Effects of serum lipoproteins on cyclosporine A cellular uptake and renal toxicity in vitro

2014 ◽  
Vol 92 (2) ◽  
pp. 140-148 ◽  
Author(s):  
Dion R. Brocks ◽  
Hetal R. Chaudhary ◽  
Mohamed Ben-Eltriki ◽  
Marwa E. Elsherbiny ◽  
Ayman O.S. El-Kadi
Keyword(s):  
Cellular Uptake ◽  
Cyclosporine A ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Serum Lipoproteins ◽  
Rat Serum ◽  
Lipid Lowering Drugs ◽  
Density Lipoprotein Receptor

In-vitro studies were performed to shed light on previous findings that showed increased uptake of cyclosporine A in the kidneys and liver of hyperlipidemic rats, and increased signs of kidney toxicity. Hepatocytes were obtained from rats, cultured, and exposed to a diluted serum from hyperlipidemic rats. Some cells were also exposed to lipid-lowering drugs. After washing out the rat serum or lipid-lowering drugs, cells were exposed to cyclosporine A embedded in serum lipoproteins. Pretreatment with hyperlipidemic serum and lipid-lowering drugs was associated with an increased uptake of cyclosporine A. As expected, atorvastatin caused an increase in low density lipoprotein receptor and a decrease in MDR1A mRNA in the hepatocytes. A decrease in NRK-52E rat renal tubular cellular viability caused by cyclosporine A was noted when cells were preincubated with diluted hyperlipidemic serum. This was matched with evidence of hyperlipidemic-serum-associated increases in the NRK-52E cellular uptake of cyclosporine A and rhodamine-123. The findings of these experiments suggested that in hyperlipidemia the expression and (or) the functional activity of P-glycoprotein was diminished, leading to greater hepatic and renal uptake of cyclosporine A, and renal cellular toxicity.

A Novel Low-Density Lipoprotein Receptor-Related Protein Mediating Cellular Uptake of Apolipoprotein E-Enriched β-VLDL in Vitro†,‡

Biochemistry ◽  
2000 ◽  
Vol 39 (51) ◽  
pp. 15817-15825 ◽  
Author(s):  
Takuya Sugiyama ◽  
Hidetoshi Kumagai ◽  
Yoshihiro Morikawa ◽  
Yoichiro Wada ◽  
Akira Sugiyama ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Cellular Uptake ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Related Protein ◽  
Density Lipoprotein Receptor ◽  
Lipoprotein Receptor Related Protein

scholarly journals Neurotoxic astrocytic glypican-4 drives APOE4-dependent tau pathology

2021 ◽  
Author(s):  
Sivaprakasam Ramamoorthy ◽  
Kirill Gorbachev ◽  
Ana Pereira
Keyword(s):  
Late Onset ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Brain Regions ◽  
Tau Proteins ◽  
Tau Pathology ◽  
Density Lipoprotein Receptor ◽  
Apoe Receptor ◽  
The Brain

Apolipoprotein E4 (APOE4) is the crucial genetic risk factor of late-onset Alzheimer disease (AD). Aggregation of tau proteins into insoluble filaments and their spreading across the brain regions are major drivers of neurodegeneration in tauopathies, including in AD. However, the exact mechanisms through which APOE4 induces tau pathology remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), a novel binding partner of APOE4, drives tau pathology. GPC-4 preferentially interacts with APOE4 in comparison to other APOE isoforms and post-mortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. The astrocyte-secreted GPC-4 induced both tau accumulation and propagation in vitro. CRISPR/dCas9 mediated activation of GPC-4 in a tauopathy animal model robustly induced tau pathology. Further, APOE4-induced tau pathology was greatly diminished in the absence of GPC-4. We found that GPC-4 promoted the stabilization of the APOE receptor low-density lipoprotein receptor-related protein 1 (LRP1) on the cellular surface, which effectively facilitates endocytosis of tau protein. Together, our data comprehensively demonstrate that one of the key APOE4-induced tau pathologies is directly mediated by GPC-4.

scholarly journals Combination of Berberine with Resveratrol Improves the Lipid-Lowering Efficacy

2018 ◽  
Vol 19 (12) ◽  
pp. 3903 ◽  
Author(s):  
Xiaofei Zhu ◽  
Jingyi Yang ◽  
Wenjuan Zhu ◽  
Xiaoxiao Yin ◽  
Beibei Yang ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
High Fat Diet ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Sirtuin 1 ◽  
Lipid Lowering ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
High Fat ◽  
Density Lipoprotein Receptor

The natural compound berberine has been reported to exhibit anti-diabetic activity and to improve disordered lipid metabolism. In our previous study, we found that such compounds upregulate expression of sirtuin 1—a key molecule in caloric restriction, it is, therefore, of great interest to examine the lipid-lowering activity of berberine in combination with a sirtuin 1 activator resveratrol. Our results showed that combination of berberine with resveratrol had enhanced hypolipidemic effects in high fat diet-induced mice and was able to decrease the lipid accumulation in adipocytes to a level significantly lower than that in monotherapies. In the high fat diet-induced hyperlipidemic mice, combination of berberine (25 mg/kg/day, oral) with resveratrol (20 mg/kg/day, oral) reduced serum total cholesterol by 27.4% ± 2.2%, and low-density lipoprotein-cholesterol by 31.6% ± 3.2%, which was more effective than that of the resveratrol (8.4% ± 2.3%, 6.6% ± 2.1%) or berberine (10.5% ± 1.95%, 9.8% ± 2.58%) monotherapy (p < 0.05 for both). In 3T3-L1 adipocytes, the treatment of 12 µmol/L or 20 µmol/L berberine combined with 25 µmol/L resveratrol showed a more significant inhibition of lipid accumulation observed by Oil red O stain compared with individual compounds. Moreover, resveratrol could increase the amount of intracellular berberine in hepatic L02 cells. In addition, the combination of berberine with resveratrol significantly increases the low-density-lipoprotein receptor expression in HepG2 cells to a level about one-fold higher in comparison to individual compound. These results implied that the enhanced effect of the combination of berberine with resveratrol on lipid-lowering may be associated with upregulation of low-density-lipoprotein receptor, and could be an effective therapy for hyperlipidemia in some obese-associated disease, such as type II diabetes and metabolic syndrome.

Sign in / Sign up

Export Citation Format

Share Document