The effects of lifibrol (K12.148) on the cholesterol metabolism of cultured cells: evidence for sterol independent stimulation of the LDL receptor pathway

Scharnagl, Hubert; Schliack, M.; Löser, R.; Nauck, Markus; Gierens, H.; Jeck, Nikola; Wieland, Heinrich; Wl, Gross; März, Winfried

doi:10.1016/s0021-9150(00)00405-6

Cited by 8 publications

(8 citation statements)

References 51 publications

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“…20 Lifibrol is a novel hypolipidemic compound that stimulates LDL receptors without substantially affecting cholesterol biosynthesis. 21,22 In conclusion, the finding of a significantly increased HDL metabolism in FDB is in clear contrast to the situation in FH. In FH there is an increased fractional catabolic rate of apoA-I combined with a decrease in apoA-I production.…”

Section: Schaefer Et Al Apoa-i Turnover In Fdbmentioning

confidence: 66%

Increased Production of HDL ApoA-I in Homozygous Familial Defective ApoB-100

Schaefer

Winkler

Schweer

et al. 2000

ATVB

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Abstract-Familial defective apolipoprotein (apo) B-100 (FDB) is a frequent cause of hypercholesterolemia. Hypercholesterolemia in homozygous FDB is less severe than in homozygotes for familial hypercholesterolemia. Recently, we showed decreased low density lipoprotein (LDL) apoB-100 fractional catabolism and decreased production of LDL due to an enhanced removal of apoE-containing precursors in a patient with homozygous FDB. The effects of defective apoB-100 on high density lipoprotein (HDL) metabolism are unknown. We studied HDL apoA-I metabolism in this FDB patient and in 6 control subjects by using 2 H 3 -L-leucine as a tracer. ApoA-I levels were normal in all study subjects. However, the fractional catabolic rate and the production rate of apoA-I were increased, by 79% and 70%, respectively, in FDB; the fractional catabolic rate of apoA-I in FDB was 0.34 day Ϫ1 compared with 0.19Ϯ0.03 day Ϫ1 in normal controls. The production rate of apoA-I in FDB was 18.4 mg ⅐ kg Key Words: hypercholesterolemia Ⅲ reverse cholesterol transport Ⅲ tracer kinetics Ⅲ stable isotopes F amilial defective apoB-100 (FDB) is one of the most common monogenetic abnormalities of lipoprotein metabolism. This disorder results from a glutamine-for-arginine substitution at position 3500 of apoB-100, which leads to defective binding of apoB-100 to the LDL receptor and the accumulation of LDL in the plasma (reviewed in References 1 and 2).Recently, we identified a homozygous FDB patient 3,4 and studied the in vivo kinetics of apoB-100 -containing lipoproteins in this subject by using a stable isotope tracer technique. 5 Our investigation revealed an increased removal of VLDL apoE, whereas the VLDL apoB-100 residence time was prolonged. The LDL apoB-100 production was reduced (7.4 versus 15 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 in normals), and the residence time of LDL was increased (8.3 versus 2.3 days in normals). 5 These findings are in agreement with data from heterozygous FDB subjects. 6 They indicate that the metabolism of apoB-100 -containing lipoproteins is distinct in FDB compared with that in familial hypercholesterolemia (FH) due to LDL receptor deficiency.In FH, HDL metabolism has also been found to be abnormal. Schaefer et al 7 demonstrated decreased production and increased fractional catabolism of apoA-I in individuals with FH, suggesting a "cross-talk" between LDL and HDL metabolism. On the background of these observations, we decided to examine whether HDL metabolism might be altered in FDB as well. We therefore investigated the kinetics of HDL apoA-I in a homozygous FDB subject by using the stable-isotope tracer technique.

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Section: Schaefer Et Al Apoa-i Turnover In Fdbmentioning

confidence: 66%

Increased Production of HDL ApoA-I in Homozygous Familial Defective ApoB-100

Schaefer

Winkler

Schweer

et al. 2000

ATVB

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“…The chemical structure and mode of action of Lifibrol are distinct from HMGRI and fibrates. Lifibrol increase the cellular uptake of LDL particles in HepG2 cells by a sterol-independent stimulation of LDL-R activity [75]. In kinetic studies using endogeneous labeling with stable isotopes, Lifibrol enhanced the receptor-mediated catabolism of LDL in patients with hypercholesterolemia type IIa and enhanced, although the steady state level of HDL was not affected [77].…”

Section: Lifibrolmentioning

confidence: 99%

New Lipid-lowering Agents Acting on LDL Receptors

Scharnagl¹,

März²

2005

CTMC

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The treatment of dyslipoproteinemia has proven a successful strategy in the prevention of cardiovascular diseases. The major target of hypolipidemic drugs is the reduction of low density lipoprotein cholesterol (LDL-C). HMG-CoA reductase inhibitors (HMGRI) effectively lower LDL-C by inhibiting the mevalonate pathway and enhancing the activity of the LDL receptor (LDL-R). Numerous clinical studies demonstrated convincingly, that the reduction of LDL-C lowers the incidence of cardiovascular events in primary and secondary prevention. Two new HMGRI, rosuvastatin and pitavastatin, have been evaluated in clinical trials. Both drugs demonstrated efficacy in lowering atherogenic lipoproteins. In addition to the reduction of LDL-C, they may have a higher potency to lower triacylglycerides (TG) and to increase HDL cholesterol (HDL-C) compared to currently available HMGRI. Other therapeutic strategies examined in experimental animals are the inhibition of squalene synthase, the first enzyme of the mevalonate pathway, which is specifically committed to cholesterol biosynthesis, and the direct up-regulation of LDL receptor activity. The latter compounds, the SCAP ligands, are the first members of a new class of hypolipidemic agents affecting the transcriptional regulation of genes involved in lipid metabolism. Recent treatment guidelines emphasise the importance of modifying lipid metabolism beyond lowering LDL-C, mainly by lowering TG and raising HDL-C. Although these actions are not primary targets of the compounds discussed here, it is interesting that drugs inducing the LDL-R usually also lower TG and, in the case of HMGRI, increase HDL-C.

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“…In the current protocol, we demonstrate the utilization of live cell imaging as a new and more effective method for measuring real time LDL uptake over a time course in various human cell lines. Human hepatic carcinoma (HepG2) cells are commonly used in studies screening for cholesterol-lowering therapeutics 21,22,23,24,25,26,39,40 . Therefore, we chose this cell type for testing the capability of a live cell imaging system for LDL influx studies.…”

Section: Disusstionmentioning

confidence: 99%

“…The results indicate the reliability of this novel technique as tested over a four-hour time course in three different human cell lines, human hepatic carcinoma (HepG2) cells, human renal epithelial (HK2) cells and human coronary arterial endothelial cells (HCAEC). These cell lines are clinically significant to LDL clearance 20,21,22,23,24,25,26,27 , kidney disease 28,29,30,31 , and heart disease 32,33 , respectively. In addition to monitoring the LDL influx, this protocol incorporates treatment with two well-known LDL uptake inhibitors, Dynasore Hydrate and recombinant PCSK9 protein as well as a statin inducer of LDLR expression and LDL uptake, simvastatin.…”

Section: Introduticonmentioning

confidence: 99%

LDL Cholesterol Uptake Assay Using Live Cell Imaging Analysis with Cell Health Monitoring

Ritter

Yousefi

Ramirez

et al. 2018

JoVE

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The regulation of LDL cholesterol uptake through LDLR-mediated endocytosis is an important area of study in various major pathologies including metabolic disorder, cardiovascular disease, and kidney disease. Currently, there is no available method to assess LDL uptake while simultaneously monitoring for health of the cells. The current study presents a protocol, using a live cell imaging analysis system, to acquire serial measurements of LDL influx with concurrent monitoring for cell health. This novel technique is tested in three human cell lines (hepatic, renal tubular epithelial, and coronary artery endothelial cells) over a four-hour time course. Moreover, the sensitivity of this technique is validated with well-known LDL uptake inhibitors, Dynasore and recombinant PCSK9 protein, as well as by an LDL uptake promoter, Simvastatin. Taken together, this method provides a medium-to-high throughput platform for simultaneously screening pharmacological activity as well as monitoring of cell morphology, hence cytotoxicity of compounds regulating LDL influx. The analysis can be used with different imaging systems and analytical software.

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The effects of lifibrol (K12.148) on the cholesterol metabolism of cultured cells: evidence for sterol independent stimulation of the LDL receptor pathway

Cited by 8 publications

References 51 publications

Increased Production of HDL ApoA-I in Homozygous Familial Defective ApoB-100

Increased Production of HDL ApoA-I in Homozygous Familial Defective ApoB-100

New Lipid-lowering Agents Acting on LDL Receptors

LDL Cholesterol Uptake Assay Using Live Cell Imaging Analysis with Cell Health Monitoring

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