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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At present, dyslipidemia is most commonly treated with lipid-altering pharmacological therapies. However, safety concerns regarding the use of these agents have prompted the need for safe and efficacious nonpharmacological lipid-altering interventions. One such natural therapy is the combination of plant sterols and endurance training. This combination lifestyle intervention has been shown to decrease total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride concentrations while increasing high-density lipoprotein (HDL) cholesterol concentrations. However, the mechanisms that underlie these positive lipid alterations have yet to be clarified. Thus, the purpose of this review is to evaluate individual effects of plant sterols and exercise training on lipid levels while attempting to elucidate the possible independent and synergistic mechanisms of action responsible for these modulations. Results reveal that plant sterols decrease both total and LDL cholesterol levels by reducing exogenous cholesterol absorption by way of cholesterol displacement in the intestinal lumen. Additionally, the intestinal membrane transport proteins, ABCG5, ABCG8, as well as NPC1L1, have also been implicated in plant sterol-mediated cholesterol lowering. Conversely, exercise decreases triglyceride levels by reducing hepatic very low-density lipoprotein secretion and increasing skeletal lipoprotein lipase activity. In addition, endurance training was shown to increase HDL cholesterol levels by way of HDL subfraction alterations, in conjunction with changing reverse cholesterol transport enzyme activities. Moreover, plant sterols and exercise may work synergistically to alter lipid levels by modulating lipoprotein transport, composition, release and metabolism. In sum, the present review lends further insight as to the metabolic benefits of adopting a healthy lifestyle, including plant sterols and endurance training, in the treatment of dyslipidemia.
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PMID:Plant sterols combined with exercise for the treatment of hypercholesterolemia: overview of independent and synergistic mechanisms of action. 1641 48

Treatment for dyslipidemia in diabetes reduces cardiovascular events. Diabetes is associated with major abnormalities in fatty acid metabolism. The resulting disturbance results in an abnormal lipoprotein cascade from the large chylomicron through to the small HDL particle. This suggests that drugs that alter formation of the chylomicron particle might have a very important role in diabetic dyslipidemia. Achieving normal glycemia will reverse the abnormalities in fatty acid metabolism, but this is difficult, particularly as the disease progresses. Genes that regulate cholesterol absorption and excretion have been described (Niemann Pick C1-like 1 [NPC1-L1] and ATP binding cassette proteins [ABC] G5 and G8). An effective NPC1-L1 inhibitor (ezetimibe) improves the reduction in cholesterol caused by statins. Agonists of ABCG5 and G8 may become important in the treatment of dyslipidemia. Microsomal triglyceride transfer protein (MTP) is responsible for the assembly of the chylomicron and VLDL particles. New MTP inhibitors, acting only on the intestine, are exciting possible treatments. The advisability of sitosterol-enriched foods to lower cholesterol may have to be reassessed for patients with diabetes, since these products may lead to an increase in chylomicron sitosterol in diabetic patients. More successful treatment of diabetic dyslipidemia is essential if we are to reduce the burden of cardiovascular disease so commonly found in diabetes.
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PMID:Targets for intervention in dyslipidemia in diabetes. 1822 92

Insulin resistance is strongly associated with metabolic dyslipidemia, which is largely a postprandial phenomenon. Though previously regarded as a consequence of delayed triglyceride-rich lipoprotein clearance, emerging evidence present intestinal overproduction of apoB-48-containing lipoproteins as a major contributor to postprandial dyslipidemia. The majority of mechanistic information is however derived from animal models, namely the fructose-fed Syrian Golden hamster, and extension to human studies to date has been limited. Work in our laboratory has established that aberrant insulin signalling exists in the enterocyte, and that inflammation appears to induce intestinal insulin resistance. The intestine is a major site of lipid synthesis in the body, and upregulated intestinal de novo lipogenesis and cholesterogenesis have been noted in insulin resistant and diabetic states. There is also enhanced dietary lipid absorption attributable to changes in ABCG5/8, NPC1L1, CD36/FAT, and FATP4. Proteins that are involved in chylomicron assembly and secretion, including MTP, MGAT, DGAT, apoAI-V, and Sar1 GTPase, show evidence of increased expression and activity levels. Increased circulating free fatty acids, typically observed in insulin resistant states, may serve to deliver lipid substrates to the intestine for enhanced chylomicron assembly and secretion. To compound the dysregulation of intestinal lipid metabolism, there are changes in the secretion of gut-derived peptides, which include GLP-1, GLP-2, and GIP. Thus, accumulating evidence presents intestinal lipoprotein secretion as a highly regulated process that is sensitive to perturbations in whole body energy homeostasis, and is severely perturbed in insulin resistant states.
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PMID:Postprandial dyslipidemia in insulin resistance: mechanisms and role of intestinal insulin sensitivity. 1865 87

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 x 10(-11); LDL, P = 2.6 x 10(-10)), TMEM57 (TC, P = 5.4 x 10(-10)), CTCF-PRMT8 region (HDL, P = 8.3 x 10(-16)), DNAH11 (LDL, P = 6.1 x 10(-9)), FADS3-FADS2 (TC, P = 1.5 x 10(-10); LDL, P = 4.4 x 10(-13)) and MADD-FOLH1 region (HDL, P = 6 x 10(-11)). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.
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PMID:Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. 1911 55

Serine palmitoyltransferase (SPT) is the key enzyme for the biosynthesis of sphingolipids. It has been reported that oral administration of myriocin (an SPT inhibitor) decreases plasma sphingomyelin (SM) and cholesterol levels, and reduces atherosclerosis in apoE knockout (KO) mice. We studied cholesterol absorption in myriocin-treated WT or apoE KO animals and found that, after myriocin treatment, the mice absorbed significantly less cholesterol than controls, with no observable pathological changes in the small intestine. More importantly, we found that heterozygous Sptlc1 (a subunit of SPT) KO mice also absorbed significantly less cholesterol than controls. To understand the mechanism, we measured protein levels of Niemann-Pick C1-like 1 (NPC1L1), ABCG5, and ABCA1, three key factors involved in intestinal cholesterol absorption. We found that NPC1L1 and ABCA1 were decreased, whereas ABCG5 was increased in the SPT deficient small intestine. SM levels on the apical membrane were also measured and they were significantly decreased in SPT deficient mice, compared with controls. In conclusion, SPT deficiency might reduce intestinal cholesterol absorption by altering NPC1L1 and ABCG5 protein levels in the apical membranes of enterocytes through lowering apical membrane SM levels. This may be also true for ABCA1 which locates on basal membrane of enterocytes. Manipulation of SPT activity could thus provide a novel alternative treatment for dyslipidemia.
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PMID:Serine palmitoyltransferase (SPT) deficient mice absorb less cholesterol. 1941 52

Exogenous cholesterol uptake involves a complex process in the intestines for the absorption of cholesterol and bile acids. This process is regulated by intestinal nuclear transcription factors such as LXR that affect sterol transporters NPC1L1, ABCG5/G8, and ABCG1, and enzymes such as ACAT-2. Plant sterol/stanols, ezetimibe, and bile acid sequestrants have a variety of effects on these various transporters, and new insights into their mechanism(s) of action have provided a plethora of exciting targets for metabolic diseases, dyslipidemia, and atherosclerosis.
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PMID:Therapies targeting exogenous cholesterol uptake: new insights and controversies. 2118 57

Sitosterolemia is a very rare autosomal recessive lipoprotein metabolic disorder caused by homozygous or compound heterozygous mutations in one of the two adenosine triphosphate-binding cassette transporter genes, ABCG5 and ABCG8. Sitosterolemia is clinically characterized by xanthomas and atherosclerosis, arthritis, fever, hemolysis and macrothrombocytopenia even in early childhood. We described a 16-month-old girl, who had numerous yellowish-brown intertriginous xanthomas along the skin creases on the extremities with severe hypercholesterolemia and elevated plant sterol levels. Histopathologically, xanthoma showed aggregation of foam cells in the dermis with a zone of mucin deposits in the dermal papilla. Electron microscopy showed numerous membrane-bound lipid droplets and multivesicular lipid bodies in the foam cells, a round cell containing lipid droplets in the basal cell layer and abundant mucin deposits just beneath the basal lamina. Diagnosis of sitosterolemia was confirmed by DNA sequencing showing compound heterozygosity for previously reported missense mutations in exon 9 of ABCG5. Infants presenting with multiple xanthomas should be investigated for sitosterolemia, if there is no family history of dyslipidemia.
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PMID:Numerous intertriginous xanthomas in infant: A diagnostic clue for sitosterolemia. 2740 67

Hypercholesterolemia is one of the important risk factors of atherosclerosis (AS). The aim of this study is to explore the effect of medium-chain fatty acids (MCFAs) on serum cholesterol levels and their mechanism of action. Hyperlipemia, as a model of abnormal lipid hypermetabolism, was established by using a high fat diet in C57BL/6J mice. Forty eight mice with dyslipidemia were randomly divided into 4 groups, 12 mice per group, including the control group, the 2% caprylic acid (C8:0)-treated group, 2% capric acid (C10:0)-treated group, and 2% oleic acid (C18:1)-treated group. All mice were fed with a high fat diet. After 16 weeks, the mice were anesthetized with chloral hydrate. The mouse portal vein blood, the liver and the start site of the ileum (1 cm) were collected. The body weight of the mice and blood lipid profiles were measured. Gene transcription and the expression level associated with bile acid metabolism in the liver and small intestine were determined by real-time PCR and the western blotting method. The concentrations of bile acid metabolites in bile and feces were analysed. After 16 weeks of treatment, the concentrations of TC and LDL-C in the caprylic acid group were significantly lower than those in the control group (P < 0.05); the transcription and expression level of LXR, CYP7A1, CYP27A1 and ABCG8 in the caprylic acid and capric acid groups were significantly higher than those in the control group in the liver (P < 0.05), however the transcription and expression level of the small heterodimer partner (SHP) were significantly lower than those in the control group (P < 0.05); the transcription and expression level of LXR, ABCG5 and ABCG8 in the caprylic acid, capric acid and oleic acid groups were significantly higher than those in the control group in the small intestine (P < 0.05). The concentrations of total bile acid, mainly cholic acid and cholesterol in bile and feces were significantly higher in the caprylic and capric acid groups than those of in the control group (P < 0.05). Thus, MCFA increased the expression of LXR and ABCG8, enhanced CYP7A1 and CYP27A1 expression, decreased and SHP expression in the liver, thereby promoted liver bile acid synthesis and excretion. In addition MCFA increased the expression of ABCG5, ABCG8 and LXR in the small intestine, thereby inhibiting small intestinal bile acid absorption, increasing the concentrations of cholesterol and bile acid in bile and feces and reducing the level of serum cholesterol.
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PMID:Medium-chain fatty acids reduce serum cholesterol by regulating the metabolism of bile acid in C57BL/6J mice. 2800 72

Westernization of dietary habits leads to an increase in lipid intake and is thought to be responsible for an increase in patients with dyslipidemia. It is a well-known fact that the impaired cholesterol homeostasis is closely related to the development of various lifestyle-related diseases such as fatty liver, diabetes, and gallstone as well as dyslipidemia leading to atherosclerosis and cardiovascular diseases such as heart attack and stroke. Therefore, appropriate management of cholesterol levels in the body is considered important in prevention and treatments of these lifestyle-related diseases and in addition, molecular mechanisms controlling plasma (and/or hepatic) cholesterol levels have been intensively studied. Due to its hydrophobicity, cholesterol was long believed to pass through cell membranes by passive diffusion. However, recent studies have identified a number of plasma membrane transporters that are responsible for the cellular uptake or efflux of cholesterol and involved in developments of lifestyle-related diseases. In this review, we focus on Niemann-Pick C1 Like 1 (NPC1L1) and a heterodimer of ATP-binding cassette transporter G5 and G8 (ABCG5/G8), both of which are responsible for intestinal cholesterol absorption and biliary cholesterol secretion, and discuss the relationship between these cholesterol transporters and lifestyle-related diseases. In addition, we also discuss the related uncertainties that need to be explored in future studies.
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PMID:Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol. 2931 70

The ATP-binding cassette (ABC) proteins play critical roles in maintaining lipid and sterol homeostasis in higher eukaryotes. In humans, several subfamily-A and -G members function as cholesterol transporters across the cellular membranes. Deficiencies of these ABC proteins can cause dyslipidemia that is associated with health conditions such as atherosclerosis, diabetes, fatty liver disease, and neurodegeneration. The physiological roles of ABC cholesterol transporters have been implicated in mediating cholesterol efflux for reverse cholesterol transport and in maintaining membrane integrity for cell survival. The precise role of these ABC transporters in cells remains elusive, and little is known about the sterol-transport mechanism. The membrane constituents of ABC transporters have been postulated to play a key role in determining the transport substrates and the translocation mechanisms via the transmembrane domains. Recent breakthroughs in determining high-resolution structures of the human sterol transporter ABCG5/G8 and its functional homologs have shed light on new structural features of ABC transporters, providing a more relevant framework for mechanistic analysis of cholesterol-transport ABC proteins. This minireview outlines what is known about ABCG cholesterol transporters, addresses key structural features in the putative sterol translocation pathway on the transmembrane domains, and concludes by proposing a mechanistic model of ABC cholesterol transporters.
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PMID:Structural snapshot of the cholesterol-transport ATP-binding cassette proteins 1. 3005 54


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