Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.34 (lipoprotein lipase)
7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conjugated linoleic acids (CLAs) decrease fat deposition in mammals, including pigs. To determine mechanisms for CLA effects on adipocyte growth, porcine stromal-vascular cells (preadipocytes) were isolated and plated in medium containing 10% fetal bovine serum. After 24 h, differentiation factors (insulin + hydrocortisone + transferrin) were added. Oleic acid (200 microM) was added to some plates as a positive control. One of two isomers of CLA (50 microM cis 9, trans 11 or >50 microM trans 10, cis 12), or a mixture of the two isomers (25 microM each) was added to other plates. The cell number increased 7+ times in 7 days after initiation of differentiation, and was not different among treatment groups. By 7 days, Oil Red O-stained material (OROSM), expressed per cell, increased 10+ times in control cells and 64 times in oleic acid-treated cells. Addition of either isomer of CLA or the mixture caused OROSM/cell to increase 10+ times at 2 days, with no further increase at later times. In CLA-treated cells there was no increase in peroxisome proliferator-activated receptor gamma (PPARgamma) or lipoprotein lipase mRNA concentrations. The increased OROSM/cell may represent triacylglycerol synthesis from medium CLA using existing biosynthetic capacity or provision of a limiting ligand for PPARgamma already present. The results are different from those observed with rodent-derived clonal cells (3T3-L1 cells), wherein proliferation and differentiation are inhibited by CLAs, and the active isomer is trans 10, cis 12-CLA. The results suggest distinctions between clonal and primary preadipocytes, or species differences.
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PMID:Effects of isomers of conjugated linoleic acid on porcine adipocyte growth and differentiation. 1283 30

The epidemic increase in type 2 diabetes can be prevented only if markers of risk can be identified and used for early intervention. We examined the clinical phenotype of individuals characterized by normal or low IRS-1 protein expression in fat cells as well as the potential molecular mechanisms related to the adipose tissue. Twenty-five non-obese individuals with low or normal IRS-1 expression in subcutaneous abdominal fat cells were extensively characterized and the results compared with 71 carefully matched subjects with or without a known genetic predisposition for type 2 diabetes. In contrast to the commonly used risk marker, known heredity for diabetes, low cellular IRS-1 identified individuals who were markedly insulin resistant, had high proinsulin and insulin levels, and exhibited evidence of early atherosclerosis measured as increased intima media thickness in the carotid artery bulb. Circulating levels of adiponectin were also significantly reduced. Gene analyses of fat cells in a parallel study showed attenuated expression of several genes related to fat cell differentiation (adiponectin, aP2, PPARgamma, and lipoprotein lipase) in the group of individuals characterized by a low IRS-1 expression and insulin resistance. A low IRS-1 expression in fat cells is a marker of insulin resistance and risk for type 2 diabetes and is associated with evidence of early vascular complications. Impaired adipocyte differentiation, including low gene expression and circulating levels of adiponectin, can provide a link between the cellular marker and the in vivo phenotype.
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PMID:A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. 1289 Jun 97

Epidemiological studies have shown a positive association of colon cancer with hyperlipidemia. Furthermore, signaling generated by peroxisome proliferator-activated receptor (PPAR) alpha and gamma ligands, suggested to be candidate tumor preventive agents, has been shown to lower serum triglyceride levels. In the present study, we assessed hyperlipidemia in Apc-deficient mice, model animals for human familial adenomatous polyposis, and examined the effects of pioglitazone and bezafibrate, respectively, PPARgamma and PPARalpha agonists, on both hyperlipidemia and intestinal polyposis. Serum lipid levels in Apc(1309) mice and Min mice from 6 to 15 weeks of age were measured. Although serum levels of triglyceride and cholesterol were low in both Apc(1309) and wild-type mice at 6 weeks, triglycerides were elevated 10-fold in Apc(1309) mice by the age of 12 weeks but not in their wild-type counterparts. Cholesterol was also increased significantly, and marked centrilobular-restricted steatosis was observed in the livers of aged Apc(1309) mice. Similar findings were observed for Min mice at 15 weeks of age. Moreover, lipoprotein lipase mRNA levels in the liver and small intestine of Apc(1309) and Min mice were demonstrated to be lower than those in wild-type mice. Treatment of Apc(1309) mice with 100 and 200 ppm pioglitazone or bezafibrate for 6 weeks from 6 weeks of age caused dose-dependent reduction in serum triglycerides and cholesterol, along with reduction in the numbers of intestinal polyps to 67% of the control value. The present study clearly demonstrated a hyperlipidemic state in Apc gene-deficient mice and a potential of PPARalpha and PPARgamma ligands to suppress both hyperlipidemia and polyp formation. Hyperlipidemia in these mice may thus be associated with their intestinal lesion development.
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PMID:Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands. 1452 40

In the present study, we investigated the role of the phytoestrogen genistein and 17beta-estradiol in human bone marrow stromal cells, undergoing induced osteogenic or adipogenic differentiation. Profiling of estrogen receptors (ERs)-alpha, -beta1, -beta2, -beta3, -beta4, -beta5, and aromatase mRNAs revealed lineage-dependent expression patterns. During osteogenic differentiation, the osteoblast-determining core binding factor-alpha1 showed a progressive increase, whereas the adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARgamma) was sequentially decreased. This temporal regulation of lineage-determining marker genes was strongly enhanced by genistein during the early osteogenic phase. Moreover, genistein increased alkaline phosphatase mRNA levels and activity, the osteoprotegerin:receptor activator of nuclear factor-kappaB ligand gene expression ratio, and the expression of TGFbeta1. During adipogenic differentiation, down-regulation in the mRNA levels of PPARgamma and CCAAT/enhancer-binding protein-alpha at d 3 and decreased lipoprotein lipase and adipsin mRNA levels at d 21 were observed after genistein treatment. This led to a lower number of adipocytes and a reduction in the size of their lipid droplets. At d 3 of adipogenesis, TGFbeta1 was strongly up-regulated by genistein in an ER-dependent manner. Blocking the TGFbeta1 pathway abolished the effects of genistein on PPARgamma protein levels and led to a reduction in the proliferation rate of precursor cells. Overall, genistein enhanced the commitment and differentiation of bone marrow stromal cells to the osteoblast lineage but did not influence the late osteogenic maturation markers. Adipogenic differentiation and maturation, on the other hand, were reduced by genistein (and 17beta-estradiol) via an ER-dependent mechanism involving autocrine or paracrine TGFbeta1 signaling.
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PMID:The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells. 1460 6

In our previous study, a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in Apc(1309) mice at doses of 100 and 200 ppm in the diet. In contrast, it has been reported that doses of 1500 or 2000 ppm of another PPAR gamma agonist, troglitazone, enhanced colon polyp development in Min mice. In the present study, we therefore investigated the effects of a wide range of pioglitazone doses on both hyperlipidemia and intestinal polyp formation in Min mice. Serum triglycerides and very low density lipoprotein (VLDL) cholesterol in the basal diet group were elevated to levels 13-15 times higher than those in the wild-type counterparts at 20 weeks of age. They were reduced dose-dependently by treatment with 100, 200, 400 and 1600 ppm pioglitazone from 6-20 weeks of age with suppression to almost the wild-type level at the highest dose. Moreover, up-regulation of the liver mRNA levels for lipoprotein lipase (LPL) was evident in the pioglitazone-treated animals. Dose-dependent reduction of intestinal polyps was observed in Min mice given 100-1600 ppm for 14 weeks, total numbers being decreased to 63-9% of the control value. A suppressive effect of pioglitazone on colon polyp formation was also found. The PPAR gamma agonist, pioglitazone, may thus be a promising candidate chemopreventive agent for colon cancer.
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PMID:Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPAR gamma ligand. 1461 72

Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPARalpha and PPARdelta, and TRalpha and TRbeta in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPARgamma coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca2+-ATPase, or SERCA2, the VLDL receptor, fatty acyl-CoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase Ibeta, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXRalpha, -beta, and -gamma, PPARalpha and -delta, and TRalpha and -beta, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis.
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PMID:Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. 1470 65

We present multiple findings on derangements in lipid metabolism in type 2 diabetes. The increase in the intracellular deposition of triglycerides (TG) in muscles, liver and pancreas in subjects prone to diabetes is well documented and demonstrated to attenuate glucose metabolism by interfering with insulin signaling and insulin secretion. The obesity often associated with type 2 diabetes is mainly central, resulting in the overload of abdominal adipocytes with TG and reducing fat depot capacity to protect other tissues from utilizing a large proportion of dietary fat. In contrast to subcutaneous adipocytes, the central adipocytes exhibit a high rate of basal lipolysis and are highly sensitive to fat mobilizing hormones, but respond poorly to lipolysis restraining insulin. The enlarged visceral adipocytes are flooding the portal circulation with free fatty acids (FFA) at metabolically inappropriate time, when FFA should be oxidized, thus exposing nonadipose tissues to fat excess. This leads to ectopic TG accumulation in muscles, liver and pancreatic beta-cells, resulting in insulin resistance and beta-cell dysfunction. This situation, based on a large number of observations in humans and experimental animals, confirms that peripheral adipose tissue is closely regulated, performing a vital role of buffering fluxes of FFA in the circulation. The central adipose tissues tend to upset this balance by releasing large amounts of FFA. To reduce the excessive fat outflow from the abdominal depots and prevent the ectopic fat deposition it is important to decrease the volume of central fat stores or increase the peripheral fat stores. One possibility is to downregulate the activity of lipoprotein lipase, which is overexpressed in abdominal relatively to subcutaneous fat stores. This can be achieved by gastrointestinal bypass or gastroplasty, which decrease dietary fat absorption, or by direct means that include surgical removal of mesenteric fat. Indirect treatment consists of the compliant application of drastic lifestyle change comprising both diet and exercise and pharmacotherapy that reduces mesenteric fat mass and activity. The first step should be an attempt to effectively induce a lifestyle change. Next comes pharmacotherapy including acarbose, metformin, PPARgamma, or PPARgammaalpha agonists, statins and orlistat, estrogens in postmenopausal women or testosterone in men. Among surgical procedures, gastric bypass has been proven to produce beneficial results in advance of other surgical techniques, the evidence basis of which still needs strengthening.
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PMID:Diabetes: insulin resistance and derangements in lipid metabolism. Cure through intervention in fat transport and storage. 1538 13

Numerous human in vivo studies on skeletal muscle gene expression have investigated the effects of given interventions. These have been founded on the assumption that presampling can be regarded as a representative control for postintervention sampling. However, many genes are responsive to the metabolic status, which varies during the day, so that observed differences in gene expression between the pre- and post-sample may therefore be a result of the daily variations rather than an intervention. Furthermore, the sampling itself can cause a local stress response, which may also influence the expression of some genes in later samples from the same localized area. To test this, we performed a short-term human endurance exercise study in which muscle biopsies were obtained from healthy untrained individuals (n=14) before and in the hours after exercise to measure the expression of mRNA for previously reported exercise-related genes (e.g., PPARgamma coactivator-1alpha (PGC-1alpha), pyruvate dehydrogenase kinase 4 (PDK4), MyoD, p21, (heat shock protein 72 (HSP72), lipoprotein lipase (LPL), citrate synthase (CS), and glucose transporter 4 (GLUT4)). To test for changes unrelated to exercise, one half of the subjects did not exercise. As suspected, several presumed exercise-induced genes were induced even without the exercise. Our data demonstrate that presampling is not always a representative control for postintervention sampling, illustrating that use of presampling can cause erroneous interpretations of the underlying induction signals.
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PMID:Are exercise-induced genes induced by exercise? 1551 73

Human mesenchymal stem cells (hMSCs) have the capacity to differentiate along several pathways to form bone, cartilage, tendon, muscle, and adipose tissues. The adult hMSCs reside in vivo in the bone marrow in niches where oxygen concentration is far below the ambient air, which is the most commonly encountered laboratory condition. The study reported here was designed to determine whether oxygen has a role in the differentiation of hMSCs into adipocytes. Indeed, when exposed to atmosphere containing only 1% of oxygen, the formation of adipocyte-like phenotype with cytoplasmic lipid inclusions was observed. The effect of hypoxia on the expression of adipocyte-specific genes was determined by real-time reverse transcription polymerase chain reaction. Interestingly, neither of the two central regulators of adipogenesis--the transcription factors peroxisome proliferator-activated receptor gamma2 (PPAR-gamma2) and ADD1/SREBP1c-was induced. Furthermore, hypoxia did not have any effect on the transcription of early (lipoprotein lipase) or late (aP2) marker genes. By the same token, neither of the mature adipocyte-specific genes--leptin and adipophilin--was found responsive to the treatment. High level of induction, however, was observed with the PPAR-gamma-induced angiopoietin-related gene, PGAR. The lack of an adipocyte-specific transcription pattern thus indicates that despite accumulation of the lipid, true adipogenic differentiation did not take place. In conclusion, hypoxia appears to exert a potent lipogenic effect independent of PPAR-gamma2 maturation pathway.
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PMID:Induction of adipocyte-like phenotype in human mesenchymal stem cells by hypoxia. 1557 52

hLpL(GPI) transgenic mice that overexpress human lipoprotein lipase (hLpL) with a glycosylphosphatidylinositol anchor on cardiomyocytes develop lipotoxic cardiomyopathy associated with increased cardiac uptake of plasma lipids. We hypothesized that peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, or a PPARalpha/gamma agonist would alter cardiac function by modulating lipid uptake by the heart. hLpL(GPI) mice were administered rosiglitazone (10 mg/kg/day), fenofibrate (100 mg/kg/day), or DRF2655, an alkoxy propanoic acid analog (10 mg/kg/day), for 16 days. Rosiglitazone reduced plasma triglyceride (TG) from 107.63 +/- 6.98 to 77.61 +/- 3.98 mg/dl, whereas fenofibrate had no effect. DRF2655 reduced TG to 33.17 +/- 4.12 mg/dl. Rosiglitazone and DRF2655 decreased heart TG and total cholesterol; fenofibrate had no effect. Molecular markers for cardiac dysfunction, atrial natriuretic factor, brain natriuretic peptide, and tumor necrosis factor-alpha were decreased with rosiglitazone and increased with fenofibrate. Echocardiographic measurements showed reduced fractional shortening and increased left ventricular systolic dimension with fenofibrate. No changes in these parameters were observed with rosiglitazone or DRF2655 treatment. Muscle-specific carnitine palmitoyltransferase-1 and fatty acid transporter protein-1 gene expression were increased with fenofibrate and DRF2655 treatment; no change in expression of these genes was noted with rosiglitazone treatment. Rosiglitazone and DRF2655 reduced TG uptake by the heart, and fenofibrate treatment increased fatty acid uptake. Thus, in a lipotoxic cardiomyopathy mouse model, a PPARgamma agonist reduced cardiac lipid and markers of cardiomyopathy, whereas an agonist of PPARalpha did not improve cardiac lipids and worsened heart function. These changes were paralleled by alterations in heart lipid uptake. Overall, PPAR activators exhibit differential effects in this model of lipotoxic dilated cardiomyopathy.
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PMID:Peroxisome proliferator-activated receptor agonists modulate heart function in transgenic mice with lipotoxic cardiomyopathy. 1567 Dec 4


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