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Group 2 ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients ◽  
Group 1

Abstract Background and Aims Dyslipidemia is common in chronic kidney disease (CKD) and cardiovascular disease (CVD)-related events are the main causes of death in end-stage renal disease (ESRD) patients on dialysis. Concerning lipid management, clinical practice emphasized treatment escalation to achieve specific low-density lipoprotein cholesterol (LDLc) targets, which implies repeated LDLc evaluations, and enhancement of statin doses or combination of lipid-lowering therapies. However, the LDLc target is not consensual, with some entities suggesting 100 mg/dl and others a more conservative level. It has been hypothesized that lipoprotein’s quality (size, composition and functionality) may be more important than their total circulating levels, as CVD risk factor. Our aim was to evaluate and compare, in ESRD patients on dialysis and under statins treatment, the levels of lipoprotein fractions and subfractions and inflammatory markers, between patients who achieved LDLc levels &lt; 100 mg/dl and those who did not achieve that target. Method We studied 110 ESRD patients on dialysis (high-flux hemodialysis or hemodiafiltration) and under statin therapy; 87 presented a LDLc &lt; 100 mg/dl (group 1) and 23 a value &gt; 100 mg/dl (group 2); levels of high-sensitivity C-reactive protein (hsCRP), interleukin(IL)-6, lipid profile including lipoprotein fractions/subfractions, and oxidized LDL (oxLDL) were evaluated. Results Group 1, as compared to group 2, presented lower values of total cholesterol (TC), triglycerides, oxLDL, TC/high-density lipoprotein cholesterol (HDLc) and LDLc/HDLc ratios. Concerning lipoprotein fractions/subfractions, group 1 presented significantly higher larger and intermediate LDL, and a trend towards lower small LDL (P=0.063), higher large HDL (P=0.069) and lower small HDL (P=0.080); no significant alterations were found for very-low-density lipoprotein and intermediate-density lipoprotein. Regarding inflammatory markers, no significant differences were observed between the 2 groups. Conclusion Patients who achieved the LDLc &lt; 100 mg/dl target presented a better non-conventional lipid profile, including lower oxLDL levels and an increase in larger (less atherogenic) LDL subfractions. According to our data, a lower LDLc level associates with a better lipid profile; the benefits of this improvement on HDL fractions and CVD-related events in ESRD patients on dialysis needs to be better clarified.

scholarly journals Punicalagin Attenuates Disturbed Flow-Induced Vascular Dysfunction by Inhibiting Force-Specific Activation of Smad1/5

2021 ◽  
Vol 9 ◽  
Author(s):  
Gulinigaer Anwaier ◽  
Guan Lian ◽  
Gui-Zhi Ma ◽  
Wan-Li Shen ◽  
Chih-I Lee ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Protective Effects ◽  
Disturbed Flow ◽  
Atherosclerosis Progression

BackgroundPathophysiological vascular remodeling in response to disturbed flow with low and oscillatory shear stress (OSS) plays important roles in atherosclerosis progression. Pomegranate extraction (PE) was reported having anti-atherogenic effects. However, whether it can exert a beneficial effect against disturbed flow-induced pathophysiological vascular remodeling to inhibit atherosclerosis remains unclear. The present study aims at investigating the anti-atherogenic effects of pomegranate peel polyphenols (PPP) extraction and its purified compound punicalagin (PU), as well as their protective effects on disturbed flow-induced vascular dysfunction and their underlying molecular mechanisms.MethodsThe anti-atherogenic effects of PPP/PU were examined on low-density lipoprotein receptor knockout mice fed with a high fat diet. The vaso-protective effects of PPP/PU were examined in rat aortas using myograph assay. A combination of in vivo experiments on rats and in vitro flow system with human endothelial cells (ECs) was used to investigate the pharmacological actions of PPP/PU on EC dysfunction induced by disturbed flow. In addition, the effects of PPP/PU on vascular smooth muscle cell (VSMC) dysfunction were also examined.ResultsPU is the effective component in PPP against atherosclerosis. PPP/PU evoked endothelium-dependent relaxation in rat aortas. PPP/PU inhibited the activation of Smad1/5 in the EC layers at post-stenotic regions of rat aortas exposed to disturbed flow with OSS. PPP/PU suppressed OSS-induced expression of cell cycle regulatory and pro-inflammatory genes in ECs. Moreover, PPP/PU inhibited inflammation-induced VSMC dysfunction.ConclusionPPP/PU protect against OSS-induced vascular remodeling through inhibiting force-specific activation of Smad1/5 in ECs and this mechanism contributes to their anti-atherogenic effects.

scholarly journals Bone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function

2011 ◽  
Vol 286 (22) ◽  
pp. 19489-19500 ◽  
Author(s):  
Olivier Leupin ◽  
Elke Piters ◽  
Christine Halleux ◽  
Shouih Hu ◽  
Ina Kramer ◽  
...  
Keyword(s):  
Bone Formation ◽  
Inhibitory Action ◽  
Molecular Mechanisms ◽  
Bone Mineralization ◽  
Affinity Purification ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Target Cells ◽  
Inhibitory Function

Humans lacking sclerostin display progressive bone overgrowth due to increased bone formation. Although it is well established that sclerostin is an osteocyte-secreted bone formation inhibitor, the underlying molecular mechanisms are not fully elucidated. We identified in tandem affinity purification proteomics screens LRP4 (low density lipoprotein-related protein 4) as a sclerostin interaction partner. Biochemical assays with recombinant proteins confirmed that sclerostin LRP4 interaction is direct. Interestingly, in vitro overexpression and RNAi-mediated knockdown experiments revealed that LRP4 specifically facilitates the previously described inhibitory action of sclerostin on Wnt1/β-catenin signaling. We found the extracellular β-propeller structured domain of LRP4 to be required for this sclerostin facilitator activity. Immunohistochemistry demonstrated that LRP4 protein is present in human and rodent osteoblasts and osteocytes, both presumed target cells of sclerostin action. Silencing of LRP4 by lentivirus-mediated shRNA delivery blocked sclerostin inhibitory action on in vitro bone mineralization. Notably, we identified two mutations in LRP4 (R1170W and W1186S) in patients suffering from bone overgrowth. We found that these mutations impair LRP4 interaction with sclerostin and its concomitant sclerostin facilitator effect. Together these data indicate that the interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone.

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