Increased Serum Cholesterol Levels Research Articles

Combination of intrauterine growth restriction and a high-fat diet impairs cholesterol elimination in rats.

Intrauterine growth restriction (IUGR) increases the risk of adult-onset hypercholesterolemia. High-fat diet (HFD) consumption potentiates IUGR-induced increased cholesterol. Cholesterol is converted to bile acids by Cyp7a1 in preparation for excretion. We hypothesized that IUGR rats fed a HFD will have increased cholesterol, decreased Cyp7a1 protein levels, and decreased bile acids compared to control rats fed a HFD. At day 21, IUGR and control pups were placed on one of three diets: a regular chow or one of two HFDs containing 1% or 2% cholesterol. Cholesterol levels and hepatic Cyp7a1 protein levels were quantified a postnatal week 28. Both HFDs increased serum cholesterol levels in control rats, and HFD fed IUGR rats had further increased serum cholesterol up to 35-fold. Both HFDs increased hepatic cholesterol levels, and IUGR further increased hepatic cholesterol levels up to fivefold. IUGR decreased hepatic Cyp7a1 protein up to 75%, and hepatic bile acids up to 54%. IUGR increased cholesterol and bile acids and decreased Cyp7a1 protein in rats fed a HFD without changing food intake. These findings suggest that IUGR increases the vulnerability of HFD fed rats to hypercholesterolemia via decreased cholesterol conversion to bile acids.

Metabolic complications during HIV-treatment with protease inhibitors in patients from Braşov

Objective: to evaluate the effects of treatment with protease inhibitors on serum level of triglycerides, cholesterol and glycemia in HIV-infected patients, in assessing the need of monitoring patients. We performed a retrospective study on 25 patients with HIV infection, in evidence of the Infectious Diseases Hospital of Brasov, treated with protease inhibitors in the treatment regimen. We studied the levels of cholesterol, serum triglycerides and blood glucose at the beginning and during treatment with protease inhibitors. We found increases in serum cholesterol levels in 72% of patients and in 83.33% of them were increasing by 50% from baseline; growth exceeded baseline in 44.45% of cases. Serum triglycerides have increased to 68% of patients, with up to 100% from baseline in 64.5% of cases and in the rest of the patients the increase was marked, beyond 100% exceeded normal values in 64.5% of cases. Blood glucose was maintained at normal levels in 56% patients and increased in 24% of cases. Treatment with protease inhibitors is associated frequently with increased serum levels of cholesterol and triglycerides; hyperglycemia has rarely occurred. Patients treated with protease inhibitors require rigorous monitoring of the metabolism of fats and carbohydrates in order to establish appropriate treatment for early complications that may have occurred.

Catechin-rich green tea extract increases the expression of genes of the cholesterol synthetic pathways in livers of normal diet- and high-fat diet-fed rats

Background In vivo studies using rodents have shown that green tea extract (GT) and catechins isolated from green tea can induce a variety of health effects, including antiobesity, hypoglycemic and hypolipidemic activities. However, we and others observed that serum cholesterol levels were increased by GT and tea catechins in rats and mice [1]. In this study, we examined whether dietary GT affects the expression of genes involved in cholesterol synthesis. Materials and methods Catechin-rich (30% catechin) GT was used for the in vivo studies. Male Sprague-Dawley rats (average weight 237.7 g) were divided into six groups. The first group was fed a normal diet (ND, 10% calories from fat); the second group a high-fat diet (HFD, 40% calories from fat); the third group a ND containing 1% GT (ND + 1% GT); the fourth group a HFD + 1% GT; the fifth group a ND + 3% GT; and the sixth group a HFD + 3% GT. After 4 weeks of feeding, rats were euthanized by whole blood collection under anesthesia. Serum metabolites were determined using a dry chemistry analyzer. Total RNA samples extracted from the liver were used for microarray and quantitative real-time PCR (qPCR) analyses. Hepatic lipids were extracted with chloroform-methanol 2:1, and liver triglyceride (TG) and cholesterol (Cho) levels were determined. Results As reported previously, GT increased the serum levels of total cholesterol (T-Cho) and high-density lipoprotein cholesterol (HDL-Cho) in a concentration-dependent manner in both ND- and HFD-fed rats. Conversely, GT lowered hepatic TG and T-cho levels. Microarray analysis data suggested that GT increased more than two-fold the mRNA expression of nine hepatic genes involved in cholesterol synthesis out of 21 analyzed in ND-fed rats. qPCR analysis revealed that GT significantly increased the mRNA levels of six genes involved in cholesterol synthesis in ND-fed rats. Similar but smaller effects of GT also were observed in HFD-fed rats. Conclusions The results suggested that GT increased serum cholesterol levels, at least in part, through the increased expression of genes in the cholesterol synthetic pathways in the liver. GT also increased the mRNA levels of Srebf2 and Insig1, which are positively regulated by SREBP2. Therefore, dietary GT may increase expression of these genes by SREBP2 activation.

Effects of Dose Level of Anti-thyroid Drug Carbimazole on Thermoregulation and Blood Constituents in Male Rabbits(Oryctolagus cuniculus)

Carbimazole (CBZ) is an anti-thyroid drug commonlyused in thetreatment of hyperthyroidism.The objective of this study was to evaluate the effects of dose level of CBZ on thermoregulation and blood constituents in mature male rabbits. Twenty animals were assigned to 4 groups (A, B, C, D) of 5 each. Group A served as control and treated animals in groups B,C,D, received daily orally CBZ doses of 10, 15 and 20 mg/animal for 3 weeks, respectively. The values of rectal temperature (Tr,), respiration rate (RR) and heart rate (HR) decreased in treated rabbits and the mean values of HR decreased with increase in the dose level of CBZ. The packed cell volume (PCV), Hb concentration and total leukocyte count (TLC) were lower in CBZ treated rabbits. Serum levels of total protein and globulins increased and serum albumin level decreased in treated groups of rabbits. Serum urea level was lower in CBZ treated groups and there was an incre ase in serum urea level with increase in CBZ dose level. Serum cholesterol level was higher in treated groups and there was an increase in serum cholesterol level with increase in CBZ dose level. Plasma glucose level decreased significantly in CBZ treated groups compared

Activation of CXCR7 Limits Atherosclerosis and Improves Hyperlipidemia by Increasing Cholesterol Uptake in Adipose Tissue

The aim of this study was to determine the role of the chemokine receptor CXCR7 in atherosclerosis and vascular remodeling. CXCR7 is the alternative receptor of CXCL12, which regulates stem cell-mediated vascular repair and limits atherosclerosis via its receptor, CXCR4. Wire-induced injury of the carotid artery was performed in mice with a ubiquitous, conditional deletion of CXCR7 and in mice treated with the synthetic CXCR7 ligand CCX771. The effect of CCX771 treatment on atherosclerosis was studied in apolipoprotein E-deficient (Apoe(-/-)) mice fed a high-fat diet for 12 weeks. Lipoprotein fractions were quantified in the plasma of Apoe(-/-) mice by fast protein liquid chromatography. Uptake of DiI-labeled very low-density lipoprotein to adipose tissue was determined by 2-photon microscopy. We show that genetic deficiency of Cxcr7 increased neointima formation and lesional macrophage accumulation in hyperlipidemic mice after vascular injury. This was related to increased serum cholesterol levels and subsequent hyperlipidemia-induced monocytosis. Conversely, administration of the CXCR7 ligand CCX771 to Apoe(-/-) mice inhibited lesion formation and ameliorated hyperlipidemia after vascular injury and during atherosclerosis. Treatment with CCX771 reduced circulating very low-density lipoprotein levels but not low-density lipoprotein or high-density lipoprotein levels and increased uptake of very low-density lipoprotein into Cxcr7-expressing white adipose tissue. This effect of CCX771 was associated with an enhanced lipase activity and reduced expression of Angptl4 in adipose tissue. CXCR7 regulates blood cholesterol by promoting its uptake in adipose tissue. This unexpected cholesterol-lowering effect of CXCR7 is beneficial for atherosclerotic vascular diseases, presumably via amelioration of hyperlipidemia-induced monocytosis, and can be augmented with a synthetic CXCR7 ligand.

Differential requirement for Dab2 in the development of embryonic and extra-embryonic tissues

BackgroundDisabled-2 (Dab2) is an endocytic adaptor protein involved in clathrin-mediated endocytosis and cargo trafficking. Since its expression is lost in several cancer types, Dab2 has been suggested to be a tumor suppressor. In vitro studies indicate that Dab2 establishes epithelial cell polarity and organization by directing endocytic trafficking of membrane glycoproteins. Dab2 also modulates cellular signaling pathways by mediating the endocytosis and recycling of surface receptors and associated signaling components. Previously, two independent gene knockout studies have been reported, with some discrepancies in the observed embryonic phenotypes. To further clarify the in vivo roles of Dab2 in development and physiology, we designed a new floxed allele to delete dab2 gene.ResultsThe constitutive dab2 deleted embryos showed a spectrum in the degree of endoderm disorganization in E5.5 and no mutant embryos persisted at E9.5. However, the mice were grossly normal when dab2 deletion was restricted to the embryo proper and the gene was retained in extraembryonic tissues using Meox2-Cre and Sox2-Cre. Adult Dab2-deficient mice had a small but statistically significant increase in serum cholesterol levels.ConclusionThe study of the new dab2 mutant allele in embryos and embryoid bodies confirms a role for Dab2 in extraembryonic endoderm development and epithelial organization. Experimental results with embryoid bodies suggest that additional endocytic adaptors such as Arh and Numb could partially compensate for Dab2 loss. Conditional deletion indicates that Dab2 is dispensable for organ development, when the vast majority of the embryonic cells are dab2 null. However, Dab2 has a physiological role in the endocytosis of lipoproteins and cholesterol metabolism.

Long-term increase of serum cholesterol level in ulcerative colitis patients treated with cyclosporine: An underdiagnosed side effect frequently associated with other drug-related complications

Introduction: Cyclosporine is one of the recommended therapeutic choices in severe ulcerative colitis (UC) refractory to steroid therapy, although several serious side-effects may limit the use of the drug. Cyclosporine has been reported to increase the total cholesterol level; however the change in the serum cholesterol levels before and after cyclosporine therapy has not been examined in UC patients. The aim of this study was to compare the serum cholesterol levels before and after the cyclosporine therapy in patients with refractory UC and to examine the association between serum cholesterol level and other common side-effects. Patients and methods: We retrospectively assessed the serum cholesterol levels of UC patients who had been treated with cyclosporine. Data of 72 patients (39 female, 33 male, mean age at diagnosis 31.8 years, mean disease duration: 13.5 years) were analyzed statistically. Results: The mean age of UC patients at the start of cyclosporine therapy was 40.3 years, and the mean disease duration at the beginning of the therapy was 8.6 years. The median duration of cyclosporine therapy was 9.6 months, and side effects developed in 52 patients. 65% of them developed increased cholesterol levels. The mean levels of serum cholesterol were 4.48, 6.1 and 5.08 mmol/l at the beginning, during and at the end of the therapy. Elevated serum cholesterol levels were detected in 47.2% of the patients. Serum cholesterol level was significantly increased during and after stopping cyclosporine therapy compared the time before the use of the drug (p

Vitamin E attenuates homocysteine and cholesterol induced damage in rat aorta

The aim of this study was to investigate the effect of vitamin E on homocysteine and cholesterol-induced damage of rat aorta. Wistar rats (all fed with a vitamin E poor diet) were divided into five groups. Control group was fed with the diet only, the second group received 1 mg kg(-1) day(-1) L-methionine in drinking water, the third group was fed with 2% cholesterol containing diet, the fourth group received L-methionine and cholesterol together, and the fifth group was fed with L-methionine and cholesterol and received intramuscular injections of vitamin E. After 4 weeks serum homocysteine, cholesterol and vitamin E levels were measured; aortas were removed; collagen and elastin and the major extracellular matrix components were evaluated microscopically as indicators of aortic degeneration. Aortic collagen content was measured by a colorimetric hydroxyproline assay. Four-week diet supplementation with methionine and cholesterol caused a twofold increase in serum homocysteine and 22% increase in serum cholesterol levels; endothelial damage and degenerative alterations in the aortic media were observed, as indicated by the dissociation of elastic fibers and accumulation of collagen. Vitamin E completely prevented the accumulation of collagen and largely prevented aorta damage as shown by the morphological data. The results indicate that, even moderate increases in homocysteine and cholesterol levels are sufficient to induce vascular degeneration that may be prevented by vitamin E supplementation.

The transient receptor potential vanilloid 4 ion channel regulates the biosynthetic response of chondrocytes to dynamic loading

The transient receptor potential vanilloid 4 ion channel regulates the biosynthetic response of chondrocytes to dynamic loading

P450 Long-term impacts of colectomy surgery among ulcerative colitis patients study (LOCUS): the final analysis

to steroid therapy, although several serious side-effects may limit the use of the drug. Cyclosporine has been reported to increase the total cholesterol level; however the change in the serum cholesterol levels before and after cyclosporine therapy has not been examined in UC patients. The aim of this study was to compare the serum cholesterol levels before and after the cyclosporine therapy in patients with refractory UC and to examine the association between serum cholesterol level and other common side-effects. Methods: We retrospectively assessed the serum cholesterol levels of UC patients who had been treated with cyclosporine. Data of 72 patients (39 female, 33 male, mean age at diagnosis 31.7 years, mean disease duration: 13.5 years) were analyzed statistically. Results: The mean age of UC patients at the start of cyclosporine therapy was 40.3 years, and the mean disease duration at the beginning of the therapy was 8.6 years. The median duration of cyclosporine therapy was 9.6 months, and side effects developed in 52 patients. 65% of them developed increased cholesterol levels. The mean levels of serum cholesterol were 4.48, 6.1 and 5.08mmol/l at the beginning, during and at the end of the therapy. Elevated serum cholesterol levels were detected in 27% of the patients. Serum cholesterol level was significantly increased during and after stopping cyclosporine therapy compared the time before the use of the drug (p < 0.001, p < 0.004). However, cholesterol levels measured during the therapy was significantly higher compared to the time after stopping cyclosporine (p < 0.001). Significant association was found between the increased serum cholesterol levels and side effects developing during cyclosporine therapy. Conclusions: Our findings suggest that cyclosporine therapy may result in increased serum cholesterol levels even in longterm after stopping the therapy. Considering that cholesterol level were significantly more common in patients developing drug-related complications, routine measurement of serum cholesterol can increase the safety of the drug.

P449 Long-term increase of serum cholesterol level in ulcerative colitis patients treated with cyclosporine: an underdiagnosed side effect frequently associated with other drug-related complications

Introduction. Several serious side effects may limit the use of cyclosporine. Cyclosporine has been reported to increase the total cholesterol level; however, the change in serum cholesterol levels before and after cyclosporine therapy has not been examined in ulcerative colitis (UC) patients. The purpose of this article was to compare serum cholesterol levels before and after cyclosporine therapy in patients with refractory UC and to examine the relationship between serum cholesterol levels and other common side effects. Patients and methods. We prospectively assessed serum cholesterol levels in UC patients who had been treated with cyclosporine. Data of 72 patients were analyzed and compared to a control group treated with Infliximab. Results. The average duration of cyclosporine therapy was 9.6 months, and side effects developed in 52 patients. Elevated cholesterol levels were detected in 47.2% of the patients. Serum cholesterol levels were significantly increased during and after discontinuation of cyclosporine therapy compared to the time before use of the drug. However, cholesterol levels measured during cyclosporine therapy were significantly higher compared to the time after its discontinuation (p < 0.001). Patients with drug-related side effects showed higher cholesterol levels after discontinuation of the therapy compared to those who did not experience any adverse events. Conclusions. Our findings suggest that cyclosporine therapy may result in increased serum cholesterol levels even in the long-term, after discontinuation of the therapy. Considering that significantly higher post-therapy cholesterol levels were more common in patients who developed drug-related complications, routine measurement of serum cholesterol may increase the safety of the drug.

Low-Dose Radiation Exposure and Protection Against Atherosclerosis inApoE–/–Mice: The Influence ofP53Heterozygosity

We recently described the effects of low-dose γ-radiation exposures on atherosclerosis in genetically susceptible (ApoE(-/-)) mice with normal p53 function. Doses as low as 25 mGy, given at either early or late stage disease, generally protected against atherosclerosis in a manner distinctly nonlinear with dose. We now report the influence of low doses (25-500 mGy) on atherosclerosis in ApoE(-/-) mice with reduced p53 function (Trp53(+/-)). Single exposures were given at either low or high dose rate (1 or 150 mGy/min) to female C57BL/6J ApoE(-/-) Trp53(+/-) mice. Mice were exposed at either early stage disease (2 months of age) and examined 3 or 6 months later, or at late stage disease (7 months of age) and examined 2 or 4 months later. In unirradiated mice, reduced p53 functionality elevated serum cholesterol and accelerated both aortic root lesion growth and severity in young mice. Radiation exposure to doses as low as 25 mGy at early stage disease, at either the high or the low dose rate, inhibited lesion growth, decreased lesion frequency and slowed the progression of lesion severity in the aortic root. In contrast, exposure at late stage disease produced generally detrimental effects. Both low-and high-dose-rate exposures accelerated lesion growth and high dose rate exposures also increased serum cholesterol levels. These results show that at early stage disease, reduced p53 function does not influence the protective effects against atherosclerosis of low doses given at low dose rate. In contrast, when exposed to the same doses at late stage disease, reduced p53 function produced detrimental effects, rather than the protective effects seen in Trp53 normal mice. As in the Trp53 normal mice, all effects were highly nonlinear with dose. These results indicate that variations in p53 functionality can dramatically alter the outcome of a low-dose exposure, and that the assumption of a linear response with dose for human populations is probably unwarranted.

Long-term increase in serum cholesterol levels in ulcerative colitis patients treated with cyclosporine: an underdiagnosed side effect frequently associated with other drug-related complications

Introduction. Several serious side effects may limit the use of cyclosporine. Cyclosporine has been reported to increase the total cholesterol level; however, the change in serum cholesterol levels before and after cyclosporine therapy has not been examined in ulcerative colitis (UC) patients. The purpose of this article was to compare serum cholesterol levels before and after cyclosporine therapy in patients with refractory UC and to examine the relationship between serum cholesterol levels and other common side effects. Patients and methods. We prospectively assessed serum cholesterol levels in UC patients who had been treated with cyclosporine. Data of 72 patients were analyzed and compared to a control group treated with Infliximab. Results. The average duration of cyclosporine therapy was 9.6 months, and side effects developed in 52 patients. Elevated cholesterol levels were detected in 47.2% of the patients. Serum cholesterol levels were significantly increased during and after discontinuation of cyclosporine therapy compared to the time before use of the drug. However, cholesterol levels measured during cyclosporine therapy were significantly higher compared to the time after its discontinuation (p < 0.001). Patients with drug-related side effects showed higher cholesterol levels after discontinuation of the therapy compared to those who did not experience any adverse events. Conclusions. Our findings suggest that cyclosporine therapy may result in increased serum cholesterol levels even in the long-term, after discontinuation of the therapy. Considering that significantly higher post-therapy cholesterol levels were more common in patients who developed drug-related complications, routine measurement of serum cholesterol may increase the safety of the drug.

Furin-cleaved Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Is Active and Modulates Low Density Lipoprotein Receptor and Serum Cholesterol Levels

Proprotein convertase subtilisin/kexin 9 (PCSK9) regulates plasma LDL cholesterol levels by regulating the degradation of LDL receptors. Another proprotein convertase, furin, cleaves PCSK9 at Arg(218)-Gln(219) in the surface-exposed "218 loop." This cleaved form circulates in blood along with the intact form, albeit at lower concentrations. To gain a better understanding of how cleavage affects PCSK9 function, we produced recombinant furin-cleaved PCSK9 using antibody Ab-3D5, which binds the intact but not the cleaved 218 loop. Using Ab-3D5, we also produced highly purified hepsin-cleaved PCSK9. Hepsin cleaves PCSK9 at Arg(218)-Gln(219) more efficiently than furin but also cleaves at Arg(215)-Phe(216). Further analysis by size exclusion chromatography and mass spectrometry indicated that furin and hepsin produced an internal cleavage in the 218 loop without the loss of the N-terminal segment (Ser(153)-Arg(218)), which remained attached to the catalytic domain. Both furin- and hepsin-cleaved PCSK9 bound to LDL receptor with only 2-fold reduced affinity compared with intact PCSK9. Moreover, they reduced LDL receptor levels in HepG2 cells and in mouse liver with only moderately lower activity than intact PCSK9, consistent with the binding data. Single injection into mice of furin-cleaved PCSK9 resulted in significantly increased serum cholesterol levels, approaching the increase by intact PCSK9. These findings indicate that circulating furin-cleaved PCSK9 is able to regulate LDL receptor and serum cholesterol levels, although somewhat less efficiently than intact PCSK9. Therapeutic anti-PCSK9 approaches that neutralize both forms should be the most effective in preserving LDL receptors and in lowering plasma LDL cholesterol.

Effects of statins and cholesterol on memory functions in mice

Studies on influence of lipid lowering therapies have generated wide controversial results on the role of cholesterol on memory function. However recent studies revealed that cholesterol lowering treatment substantially reduce the risk of dementia. The objectives of this study were to analyze the effect of statins on memory function and to establish the relationship between increase/decrease in cholesterol synthesis, total cholesterol level and memory function in animals. We examined the relationship between biosynthesis of cholesterol and memory function using two statins (lipophilic simvastatin and hydrophilic pravastatin) and high cholesterol diet in mice for 15days and 4months. Memory performance was evaluated with two different behavioral tests and various biochemical parameters such as serum cholesterol, whole brain cholesterol, brain 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) activity and brain acetylcholine esterase (AChE) activity. We found that statin treatment for 4months, but not for 15days, showed significant improvement in memory function whereas high cholesterol diet showed significant impairment of memory. However long-term statin treatment showed significant decrease in serum cholesterol level as well as brain AChE level. Moreover high cholesterol diet showed significant decrease in memory function with an increase in serum cholesterol level as well as brain AChE level. There is no direct correlation between brain cholesterol level, as well as HMG-CoA activity with memory function regulation. However there is definite link between plasma cholesterol level and AChE level. A long-standing plasma cholesterol alteration may be essential to regulate memory function which in turn might be mediated through AChE modulated pathway.

Effects of dietary fucoxanthin on cholesterol metabolism in diabetic/obese KK-A y mice

BackgroundFucoxanthin is a xanthophyll present in brown seaweeds and has several beneficial effects, including anti-obesity and anti-diabetic effects. However, we and another group previously observed that fucoxanthin increases serum cholesterol levels in rodents. Cholesterol is an important component of cell membranes and biosynthesis of bile acids. Serum cholesterol levels are also closely associated with atherosclerosis. Therefore, we sought to identify the mechanism underlying the increase in serum cholesterol levels by fucoxanthin.MethodsDiabetic/obese KK-Ay mice were fed a diet containing 0.2% fucoxanthin for 4 weeks. The mice were sacrificed, and total blood samples were collected for the measurement of serum total cholesterol, HDL-cholesterol and non-HDL-cholesterol levels. Cholesterol content in tissues was also analyzed. Real-time PCR and Western blotting were performed to determine hepatic mRNA and protein expression of genes involved in cholesterol metabolism, respectively.ResultsDietary fucoxanthin significantly increased serum HDL and non-HDL cholesterol levels, and reduced hepatic cholesterol content. In liver, the expression of SREBP1, SREBP2 and their target genes involved in cholesterol biosynthesis significantly increased and tended to increase in the fucoxanthin-fed mice, respectively. In contrast, hepatic levels of LDLR and SR-B1 proteins which is important factors for LDL-cholesterol and HDL-cholesterol uptake in the liver from serum, decreased to 60% and 80% in the fucoxanthin-fed mice, respectively, compared with the control mice. Further, we found that dietary fucoxanthin significantly increased the mRNA expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), which enhances intracellular degradation of LDLR in lysosomes.ConclusionsFucoxanthin increased HDL-cholesterol and non-HDL-cholesterol levels in KK-Ay mice by inducing SREBP expression and reduced cholesterol uptake in the liver via down-regulation of LDLR and SR-B1, resulted in increased serum cholesterol in the mice.

Catechin-rich green tea extract increases serum cholesterol levels in normal diet- and high fat diet-fed rats

Background In vivo studies using rodents have shown that green tea extract and catechins isolated from green tea can induce a variety of health effects, including anti-obesity, hypoglycemic and hypolipidemic activities [1]. These beneficial effects of green tea have been observed in experiments using high fat, high cholesterol and high fructose diet-fed animals. In the present study, we examined the effects of catechinrich green tea extract on serum glucose and lipid levels in normal diet-and high fat diet-fed rats.

Iron overload potentiates diet‐induced hypercholesterolemia and reduces liver ppar‐α expression in hamsters

Iron stores and lipids are related to the development of cardiovascular disease. Given that peroxisome proliferator-activated receptor alpha (PPAR-α) regulates important physiological processes that impact lipid and glucose homeostasis, we decided to investigate the effects of iron overload on serum lipids and the liver expression of PPAR-α, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and cholesterol 7α-hydroxylase. Hamsters were divided into four groups. The standard group (S) was fed the AIN-93M diet, the SI group was fed the diet and iron injections, the hypercholesterolemic group (H) was fed a standard diet containing cholesterol, and the HI group was fed a high-cholesterol diet and iron injections. Serum cholesterol in the HI group was higher than in the H group. Gene expression analysis of PPAR-α showed that the HI group had a lower PPAR-α expression than H. These data show that iron, when associated with a high-fat diet, can cause increased serum cholesterol levels, possibly due to a reduction in PPAR-α expression.

Abstract 350: Inhibition of IGF-1 Signaling Increases Serum Cholesterol and Plaque Burden in ApoE Knockout Mice but Promotes a Stable Plaque Phenotype

Insulin like growth factor-1 (IGF-1) has been shown to have a prominent effect on smooth muscle cell proliferation, migration and apoptosis. We and others have previously shown that inhibition of IGF-1 related signaling can attenuate intimal hyperplasia by attenuating smooth muscle cell proliferation and promoting apoptosis after vascular injury. We hypothesized with support from preliminary work in our laboratory that IGF-1 inhibition will decrease atherosclerosis burden, but may negatively affect plaque stability by increasing SMC apoptosis. Picropodophyllin(PPP) is a specific inhibitor of the IGF-1 receptor phosphorylation and is currently under development as an anti-cancer drug. The aim of this study was to study the short and long term effects of IGF-1 inhibition using PPP in ApoE deficient mice Methods and Results 12 week old Apo E deficient mice (n=64) were treated with an oral preparation of PPP or vehicle (controls) for a period of 10 and 18 weeks. Blood samples were collected before sacrifice and aortas, brachiocephalic trunks and liver samples harvested. Semi-quantitative analysis of the aortic and brachiocephalic trunks using Sudan IV enface staining showed an increase in plaque burden and was significant after 18 weeks. There were no significant differences in weight, serum creatinine, albumin or glucose levels between the two groups. However, we noted 18% lower levels of IGF-1, doubled levels of growth hormone, 30% increase in serum cholesterol levels in the PPP treated group (p&lt;0.05). RT-PCR analysis showed a 38% decrease in LDL receptor expression in the liver in the PPP group. Further immunohistochemical analysis of the plaques showed more fibrosis and lower cholesterol in the sections of the brachiocephalic trunks of the PPP group. Conclusion In contrast to our hypothesis, PPP treatment increased plaque burden but led to plaques with a more stable phenotype. The proposed mechanism is via an increase in serum cholesterol, however further work has to be performed to confirm the pathways involved. In summary, our results suggest that the effects of inhibition of IGF-1R phosphorylation in atherosclerotic animals cannot be extrapolated from results in healthy subjects and has to be considered when designing drugs in the future.

Lipid disorders in Chinese populations

China has undergone rapid socioeconomic development over the past 30 years, which has led to significant changes in lifestyle with a resulting increase in cardiovascular disease prevalence. A shift from traditional diets to high-fat diets and reduced physical activity, has contributed to a rapid increase in obesity and an increase in serum cholesterol levels in China, and these increases interact with the high prevalence of hypertension affecting the pattern of cardiovascular diseases. In China, lipid levels were higher in populations in the north or in urban areas compared with the south or rural areas, respectively. Chinese people in Singapore used to have higher total cholesterol and LDL-C levels than in China, but these have declined since the 1980s, whereas the cholesterol levels in Hong Kong and Taiwan have been in between those in China and Singapore. A higher ratio of unsaturated to saturated fats in the diet appears to have contributed to a lower incidence of coronary heart disease in Hong Kong a...