scholarly journals Endotoxin suppresses rat hepatic low-density lipoprotein receptor expression

1996 ◽  
Vol 313 (3) ◽  
pp. 873-878 ◽  
Author(s):  
Wei LIAO ◽  
Mats RUDLING ◽  
Bo ANGELIN
Keyword(s):  
Time Course ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Plasma Lipoproteins ◽  
Low Density ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Receptor Mrna

Endotoxin induces hyperlipidaemia in experimental animals. In the current study, we investigated whether endotoxin alters hepatic low-density lipoprotein (LDL) receptor expression in rats. Endotoxin treatment suppressed hepatic LDL receptor expression in a dose- and time-dependent manner. Eighteen hours after intraperitoneal injection of increasing amounts of endotoxin, LDL receptor and its mRNA levels were determined by ligand blot and solution hybridization respectively. LDL receptor expression was inhibited by about 70% at a dose of 500 μg/100 g body weight. However, LDL receptor mRNA levels were markedly increased in all endotoxin-treated groups at this time point (by 83–136%; P < 0.001). Time-course experiments showed that LDL receptor expression was already reduced by 48% 4 h after endotoxin injection and was maximally reduced (by 63–65%) between 8 and 18 h. Changes in hepatic LDL receptor mRNA showed a different pattern. By 4 h after endotoxin injection, LDL receptor mRNA had decreased by 78% (P < 0.001). However, by 8 h after endotoxin injection, LDL receptor mRNA had returned to levels similar to controls, and 18 and 24 h after endotoxin injection, they were increased by about 60% (P < 0.05). Separation of plasma lipoproteins by FPLC demonstrated that endotoxin-induced changes in plasma triacylglycerols and cholesterol were due to accumulation of plasma apolipoprotein B-containing lipoproteins among very-low-density lipoprotein, intermediate-density lipoprotein and LDL. It is concluded that endotoxin suppresses hepatic LDL receptor expression in vivo in rats.

Oxidized low-density lipoprotein and peroxisome-proliferator-activated receptor α down-regulate platelet-activating-factor receptor expression in human macrophages

2001 ◽  
Vol 354 (1) ◽  
pp. 225-232 ◽  
Author(s):  
Delphine HOURTON ◽  
Philippe DELERIVE ◽  
Jana STANKOVA ◽  
Bart STAELS ◽  
M. John CHAPMAN ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Platelet Activating Factor ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Peroxisome Proliferator ◽  
Low Density ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Mrna ◽  
Paf Receptor ◽  
Pparα Agonist

Regulation of the expression of platelet-activating factor (PAF) receptor by atherogenic lipoproteins might contribute to atherogenesis. We show that progressive oxidation of low-density lipoprotein (LDL) gradually inhibits PAF receptor expression on the macrophage cell surface. We tested the effect of oxidized LDL (oxLDL) on PAF receptor expression in human monocytes that do not contain peroxisome-proliferator-activated receptor γ (PPARγ), a nuclear receptor activated by oxLDL. OxLDL decreased by 50% (P ⩽0.001) and by 29% (P⩽0.05) the binding of PAF and the expression of PAF receptor mRNA respectively. Next we demonstrated that progressive oxidation of LDLs significantly activated PPARα-dependent transcription in transfected mouse aortic endothelial cells. Finally we demonstrated, in mature macrophages, that fenofibrate (20µM), a specific PPARα agonist, but not the specific PPARγ agonist BRL49653 (20nM), significantly decreased both PAF binding and PAF receptor mRNA expression, by 65% and 40% (P⩽0.001) respectively. Additionally, another PPARα agonist, Wy14,643, decreased PAF receptor promoter activity by 70% (P⩽0.05) in transfected THP-1 cells, suggesting the involvement of the proximal promoter region (-980 to -500) containing a series of four nuclear factor (NF)-κB motifs. Thus PPARα might be involved in the down-regulation of PAF receptor gene expression by oxLDLs in human monocytes/macrophages. The oxidation of one or more lipid components of LDLs might result in the formation of natural activators of PPARα. It is hypothesized that such activators might modulate inflammation and apoptosis upon atherogenesis by decreasing the expression of PAF receptor.

Flow cytometry with a monoclonal antibody to the low density lipoprotein receptor compared with gene mutation detection in diagnosis of heterozygous familial hypercholesterolemia

1998 ◽  
Vol 44 (5) ◽  
pp. 966-972 ◽  
Author(s):  
Bent Raungaard ◽  
Finn Heath ◽  
Jens Uffe Brorholt-Petersen ◽  
Henrik Kjærulf Jensen ◽  
Ole Faergeman
Keyword(s):  
Flow Cytometry ◽  
T Lymphocytes ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Low Density ◽  
Flow Cytometry Assay ◽  
Stop Mutation

Abstract We used a fluorescence flow cytometry assay with a monoclonal low density lipoprotein (LDL) receptor-specific antibody to detect LDL receptor expression on blood T lymphocytes and monocytes. We prepared peripheral blood mononuclear cells from patients with genetically verified LDL receptor-defective (Trp66-Gly mutation, n = 17) or receptor-negative (Trp23-stop mutation, n = 17) heterozygous familial hypercholesterolemia (FH) and from healthy individuals (n = 24). The cells were stimulated to express the maximum amount of LDL receptor by preincubation in lipoprotein-deficient medium. A dual-labeling technique allowed flow cytometric analysis of LDL receptor expression on cells identified by fluorescently conjugated surface marker antibodies. Knowing the LDL receptor gene mutation of the FH patients allowed us to compare the diagnostic capability of this functional assay with the DNA diagnosis and to validate the assay with molecular genetics instead of clinical indices of heterozygous FH. T lymphocytes expressed more LDL receptors and gave better diagnostic results than monocytes, and cells from patients with either the Trp66-Gly or the Trp23-stop mutation had variable but significantly reduced LDL receptor expression. The data indicate that this fluorescence flow cytometry assay is unsuitable for diagnosis of individual cases of heterozygous FH but that it may be useful for functionally characterizing mutations in the LDL receptor gene.

Abstract 398: LDL Receptor Signaling Mediates the Triglyceride-lowering Action of Akkermansia Muciniphila in Genetic Induced Hyperlipidemia

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jing Shen ◽  
Xuedong Tong ◽  
Neetu Sud ◽  
Qiaozhu Su
Keyword(s):  
Insulin Sensitivity ◽  
Er Stress ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Low Density ◽  
Gi Tract ◽  
Metabolic Inflammation ◽  
Akkermansia Muciniphila

Akkermansia muciniphila ( A. muciniphila ) is a mucin-degrading bacterium that resides in the mucus layer whose abundance inversely correlates with body weight and the development of diabetes in mice and humans. The objective of this study was to explore the regulatory effect of A. muciniphila on host lipoprotein metabolism, insulin sensitivity and hepatic metabolic inflammation. By establishing a novel mouse model that colonized the A. muciniphila in the gastrointestinal(GI) tract of the cAMP-responsive binding protein H (CREBH)-deficient mouse and in vivo chylomicron assay, we found that increased colonization of A. muciniphila in the GI tract of wild-type mice protected mice from an acute fat load-induced hyperlipidemia compared to vehicle-treated mice. A. muciniphila administration also significantly ameliorated chronic hypertriglyceridemia, improved insulin sensitivity and prevented overproduction of postprandial chylomicrons in the CREBH-null mice. Mechanistic studies revealed that increased A. muciniphila colonization induced expression of low density lipoprotein (LDL) receptors and apolipoprotein E (apoE) in the hepatocytes of CREBH-null mice, which facilitated the uptake of intermediate density lipoprotein (IDL) via the mediation of apolipoprotein B100 (apoB) and apoE, leading to the increased clearance of triglyceride-rich very-low-density lipoprotein (VLDL) particles, the precursors of IDLs, from the circulation. Treatment with A. muciniphila further improved hepatic ER stress and metabolic inflammation in CREBH-null mice. Conclusion: Increased colonization of the disease-protective gut bacteria A. muciniphila protected the host from acute and chronic hyperlipidemia by enhancing the LDL receptor expression and alleviating hepatic ER stress and the inflammatory response in CREBH-null mice.

Short-term effects of ACTH on the low-density lipoprotein receptor mRNA level in rat and hamster adrenals

1991 ◽  
Vol 6 (3) ◽  
pp. 223-230 ◽  
Author(s):  
J.-G. Lehoux ◽  
A. Lefebvre
Keyword(s):  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cholesterol Content ◽  
Low Density ◽  
Short Term ◽  
Hmg Coa Reductase ◽  
Receptor Mrna ◽  
Coa Reductase

ABSTRACT Low-density lipoprotein (LDL) receptor mRNA was found in both rat and hamster adrenals. Within 30 min after ACTH administration a significant increase in the levels of both LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) mRNAs was observed in rat adrenals; these levels remained increased for up to 240 min. The increase in the levels of LDL receptor and HMG-CoA reductase mRNAs produced by ACTH was reduced by co-administration of aminoglutethimide while, at the same time, the adrenal cholesterol content of rats treated with both aminoglutethimide and ACTH was significantly increased compared with that in groups treated with ACTH alone. Cycloheximide also induced increased levels of rat adrenal mRNAs for LDL receptor and HMG-CoA reductase, but this effect was not additive with that of ACTH. These results suggest that, in the rat, the short-term effect of ACTH on the levels of mRNAs for the LDL receptor and HMG-CoA reductase is similarly controlled and might be mediated through changes in the adrenal cholesterol content. In the hamster adrenal, however, no significant fluctuations were found in the level of LDL receptor mRNA, although a marked increase was found in the level of HMG-CoA reductase mRNA, 2 h after ACTH administration. This indicates that an important effect of ACTH on cholesterol metabolism in the hamster adrenal is at the level of HMG-CoA reductase. In the hamster, therefore, where the main source of cholesterol for the adrenal gland is de-novo synthesis, it seems that a complex mechanism is involved in the control of LDL receptor gene expression.

scholarly journals Modulation of the low-density-lipoprotein-receptor-related protein and its relevance to chylomicron-remnant metabolism

1992 ◽  
Vol 288 (3) ◽  
pp. 791-794 ◽  
Author(s):  
A Szanto ◽  
S Balasubramaniam ◽  
P D Roach ◽  
P J Nestel
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Chylomicron Remnant ◽  
Related Protein ◽  
Density Lipoprotein Receptor ◽  
Lipoprotein Receptor Related Protein

Hepatic levels of the low-density-lipoprotein (LDL)-receptor-related protein (LRP) and the LDL receptor were measured in rats subjected to treatments known to affect the expression of the LDL receptor. Propylthiouracil decreased both hepatic LRP and LDL receptor expression by 30-40%. Thyroxine treatment increased LDL receptor levels by 3-fold without altering LRP levels. In contrast, 17 alpha-ethinyloestradiol decreased LRP by 50%, whereas the LDL receptor was increased 5-fold. Plasma chylomicrons and their remnants were decreased to insignificant levels with this treatment. In rats fed with cholesterol there was a significant increase in these particles in plasma (1.21 +/- 0.4 versus 5.71 +/- 0.4 mg/dl), whereas the expression of LRP was unaltered. In Watanabe heritable hyperlipidaemic and cholesterol-fed rabbits, in which the LDL receptor expression is absent or decreased, the expression of LRP was not significantly different from that in normal rabbits. These results suggest that the expression of hepatic LRP can be modulated by changes in the hormonal status of the rat and that this modulation is not tightly co-ordinated with that of the LDL receptor. Moreover, LRP does not appear to have a significant role in chylomicron-remnant clearance, whereas the LDL receptor is actively involved in this process.

scholarly journals SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1

2020 ◽  
pp. jbc.RA120.015420
Author(s):  
Ju-Qiong Wang ◽  
Zi-Cun Lin ◽  
Liang-Liang Li ◽  
Shao-Fang Zhang ◽  
Wei-Hui Li ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Cultured Cells ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Dependent Manner ◽  
Post Translational Modification ◽  
Protein Levels ◽  
Density Lipoprotein Receptor

Inducible degrader of the low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase mediating degradation of low-density lipoprotein (LDL) receptor (LDLR). IDOL also controls its own stability through autoubiquitination, primarily at lysine 293. Whether IDOL may undergo other forms of post-translational modification is unknown. In this study, we show that IDOL can be modified by small ubiquitin-like modifier 1 (SUMO1) at the K293 residue at least. The SUMOylation of IDOL counteracts its ubiquitination and augments IDOL protein levels. SUMOylation and the associated increase of IDOL protein are effectively reversed by SUMO specific peptidase 1 (SENP1) in an activity-dependent manner. We further demonstrate that SENP1 affects LDLR protein levels by modulating IDOL. Overexpression of SENP1 increases LDLR protein levels and enhances LDL uptake in cultured cells. On the contrary, loss of SENP1 lowers LDLR levels in an IDOL-dependent manner and reduces LDL endocytosis. Collectively, our results reveal SUMOylation as a new regulatory post-translational modification of IDOL, and suggest that SENP1 positively regulates the LDLR pathway via deSUMOylation of IDOL and may therefore be exploited for the treatment of cardiovascular disease.

Low-density lipoprotein receptors in rat adipocytes: regulation with fasting

1994 ◽  
Vol 266 (1) ◽  
pp. E26-E32 ◽  
Author(s):  
F. B. Kraemer ◽  
C. Laane ◽  
B. Park ◽  
C. Sztalryd
Keyword(s):  
Adipose Tissue ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Low Density ◽  
Fat Cell ◽  
Ldl Receptors ◽  
Rat Adipocytes ◽  
Epididymal Fat

Adipose tissue metabolism is exquisitely sensitive to caloric intake. With increasing adiposity more triglyceride and cholesterol are stored within increasingly large adipocytes, whereas less triglyceride and cholesterol are stored as the size of the fat cell decreases. A portion of the uptake of cholesterol by adipocytes is mediated by low-density lipoprotein (LDL) receptors. The present studies addressed whether LDL receptors are differentially regulated in adipose tissue and the liver during fasting in the rat. Two days of fasting caused a reduction in body weight with an approximately 40% decrease in the epididymal fat depot and fat cell size. No changes in serum cholesterol were noted, but serum triglycerides fell approximately 55% with fasting. LDL receptors detected by immunoblotting decreased progressively with fasting to levels that were 95% below controls in adipocytes isolated from epididymal fat pads by 2-3 days. In contrast, hepatic LDL receptor expression was unaltered by fasting. After 2 days of fasting, the rate of synthesis of LDL receptors in isolated adipose cells was decreased approximately 35%, whereas levels of LDL receptor mRNA were diminished approximately 55%. It is concluded that the expression of LDL receptors in rat adipocytes is markedly downregulated during fasting through transcriptional and posttranscriptional mechanisms. Furthermore, LDL receptor expression is differentially regulated in adipose tissue and liver during fasting in the rat.

Location and regulation of low-density lipoprotein receptors in intestinal epithelium

1995 ◽  
Vol 269 (1) ◽  
pp. G60-G72 ◽  
Author(s):  
L. G. Fong ◽  
S. E. Fujishima ◽  
M. C. Komaromy ◽  
Y. K. Pak ◽  
J. L. Ellsworth ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Ethinyl Estradiol ◽  
Intestinal Epithelial Cells ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Intestinal Epithelial ◽  
Ldl Receptors ◽  
Receptor Mrna

The expression, distribution, and some aspects of the regulation of low-density lipoprotein (LDL) receptors in rat intestinal epithelial cells were examined. Cells prepared by a perfusion technique provided a pure preparation of epithelial cells and could be manipulated to produce crypt-villus units or villi alone. On a total protein basis, the abundance of LDL receptors in villus cell membranes was half that in hepatic membranes. The level of receptors in both tissues was reduced by feeding an atherogenic diet but was increased only in the liver by ethinyl estradiol-induced hypocholesterolemia. The level of LDL receptor mRNA in intestinal epithelial cells was somewhat lower than in liver. Regulation of LDL receptor mRNA was similar to that of protein. Judged by the ratio of mRNA in villus cells to the villus-crypt unit and nuclear run-on assay for LDL receptor gene transcription, we conclude that LDL receptor mRNA is produced in the villus cells. The effect of fat feeding was regulated at the level of transcription. Expression in villus cells in ileum was severalfold higher than in jejunum and higher than in the liver. Together the results suggest serum cholesterol level is not the prime determinant of LDL receptor level in intestine, but LDL degradation in this organ may be regulated by factors in the lumen.

Tri-iodothyronine prevents the amiodarone-induced decrease in the expression of the liver low-density lipoprotein receptor gene

1997 ◽  
Vol 152 (3) ◽  
pp. 413-421 ◽  
Author(s):  
F Hudig ◽  
O Bakker ◽  
W M Wiersinga
Keyword(s):  
Ldl Cholesterol ◽  
Plasma Cholesterol ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Ldl Receptors ◽  
Receptor Mrna ◽  
Receptor Gene Expression

Treatment with amiodarone, a potent antiarrhythmic drug, is associated with a dose-dependent increase in plasma cholesterol resulting from a decreased number of liver low-density lipoprotein (LDL) receptors. Similar changes occur in hypothyroidism, and it has been suggested that amiodarone acts via induction of a local 'hypothyroid-like' state in extrathyroidal tissues. The present study was designed to evaluate whether exogenous tri-iodothyronine (T3) could prevent the effects of amiodarone on LDL cholesterol. Rats were treated for 14 days with water, amiodarone 10 mg/100 g body weight (BW), or amiodarone and 2·5, 5 or 10 μg T3/100 g BW respectively. Relative to controls, amiodarone increased plasma LDL cholesterol by 31% and decreased liver LDL receptor mRNA by 56% and protein by 45%; liver T3 content was reduced by 21%. Addition of T3 to the treatment with amiodarone dose-dependently reversed all these changes, with a return to control values of plasma cholesterol and the number of liver LDL receptors, although LDL receptor mRNA remained slightly lower. Treatment of rats for 14 days with T3 alone (5 μg/100 g BW) decreased plasma LDL cholesterol by 19% and increased liver LDL receptor mRNA by 41%. In conclusion, T3 prevents the amiodarone-induced changes in plasma LDL cholesterol and liver LDL receptor gene expression. These findings suggest that the inhibitory effect of amiodarone on LDL receptor gene expression is mediated by T3-dependent pathways. Journal of Endocrinology (1997) 152, 413–421

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