Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The esterification of alcohols such as sterols, diacylglycerols, and monoacylglycerols with fatty acids represents the formation of both storage and cytoprotective molecules. Conversely, the overproduction of these molecules is associated with several disease pathologies, including atherosclerosis and obesity. The human acyl-CoA:diacylglycerol acyltransferase (DGAT) 2 gene superfamily comprises seven members, four of which have been previously implicated in the synthesis of di- or triacylglycerol. The remaining 3 members comprise an X-linked locus and have not been characterized. We describe here the expression of DGAT2 and the three X-linked genes in Saccharomyces cerevisiae strains virtually devoid of neutral lipids. All four gene products mediate the synthesis of triacylglycerol; however, two of the X-linked genes act as acyl-CoA wax alcohol acyltransferases (AWAT 1 and 2) that predominantly esterify long chain (wax) alcohols with acyl-CoA-derived fatty acids to produce wax esters. AWAT1 and AWAT2 have very distinct substrate preferences in terms of alcohol chain length and fatty acyl saturation. The enzymes are expressed in many human tissues but predominate in skin. In situ hybridizations demonstrate a differentiation-specific expression pattern within the human sebaceous gland for the two AWAT genes, consistent with a significant role in the composition of sebum.
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PMID:Identification of two novel human acyl-CoA wax alcohol acyltransferases: members of the diacylglycerol acyltransferase 2 (DGAT2) gene superfamily. 1567 Oct 38

Epidemiologic evidence shows an inverse relationship between fish consumption and coronary heart disease (CHD) mortality. Associations between dietary intake of long chain n-3 polyunsaturated fatty acids (PUFA) and serum high density lipoprotein (HDL) cholesterol concentration are unknown. In this study, the association between n-3 PUFA (eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA)) intake and serum HDL cholesterol among Japanese men and women in Japan and Hawaii was examined. The study population consisted of Japanese ancestries from five research centers of the International Study of Macronutrients and Blood Pressure (INTERMAP) study, in Japan and Hawaii (672 men and 676 women), surveyed between 1996 and 1998. Four 24-h dietary recalls and one set of serum lipid measurements were performed. For men, n-3 PUFA intake and HDL cholesterol were higher in Japan than in Hawaii (n-3 PUFA: 1.32 g/day versus 0.47 g/day, p<0.001). For women, n-3 PUFA intake was higher in Japan than in Hawaii (p<0.001) but HDL cholesterol was not significantly different (p=0.752). After adjustment for age, body mass index, physical activity, number of cigarettes per day, alcohol intake, and hormone replacement therapy (for women), n-3 PUFA intake was positively associated with serum HDL cholesterol in men (4.6 mg/dl higher HDL cholesterol with 1%kcal higher n-3 PUFA intake, p=0.011). This association was not observed in women. This positive association of dietary n-3 PUFA with serum HDL cholesterol may partially explain the low mortality from CHD among Japanese men.
Atherosclerosis 2005 Feb
PMID:Relation of long chain n-3 polyunsaturated fatty acid intake to serum high density lipoprotein cholesterol among Japanese men in Japan and Japanese-American men in Hawaii: the INTERLIPID study. 1569 47

Sphingolipids play a very important role in cell membrane formation, signal transduction, and plasma lipoprotein metabolism, and all these functions may have an impact on atherosclerotic development. Serine palmitoyl-CoA transferase (SPT) is the key enzyme in sphingolipid biosynthesis. To evaluate in vivo SPT activity and its role in sphingolipid metabolism, we applied homologous recombination to embryonic stem cells, producing mice with long chain base 1 (Sptlc1) and long chain base 2 (Sptlc2), two subunits of SPT, gene deficiency. Homozygous Sptlc11 and Sptlc2 mice are embryonic lethal, whereas heterozygous versions of both animals (Sptlc1(+/-), Sptlc2(+/-)) are healthy. Analysis showed that, compared with WT mice, Sptlc1(+/-) and Sptlc2(+/-) mice had: (1) decreased liver Sptlc1 and Sptlc2 mRNA by 44% and 57% (P<0.01 and P<0.0001, respectively); (2) decreased liver Sptlc1 mass by 50% and Sptlc2 mass by 70% (P<0.01 and P<0.01, respectively), moreover, Sptlc1 mass decreased by 70% in Sptlc2(+/-) mouse liver, while Sptlc2 mass decreased by 53% in Sptlc1(+/-) mouse liver (P<0.001 and P<0.01, respectively); (3) decreased liver SPT activity by 45% and 60% (P<0.01, respectively); (4) decreased liver ceramide (22% and 39%, P<0.05 and P<0.01, respectively) and sphingosine levels (22% and 31%, P<0.05 and P<0.01, respectively); (5) decreased plasma ceramide (45% and 39%, P<0.01, respectively), sphingosine-1-phosphate (31% and 32%, P<0.01, respectively) and sphingosine levels (22.5% and 25%, P<0.01, respectively); (6) dramatically decreased plasma lysosphingomyelin (17-fold and 16-fold, P<0.0001, respectively); and (7) no change of plasma sphingomyelin, triglyceride, total cholesterol, phospholipids, and liver sphingomyelin levels. These results indicated that both Sptlc1 and Sptlc2 interactions are necessary for SPT activity in vivo, and that SPT activity directly influences plasma sphingolipid levels. Furthermore, manipulation of SPT activity might well influence the course of such diseases as atherosclerosis.
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PMID:Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice. 1621 50

Acyl-CoA: cholesterol acyltransferase (ACAT) catalyzes the acylation of cholesterol to cholesteryl ester with long chain fatty acids and ACAT inhibition is a useful strategy for treating hypercholesterolemia or atherosclerosis. Pentacyclic triterpenes, ursolic acid (1), oleanolic acid (2), and betulinic acid (3) were isolated from the methanol extracts of the leaves of Lycopus lucidus TURCZ. by bioassay-guided fractionation. The structures of compounds 1-3 were elucidated by their spectroscopic data analysis. Among them, betulinic acid (3) exhibited more potent human ACAT-1 and ACAT-2 inhibitory activities with IC(50) values of 16.2+/-0.6 and 28.8+/-1.3 microM, respectively.
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PMID:Human ACAT-1 and ACAT-2 inhibitory activities of pentacyclic triterpenes from the leaves of Lycopus lucidus TURCZ. 1646 51

The effect of PLTP deficiency on hepatic lipid status and apolipoprotein A-I (apoA-I) biosynthesis in PLTP knockout (PLTP-KO) mice was investigated. PLTP-KO mice exhibited a marked reduction in HDL levels, but also increased triglycerides (TG), phospholipids (PL), and cholesterol in very-low-density lipoproteins (VLDL). Both male and female PLTP-KO mice displayed increased hepatic PL and decreased TG, and in the females, increased hepatic cholesterol was also detected. Primary hepatocytes from PLTP-KO mice displayed a different PL molecular species composition to the wild type (WT) controls, with prominent changes being a reduction of long chain fatty acid-containing and an increase of medium chain mono- or di-unsaturated fatty acid containing PL species. Cultured PLTP-KO hepatocytes synthesized and secreted apoA-I in similar quantities as the WT cells. However, the apoA-I secreted by PLTP-KO hepatocytes contained less choline PL, differing also in phosphatidylcholine/sphingomyelin ratio and fatty acyl species composition when compared to apoA-I from WT hepatocytes. Furthermore, the PLTP-KO-derived PL-deficient apoA-I was less stable in the hepatocyte culture medium than that produced by WT cells. These results demonstrate a complex regulatory role of PLTP in serum and liver lipid homeostasis, as well as in the formation of nascent apoA-I-PL complexes from the liver.
Atherosclerosis 2007 Jan
PMID:Altered hepatic lipid status and apolipoprotein A-I metabolism in mice lacking phospholipid transfer protein. 1655 55

Peripheral arterial disease (PAD) is an atherosclerotic disease. Evidence suggests that atherosclerosis is an inflammatory condition and long chain n-3 fatty acids, found in oily fish and fish oils, have been shown to reduce inflammation. Genetic and lifestyle factors such as body mass index (BMI) also influence inflammation. In this study we have examined the effect of fish oil in patients with claudication secondary to PAD. Fish oil supplementation, providing 1g EPA and 0.7 g DHA per day for 12 weeks, increased walking distance on a treadmill set at 3.2 km/h with a 7% incline. Walking distance to first pain increased from 76.2+/-8.5 m before fish oil to 140.6+/-25.5 m after fish oil (mean+/-SEM, p=0.004) and total distance walked increased from 160.0+/-21.5 m before fish oil to 242.1+/-34.5 m after fish oil (p=0.002). Fish oil supplementation also improved ankle brachial pressure index (ABPI) from 0.599+/-0.017 before fish oil to 0.776+/-0.030 after fish oil (p<0.001). The increase in walking distance was dependent on both BMI and genotype for single nucleotide polymorphisms in the genes encoding the pro-inflammatory cytokines tumour necrosis factor-alpha and interleukin (IL)-1beta and the anti-inflammatory cytokine IL-10 (detected using amplification refractory mutation system polymerase chain reaction). Neither BMI nor any of the genotypes examined affected the ability of fish oil to increase ABPI. The mechanisms by which fish oil affects walking distance and ABPI do not appear to be the same.
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PMID:Fish oil induced increase in walking distance, but not ankle brachial pressure index, in peripheral arterial disease is dependent on both body mass index and inflammatory genotype. 1760 Jun 95

Long-chain EPA/DHA omega-3 fatty acid supplementation can be co-preventative and co-therapeutic. Current research suggests increasing accumulated long chain omega-3s for health benefits and as natural medicine in several major diseases. But many believe plant omega-3 sources are nutritionally and therapeutically equivalent to the EPA/DHA omega-3 in fish oil. Although healthy, precursor ALA bio-conversion to EPA is inefficient and production of DHA is nearly absent, limiting the protective value of ALA supplementation from flax-oil, for example. Along with pollutants certain fish acquire high levels of EPA/DHA as predatory species. However, the origin of EPA/DHA in aquatic ecosystems is algae. Certain microalgae produce high levels of EPA or DHA. Now, organically produced DHA-rich microalgae oil is available. Clinical trials with DHA-rich oil indicate comparable efficacies to fish oil for protection from cardiovascular risk factors by lowering plasma triglycerides and oxidative stress. This review discusses 1) omega-3 fatty acids in nutrition and medicine; 2) omega-3s in physiology and gene regulation; 3) possible protective mechanisms of EPA/DHA in major diseases such as coronary heart disease, atherosclerosis, cancer and type 2 diabetes; 4) EPA and DHA requirements considering fish oil safety; and 5) microalgae EPA and DHA-rich oils and recent clinical results.
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PMID:Omega-3 fatty acids for nutrition and medicine: considering microalgae oil as a vegetarian source of EPA and DHA. 1822 Jun 72

The susceptibility of fatty acids to oxidation is thought to be directly dependent on their degree of unsaturation. However, some in vitro and in vivo studies suggest that the relation between chemical structure and susceptibility to oxidation is not as straightforward as hypothesized from theoretical viewpoints. Indeed, long chain polyunsaturated fatty acids (LC-PUFAs) might be less oxidizable than others under specific experimental conditions. We investigated the free radical-scavenging potential of PUFA and the production of reactive oxygen/nitrogen (ROS/RNS) species by human aortic endothelial cells (HAECs) supplemented with different fatty acids. Fatty acid micelles scavenged superoxide in an unsaturation-dependent manner, up to eicosapentaenoic acid, which was the most effective fatty acid. Supplementation of HAEC with polyunsaturated fatty acids of the omega 3 series resulted in lower formation of ROS, as compared with cells supplemented with saturates, monounsaturates, or polyunsaturates of the omega 6 series. This effect was maximal at concentrations of 10muM. The effects of omega 3 fatty acids on reactive species production appear to be stronger when ROS were evaluated, as a milder, albeit significant effect was observed on RNS generation. Based on in vivo data showing reduced excretion of lipid peroxidation products after omega 3 intake and our data on ROS production and direct superoxide scavenging by LC-PUFAs, notably those of the omega 3 series, we propose that this series of fatty acid might act as indirect anti- rather than pro-oxidant in vascular endothelial cells, hence diminishing inflammation and, in turn, the risk of atherosclerosis and cardiovascular disease.
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PMID:Polyunsaturated fatty acids as antioxidants. 1858 47

Dietary very long chain omega (omega)-3 polyunsaturated fatty acids (PUFA) have been associated with reduced CVD risk, the mechanisms of which have yet to be fully elucidated. LDL receptor null mice (LDLr-/-) were used to assess the effect of different ratios of dietary omega-6 PUFA to eicosapentaenoic acid plus docosahexaenoic acid (omega-6:EPA+DHA) on atherogenesis and inflammatory response. Mice were fed high saturated fat diets without EPA and DHA (HSF omega-6), or with omega-6:EPA+DHA at ratios of 20:1 (HSF R=20:1), 4:1 (HSF R=4:1), and 1:1 (HSF R=1:1) for 32 weeks. Mice fed the lowest omega-6:EPA+DHA ratio diet had lower circulating concentrations of non-HDL cholesterol (25%, P<0.05) and interleukin-6 (IL-6) (44%, P<0.05) compared to mice fed the HSF omega-6 diet. Aortic and elicited peritoneal macrophage (Mphi) total cholesterol were 24% (P=0.07) and 25% (P<0.05) lower, respectively, in HSF R=1:1 compared to HSF omega-6 fed mice. MCP-1 mRNA levels and secretion were 37% (P<0.05) and 38% (P<0.05) lower, respectively, in elicited peritoneal Mphi isolated from HSF R=1:1 compared to HSF omega-6 fed mice. mRNA and protein levels of ATP-binding cassette A1, and mRNA levels of TNFalpha were significantly lower in elicited peritoneal Mphi isolated from HSF R=1:1 fed mice, whereas there was no significant effect of diets with different omega-6:EPA+DHA ratios on CD36, Mphi scavenger receptor 1, scavenger receptor B1 and IL-6 mRNA or protein levels. These data suggest that lower omega-6:EPA+DHA ratio diets lowered some measures of inflammation and Mphi cholesterol accumulation, which was associated with less aortic lesion formation in LDLr-/- mice.
Atherosclerosis 2009 May
PMID:Reduction in dietary omega-6 polyunsaturated fatty acids: eicosapentaenoic acid plus docosahexaenoic acid ratio minimizes atherosclerotic lesion formation and inflammatory response in the LDL receptor null mouse. 1884 66

The lipid composition of arterial walls changes during development, ageing and pathological processes. Preeclampsia is the most common pregnancy-associated pathological syndrome. It is accompanied by significant remodelling of the extracellular matrix, both in the umbilical cord vessels and in the surrounding Wharton's jelly. Lipids of the umbilical cord have not been extensively studied. Here we evaluate the lipid composition of the umbilical cord artery (UCA) and its alteration in preeclampsia. Thin layer chromatography and high-performance liquid chromatography were employed for these analyses. It was found that the UCA wall, as with most human tissues, contains free fatty acids, mono-, di- and triacylglycerols, free cholesterol and its esters. The characteristic feature of the UCA wall is the presence of high amounts of long chain polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (C20:5) and docosahexaenoic acid (C22:6), which are rather minor lipid components of most human tissues. They exist both in a free form and in a form of acylglycerols and cholesterol esters. Preeclampsia is associated with a marked decrease in most free fatty acids and acylglycerols. The total amount of long chain PUFA: C18:2, C:18:3, C20:4, C20:5 and C22:6 in these lipid fractions is decreased by half, with a concomitant increase in free cholesterol and its esters. We propose that these lower levels of PUFA may reduce prostaglandin synthesis in the arterial wall and thereby impair blood flow in the foetal vascular system, leading to preeclamptic symptoms.
Atherosclerosis 2009 Jun
PMID:Lipid compounds of the umbilical cord artery and their alterations in preeclampsia. 1911 Feb 48


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