VLDL Receptor Expression Research Articles

Effects of dietary lysine on productivity, reproductive performance, protein and lipid metabolism-related gene expression in laying duck breeders

This study investigated whether dietary lysine (Lys) affects productive performance and expression of genes related to protein and lipid metabolism in laying duck breeders. Longyan duck breeders (n = 540, 19 wk of age) were randomly assigned to 6 groups with 6 replicates of 15 birds each. Breeders were fed diets with 6 total Lys levels (6.4, 7.2, 8.0, 8.8, 9.6, and 10.4g/kg) for 26 wk duration. Egg production, egg weight, egg mass, feed conversion ratio, hatchability, hatchling weight, albumen weight, eggshell weight, yolk weight, and yolk proportion increased with dietary Lys levels (P < 0.05). Dietary Lys level had a linear (P < 0.05) and quadratic (P < 0.05) effects on maternal hepatic expression of mechanistic target of rapamycin, eukaryotic translation initiation factor 4E binding protein 1, ubiquitin conjugating enzyme E2K (UBE2K), cathepsin B (CTSB), and quadratically (P < 0.05) increased the concentrations of plasma Lys, leucine, threonine, and tryptophan in duck breeders. In contrast, maternal dietary Lys suppressed expression of proteasome 26S subunit, UBE2K, and CTSB in the liver of hatchlings. Moreover, relative expression of peroxisome proliferator-activated receptors alpha, carnitine palmitoyltransferase 1A, and very low density apolipoprotein-II increased linearly (P < 0.05) and quadratically (P < 0.05), and that of VLDL receptor (VLDLR) decreased quadratically (P < 0.05) in the liver of duck breeders with increasing dietary Lys levels; hepatic triglyceride and cholesterol contents were reduced. Maternal dietary Lys suppressed hepatic expression of VLDLR in the hatchlings. A diet containing 8.6g Lys/kg promoted protein turnover and lipid metabolism in laying duck breeders, which positively reflected in the productivity and reproductive performance.

Chronic fructose intake does not induce liver steatosis and inflammation in female Sprague-Dawley rats, but causes hypertriglyceridemia related to decreased VLDL receptor expression.

Sugar-sweetened beverage intake is a risk factor for insulin resistance, dyslipidemia, fatty liver, and steatohepatitis (NASH). Sub-chronic supplementation of liquid fructose, but not glucose, in female rats increases liver and plasma triglycerides without inflammation. We hypothesized that chronic supplementation of fructose would cause NASH and liver insulin resistance. We supplemented female Sprague-Dawley rats with water or either fructose or glucose 10% w/v solutions under isocaloric conditions for 7months. At the end, plasma analytes, insulin, and adiponectin were determined, as well as liver triglyceride content and the expression of key genes controlling inflammation, fatty acid synthesis and oxidation, endoplasmic reticulum stress, and plasma VLDL clearance, by biochemical and histological methods. Although sugar-supplemented rats increased their energy intake by 50-60%, we found no manifestation of liver steatosis, fibrosis or necrosis, unchanged plasma or tissue markers of inflammation or fibrosis, and reduced liver expression of gluconeogenic enzymes, despite both sugars increased fatty acid synthesis, mTORC1, and IRE1 activity, while decreasing fatty acid oxidation and PPARα activity. Only fructose-supplemented rats were hypertriglyceridemic, showing a reduced expression of VLDL receptor and lipoprotein lipase in skeletal muscle and vWAT. Glucose-supplemented rats showed increased adiponectinemia, which would explain the different metabolic outcomes of the two sugars. Chronic liquid simple sugar supplementation, as the sole risk factor, is not enough for female rats to develop NASH and increased liver gluconeogenesis. Nevertheless, under isocaloric conditions, only fructose induced hypertriglyceridemia, thus confirming that also the type of nutrient matters in the development of metabolic diseases.

Minor components of pomace olive oil enhance VLDL-receptor expression in macrophages when treated with postprandial triglyceride-rich lipoproteins

Pomace olive oil (POO) is rich in minor components, which can modulate the composition of postprandial triglyceride-rich lipoproteins (TRL) and their uptake by macrophages. The aim of the present study was to investigate the effects of postprandial TRL obtained after the ingestion of meals containing POO or refined olive oil (ROO) on foam cell formation, one of the initial steps of atherogenesis. Meals were administered to 9 healthy men and TRL were isolated from serum 4h after the intake. POO intake led to TRL with lower triglyceride/apo B48 and triglyceride/apo B100 ratios compared to ROO. Upon incubation of THP-1 macrophages with the TRL, an increase in the intracellular triglyceride content and foam cell formation was observed. Compared to ROO-TRL, the only receptor involved in lipoprotein uptake that showed changes in the mRNA expression after treatment with POO-TRL was the VLDL-receptor (VLDLr). In conclusion, the intake of POO modified the composition of human TRL, which increased the VLDLr gene expression in macrophages. However, the changes were not sufficient to enhance foam cell formation.

SalA Attenuates Hypoxia-Induced Endothelial Endoplasmic Reticulum Stress and Apoptosis via Down-Regulation of VLDL Receptor Expression

Background: Salvianolic acid A (SalA) has been shown to display robust protection against endothelial injury. VLDL receptor (VLDLr) is expressed at high levels in the endothelial cells. However its endothelial biological function has not been completely elucidated. Here, we investigated molecular effects of SalA on endothelial VLDLr expression, ER stress, and apoptosis under hypoxia condition. Methods: Human umbilical vein endothelial cells (HUVECs) pretreated with SalA were subjected to hypoxia stimulation. Endothelial ER stress and apoptosis were examined. The mRNA levels were tested by real-time RT-PCR, and the protein levels were determined by immunoblot analysis. Results: Pretreatment of HUVECs with SalA markedly attenuated hypoxia-induced endothelial ER stress and apoptosis. Hypoxia resulted in enhancement of VLDLr expression, which was effectively inhibited by SalA pretreatment. Furthermore, luciferase reporter gene assays indicated that SalA inhibited vldlr gene promoter activity, and ChIP assays showed that hypoxia increase the recruitment of HIF-1α to the vldlr gene promoter, and this process was hampered markedly by pretreatment of SalA. Finally, overexpression of VLDLr abolished SalA-mediated protection of endothelial cells from ER stress and apoptosis. Knockdown of VLDLr mimicked SalA protective effect. Conclusion: These results for the first time demonstrate that SalA protects against hypoxia-induced endothelial ER stress and apoptosis through inhibiting recruitment of HIF-1α to vldlr gene promoter and thus suppressing VLDLr expression.

Upregulation of hepatic VLDLR via PPARα is required for the triglyceride-lowering effect of fenofibrate

The liver and the VLDL receptor (VLDLR) play major roles in TG and VLDL metabolism. However, the exact role of liver VLDLR is not well known because of the absence of or difficulty in detecting VLDLR in the liver. In this study, we demonstrate that fenofibrate, a PPARα agonist and widely used TG-lowering drug, markedly upregulated hepatic VLDLR, which is essential for lowering TG. This study also shows that the distinct regulatory roles of PPARα agonists on VLDLR in the liver and peripheral tissues including adipose tissues, heart, and skeletal muscles are due to the pattern of expression of PPARα. The in vivo portion of our study demonstrated that oral fenofibrate robustly increased liver VLDLR expression levels in hyperlipidemic and diabetic mice and significantly reduced the increase in serum TG observed in wt mice after feeding with high-fat diet (HFD) but not in Vldlr(-/-) mice or Pparα(-/-) mice. However, overexpression of mouse VLDLR in livers of Vldlr(-/-) mice significantly prevented the increase in serum TG induced by HFD. The in vitro portion of our study showed that fenofibrate upregulated VLDLR transcriptional activity through PPAR response element binding to the VLDLR promoter. The conclusions of our study provide a novel mechanism for the TG-lowering effects of fenofibrate in the treatment of dyslipidemia.

Sitagliptin attenuates methionine/choline-deficient diet-induced steatohepatitis

AimsAccumulating evidence suggests that inhibitors of dipeptidyl peptidase-4 (DPP-4), such as sitagliptin, may play an important role in the prevention of non-alcoholic steatohepatitis (NASH). This study was conducted to elucidate whether sitagliptin could prevent steatohepatitis by inhibiting pathways involved in hepatic steatosis, inflammation, and fibrosis. MethodsC57BL/6 mice were fed a methionine/choline-deficient (MCD) diet with or without supplement with sitagliptin for 5 weeks. Liver and adipose tissue from mice were examined histologically and immunohistochemically to estimate the effect of sitagliptin on the development of NASH. ResultsSupplementation with sitagliptin resulted in significant improvement of MCD diet-induced fat accumulation in the liver. In addition, sitagliptin treatment lowered fatty acid uptake, expression of VLDL receptor and hepatic triglyceride content. Sitagliptin also effectively attenuated MCD diet-induced hepatic inflammation, endoplasmic reticulum (ER) stress, and liver injury, as evidenced by reduced proinflammatory cytokine levels, ER stress markers, and TUNEL staining. Expression of CYP2E1 and 4NHE were strongly increased by the MCD diet, but this effect was successfully prevented by sitagliptin treatment. Furthermore, sitagliptin significantly decreased levels of MCD diet-induced fibrosis-associated proteins such as fibronectin and α-SMA in the liver. Inflammatory and atrophic changes of adipose tissue by MCD diet were restored by sitagliptin treatment. ConclusionsSitagliptin attenuated MCD diet-induced hepatic steatosis, inflammation, and fibrosis in mice through amelioration of mechanisms responsible for the development of NASH, including CD36 expression, NF-κB activation, ER stress, CYP2E1 expression, and lipid peroxidation. Treatment with sitagliptin may represent an effective approach for the prevention and treatment of NASH.

SalA Attenuates Ischemia/Reperfusion-Induced Endothelial Barrier Dysfunction via Down-Regulation of VLDL Receptor Expression

Background: Salvianolic acid A (SalA) has been shown to confer robust protection against endothelial injury. VLDL receptor is expressed at high levels on the endothelial surface, however its biological effect on endothelial cells has not yet been completely elucidated. Here, we investigated molecular effects of SalA on endothelial VLDL expression and barrier dysfunction under conditions of ischemia/reperfusion (IS/RP). Methods: Human umbilical vein endothelial cells (HUVECs) treated with SalA were subjected to IS/RP stimulation. Endothelial permeability, ZO-1 distribution, actin cytoskeleton reorganization, and intracellular reactive oxygen species (ROS) generation were examined. The mRNA levels were tested by real-time RT-PCR and the protein levels were determined by immunoblot analysis. Results: Pretreatment of HUVECs with SalA markedly attenuated IS/RP-induced endothelial hyperpermeability, discontinuous ZO-1 staining, actin stress fiber formation, and intracellular ROS generation. IS/RP activated p38 MAPK signaling and enhanced VLDL receptor expression, and inactivation of p38 MAPK abolished increase of VLDL receptor expression. Furthermore, siRNA experiments showed that VLDL receptor was a crucial mediator of endothelial barrier dysfunction and intracellular ROS generation induced by IS/RP. Importantly, SalA effectively suppressed IS/RP-induced activation of p38 MAPK signaling and increase of VLDL receptor expression. Conclusion: These results for the first time demonstrated that SalA protected against IS/RP-induced endothelial barrier dysfunction through suppression of VLDL receptor expression.

Comparative reactivity of remnant-like lipoprotein particles (RLP) and low-density lipoprotein (LDL) to LDL receptor and VLDL receptor: Effect of a high-dose statin on VLDL receptor expression

Background Comparison of the reactivity of remnant-like lipoprotein particles (RLP) and LDL particles to LDL receptor and VLDL receptor has not been investigated. Methods LDL receptor- or VLDL receptor-transfected ldlA-7, HepG2 and L6 cells were used. Human LDL and rabbit β-VLDL were isolated by ultracentrifugation. Human RLP was isolated using an immunoaffinity mixed gel. The effect of statin on lipoprotein receptors was examined. Results Both LDL receptor and VLDL receptor recognized RLP. In LDL receptor transfectants, RLP, β-VLDL and LDL all bound to LDL receptor. Cold RLP competed efficiently with DiI-β-VLDL; however, cold LDL competed weakly. In VLDL receptor transfectants, RLP and β-VLDL bound to VLDL receptor, but not LDL. RLP bound to VLDL receptor with higher affinity than β-VLDL because of higher apolipoprotein E in RLP. LDL receptor expression was induced in HepG2 by the low concentration of statin while VLDL receptor expression was induced in L6 myoblasts at higher concentration. Conclusions RLP are bound to hepatic LDL receptor more efficiently than LDL, which may explain the mechanism by which statins prevent cardiovascular risk by primarily reducing plasma RLP rather than by reducing LDL. Additionally, a high-dose of statins also may reduce plasma RLP through muscular VLDL receptor.

The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction

Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1α through its interaction with a hypoxia-responsive element in the Vldlr promoter, and VLDLR promoted the endocytosis of lipoproteins. Furthermore, VLDLR expression was higher in ischemic compared with nonischemic left ventricles from human hearts and was correlated with the total lipid droplet area in the cardiomyocytes. Importantly, Vldlr-/- mice showed improved survival and decreased infarct area following an induced myocardial infarction. ER stress, which leads to apoptosis, is known to be involved in ischemic heart disease. We found that ischemia-induced ER stress and apoptosis in mouse hearts were reduced in Vldlr-/- mice and in mice treated with antibodies specific for VLDLR. These findings suggest that VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis.

Hypoxia exacerbates Ca 2+-handling disturbances induced by very low density lipoproteins (VLDL) in neonatal rat cardiomyocytes

It is known that myocardium suffers serious alterations under ischemic conditions such as lipid overloading and electrophysiological alterations. However, it is unknown whether intracellular lipid accumulation and calcium dysfunction share common pathophysiological mechanisms under ischemia. The aims of this study were 1) to analyze the effect of normal and high doses of very low density lipoproteins (VLDL) on lipid content and calcium handling; 2) to investigate whether hypoxia modulates the effect of high VLDL doses; and 3) to identify potentially underlying mechanisms in cardiomyocytes. For this purpose, neonatal rat ventricular myocytes cultures were prepared from hearts of 3–4-day-old rats. High doses of VLDL that induced cholesteryl ester (CE) and triglyceride (TG) accumulation strongly reduced sarco(endo)plasmic reticulum Ca ATPase-2 (SERCA-2) expression, calcium transient amplitude and sarcoplasmic reticulum (SR) calcium loading. Interestingly, hypoxia, by upregulating VLDL-receptor expression (4.5-fold at 16 h) increased CE (1.5-fold) and TG (3-fold) cardiomyocyte content and exacerbated the negative effect of VLDL on SERCA-2 expression. Functionally, the hypoxic exacerbation of VLDL-mediated SERCA-2 downregulation was translated into a stronger decrease in calcium transient amplitude and SR calcium loading in myocytes exposed simultaneously to hypoxia and high VLDL. In conclusion, high VLDL doses alter calcium handling in cardiomyocytes and SERCA-2 play a pivotal role in the hypoxic exacerbation of VLDL-mediated effects on cardiac calcium handling. Potentiation of VLDL's effects under hypoxia is explained, at least in part, by hypoxic upregulation of the expression of VLDL-receptor.

Up-regulation of VLDL receptor expression and its signaling pathway induced by VLDL and β-VLDL

Very low density lipoprotein receptor (VLDLR) is thought to participate in the pathogenesis of atherosclerosis induced by VLDL and beta-VLDL. The present study was undertaken to elucidate the effects of VLDL and beta-VLDL on VLDLR expression and its signaling pathway. RAW264.7 cells were incubated with VLDL and beta-VLDL. The expression of VLDLR mRNA was detected by RT-PCR. The transcriptional activity of VLDLR gene was detected in recombinant plasmid pGL4.2VR-luciferase transfected RAW264.7. Western blot assay was used to detect the changes of phosphorylated ERK1/2 protein. Inhibitors or activators were used to observe the signal pathway involving VLDLR expression regulation. The results showed that VLDL and beta-VLDL stimulated ERK1/2 activity in a PKC-dependent manner. VLDL or beta-VLDL-induced VLDLR expression on macrophages was extremely abolished by inhibitors ERK1/2 or PKC. Our findings revealed that VLDL or beta-VLDL-induced VLDLR expression via PKC/ERK cascades and the effect was linked to the transcriptional activation of VLDLR gene promoter.

Adiponectin Reduces Plasma Triglyceride by Increasing VLDL Triglyceride Catabolism

OBJECTIVE—Adiponectin is an adipocyte-derived hormone that plays an important role in glucose and lipid metabolism. The main aims of this study are to investigate the effects of adiponectin on VLDL triglyceride (VLDL-TG) metabolism and the underlying mechanism.RESEARCH DESIGN AND METHODS—Adenoviruses were used to generate a mouse model with elevated circulating adiponectin. HepG2 and C2C12 cells were treated with recombinant human adiponectin.RESULTS—Three days after Ad-mACRP30 adenovirus injection, plasma adiponectin protein levels were increased 12-fold. All three main multimeric adiponectin molecules were proportionally elevated. Fasting plasma TG levels were significantly decreased (∼40%) in the mice with elevated adiponectin in circulation, as were the plasma levels of large and medium VLDL subclasses. Although apolipoprotein B mRNA levels were robustly suppressed in the livers of adiponectin-overexpressing mice and in cultured HepG2 cells treated with recombinant human adiponectin, hepatic VLDL-TG secretion rates were not altered by elevated plasma adiponectin. However, Ad-mACRP30–treated mice exhibited a significant increase of postheparin plasma lipoprotein lipase (LPL) activity compared with mice that received control viral vector. Skeletal muscle LPL activity and mRNA levels of LPL and VLDL receptor (VLDLr) were also increased in Ad-mACRP30–treated mice. Recombinant human adiponectin treatment increased LPL and VLDLr mRNA levels in differentiated C1C12 myotubes.CONCLUSIONS—These results suggest that adiponectin decreases plasma TG levels by increasing skeletal muscle LPL and VLDLr expression and consequently VLDL-TG catabolism.

Association between seasonal changes in fatty-acid composition, expression of VLDL receptor and bovine sperm quality

Reduced reproductive performance of dairy cows during the summer is often associated with elevated temperature. Semen collected and cryopreserved during the summer may be of low quality and might contribute to the compromised fertility of dairy cows during this season. The present study examined the association between seasonality, semen quality and its potential to survive cryopreservation. A comparison between semen collected during the summer (July to August) and that collected during the winter (November to December) revealed the summer semen to be inferior, as reflected by low motility and high mortality of sperm. Furthermore, samples that were defined as good quality had changes in lipid concentration and fatty-acid composition in both the seminal plasma and cell compartment. In particular, semen collected during the summer had reduced levels of polyunsaturated arachidonic acid (20:4; P < 0.05) and decreased levels of linoleic acid (18:2; P < 0.05) in the cell compartment; corresponding reductions in cholesterol ( P < 0.06) and fatty-acid concentrations ( P < 0.001) were detected in seminal plasma of semen collected during the summer. In addition, we provided the first evidence for the existence of a very-low-density lipoprotein receptor (VLDLr) in bovine sperm, suggesting a mechanism for sperm utilization of extracellular lipids. Interestingly, the expression of VLDLr was three-fold greater in samples collected during the winter than in those collected in the summer ( P < 0.01) and was negatively associated with saturated fatty-acid concentration ( P < 0.018) but not with that of cholesterol. An opposite pattern was noted for samples obtained during the summer; mRNA expression of VLDLr was negatively associated with cholesterol concentration ( P < 0.01) but not with that of saturated fatty acids. Such modifications associated with extracellular lipid utilization and fatty-acid composition might explain, in part, the reduced quality of summer semen.

Dietary soya protein concentrate enriched with isoflavones reduced fatty liver, increased hepatic fatty acid oxidation and decreased the hepatic mRNA level of VLDL receptor in obese Zucker rats

Casein-based diets containing a low (LDI) or high (HDI) dose of soya protein concentrate enriched with isoflavones were fed to obese Zucker rats for 6 weeks. HDI feeding, but not LDI feeding, reduced the fatty liver and decreased the plasma levels of alanine transaminase and aspartate transaminase. This was accompanied by increased activities of mitochondrial and peroxisomal beta-oxidation, acetyl-CoA carboxylase, fatty acid synthase and glycerol-3-phosphate acyltransferase in liver and increased triacylglycerol level in plasma. The decreased fatty liver and the increased plasma triacylglycerol level appeared not to be caused by an increased secretion of VLDL, as HDI decreased the hepatic mRNA levels of apo B and arylacetamide deacetylase. However, the gene expression of VLDL receptor was markedly decreased in liver, but unchanged in epididymal white adipose tissue and skeletal muscle of rats fed HDI, indicating that the liver may be the key organ for the reduced clearance of triacylglycerol-rich lipoproteins from plasma after HDI feeding. The n-3/n-6, 20:4n-6/18:2n-6 and (20:5n-3+22:6n-3)/18:3n-3 ratios were increased in liver triacylglycerol by HDI. The phospholipids in liver of rats fed HDI contained a low level of 20:4n-6 and a high level of 20:5n-3, favouring the production of anti-inflammatory eicosanoids. When obese Zucker rats were fed soya protein, this also resulted in reduced fatty liver, possibly through reduced clearance of VLDL by the liver. We conclude that the isoflavone-enriched soya concentrate as well as soya protein may be promising dietary supplements for treatment of non-alcoholic fatty liver.

Evidence of macrophage foam cell formation by very low-density lipoprotein receptor: interferon-gamma inhibition of very low-density lipoprotein receptor expression and foam cell formation in macrophages.

Expression of the VLDL receptor, primarily in macrophages, has been confirmed in human and rabbit atherosclerotic lesions. The high binding affinity of the VLDL receptor for remnant particles implicates the VLDL receptor pathway in the foam cell formation mechanism in macrophages. This study investigates the effect of interferon (IFN)-gamma on VLDL receptor expression in phorbol-12-myristate-13-acetate (PMA)-treated THP-1, HL-60 macrophages, and human monocyte-derived macrophages. THP-1 cells were induced to differentiate into macrophages by PMA treatment. IFN-gamma was added to the medium, and expression of the VLDL receptor was determined. (125)I-beta-VLDL degradation study and oil red O staining were examined. In THP-1 macrophages, VLDL receptor protein expression decreased at 2 days after PMA treatment but increased at 3 days and increased up to 5 days. Scavenger receptor proteins, which were not originally present, appeared at 3 days after PMA treatment. IFN-gamma inhibited VLDL receptor expression in a dose-and time-dependent manner in macrophages. However, no inhibitory effect was observed in monocytes. Moreover, IFN-gamma receptor mRNA increased during differentiation to macrophages. (125)I-beta-VLDL degradation study and oil red O staining showed that IFN-gamma significantly inhibited foam cell formation after the uptake of beta-VLDL. LDL receptor-related protein (LRP) and LDL receptor mRNAs were not expressed in macrophages. In PMA-treated HL-60 macrophages and human monocyte-derived macrophages, IFN-gamma also inhibited VLDL receptor expression and foam cell formation by beta-VLDL. VLDL receptor expression is upregulated during monocyte-macrophage differentiation. IFN-gamma inhibits VLDL receptor expression and foam cell formation only in macrophages. Remnant particles induce macrophage foam cell formation through the VLDL receptor pathway.

Expression of LDL receptor, VLDL receptor, LDL receptor-related protein, and scavenger receptor in rabbit atherosclerotic lesions: marked induction of scavenger receptor and VLDL receptor expression during lesion development.

Atherosclerotic lesions contain foam cells that arise from monocyte-macrophages and smooth muscle cells (SMCs) by excessive uptake of lipoproteins. There are many candidate receptors for the lipid accumulation, such as LDL receptor (LDLR), VLDL receptor (VLDLR), LDL receptor-related protein (LRP), and scavenger receptors (SRs). However, little quantitative information exists on the expression of these receptors in normal and atherosclerotic arteries. Competitive reverse transcription-polymerase chain reaction and in situ hybridization were used for the studies in New Zealand White (NZW) and Watanabe heritable hyperlipidemic (WHHL) rabbit aortic intima-medias. NZW rabbits were fed a 1% cholesterol diet for 0 (control group), 3, 6, or 14 weeks. LDLR mRNA expression was low in aortic intima-medias of all groups. Of the analyzed receptors, LRP had the highest expression in the control group, and its mRNA was induced threefold in the 14-week group, the aortas of which had extensive lesions. SR expression was low and VLDLR expression moderate in the control group. Both receptors were highly induced during cholesterol feeding (SRs, 3-fold and 270-fold induction; VLDLR, 15-fold and 100-fold induction in the 3-week and 14-week groups, respectively). Comparable results were obtained from WHHL rabbits: high basal LRP mRNA in normal intima-medias; moderate induction of LRP and marked induction of SRs and VLDLR in fatty streaks and fatty plaques. In situ hybridization indicated that LRP and VLDLR were expressed in SMCs and macrophages. VLDLR expression was also observed in endothelial cells. SR expression was detected only in macrophages. SR and VLDLR mRNAs were highly induced in atherosclerotic lesions. VLDLR and LRP may be involved in the formation of both SMC-and macrophage-derived foam cells, whereas SRs play an important role in lipid uptake in macrophages.

Down-regulation of VLDL receptor expression in chronic experimental renal failure

VLDL receptor (VLDL-R) is a novel member of the LDL receptor gene family with distinct tissue distribution and function. It binds and internalizes VLDL particles and is primarily expressed in skeletal muscle, heart, brain and adipose tissue, which use fatty acids for energy production or storage. CRF is associated with elevated serum triglyceride and VLDL concentrations and depressed VLDL and chylomicron clearance. We have recently shown marked down-regulation of lipoprotein lipase expression in CRF. This study was conducted to test the hypothesis that VLDL-R expression may be similarly depressed in CRF. To this end, VLDL-R mRNA (Northern blot) and protein mass (Western blot) of skeletal muscle (soleus) and heart were measured in male Sprague-Dawley rats six weeks after 5/6 nephrectomy (CRF group) or sham operation (NL group). A group of erythropoietin (EPO)-treated (150 U/kg twice weekly) CRF animals was included to determine the possible effect of EPO-deficiency anemia (EPO-CRF group). Subgroups of animals were studied at weeks 1, 3 and 6. The CRF group showed a fivefold increase in plasma triglyceride concentration. This was associated with an impressive fourfold reduction in heart and skeletal muscle VLDL-R mRNA and protein mass. VLDL-R mRNA levels in the heart and skeletal muscle were directly related to creatinine clearance and inversely related to serum triglyceride and VLDL concentrations. EPO therapy led to a mild improvement in CRF hypertriglyceridemia but failed to improve VLDL-R expression. Thus, the rise in plasma triglyceride and VLDL concentrations in CRF animals was associated with marked down-regulation of VLDL-R expression. Down-regulation of VLDL-R expression, shown here for the first time, reveals another facet of disturbed lipid metabolism in CRF.

Mechanism of foam cell formation by intimal smooth muscle cells through getting expression of VLDL receptor

Mechanism of foam cell formation by intimal smooth muscle cells through getting expression of VLDL receptor