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) reduce fat deposition in several mammalian species. Among the proposed mechanisms for this effect are reduced preadipocyte proliferation and differentiation. We measured proliferation and differentiation of cultured human preadipocytes treated with CLAs. Preadipocytes were differentiated with insulin, hydrocortisone, transferrin, and 10% fetal bovine serum, with isobutyl-methylxanthine included for the first 2 d. The differentiation medium contained 200 microM oleic acid (C18:1), 50 microM cis-9,trans-11-CLA (9,11-CLA), or 50 microM trans-10,cis-12-CLA (10,12-CLA); the negative control medium contained no added fatty acid, and the cells did not differentiate. Cell number increased three to four times during the 17 d of differentiation, but was 30-35% lower in the CLA-treated cells than in the negative control cells. Compared with the negative control cells, differentiation was increased in the cells treated with C18:1 (increased Oil Red O-stained material [OROSM], triacylglycerol, glycerol 3-phosphate dehydrogenase activity [GPDH], peroxisome proliferator-activated receptor-gamma [PPAR gamma] messenger ribonucleic acid [mRNA], and lipoprotein lipase [LPL] mRNA). In effect, the C18:1-treated cells act as a positive control to demonstrate the differentiation capacity of each cell lot. Both 9,11-CLA- and 10,12-CLA-treated cells had increased differentiation (increased OROSM, triacylglycerol, GPDH, PPAR gamma, and LPL) compared with the negative control cells. The data suggest that early in differentiation when de novo fatty acid (FA) synthesis is limited and competition for FAs by membrane and triacylglycerol synthetic pathways is great, human preadipocytes do not differentiate unless a PPAR gamma ligand is added. Either CLA isomer or C18:1 can provide such a ligand.
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PMID:Isomers of conjugated linoleic acid modulate human preadipocyte differentiation. 1503 76

Infection and inflammation induce the acute-phase response (APR), leading to multiple alterations in lipid and lipoprotein metabolism. Plasma triglyceride levels increase from increased VLDL secretion as a result of adipose tissue lipolysis, increased de novo hepatic fatty acid synthesis, and suppression of fatty acid oxidation. With more severe infection, VLDL clearance decreases secondary to decreased lipoprotein lipase and apolipoprotein E in VLDL. In rodents, hypercholesterolemia occurs attributable to increased hepatic cholesterol synthesis and decreased LDL clearance, conversion of cholesterol to bile acids, and secretion of cholesterol into the bile. Marked alterations in proteins important in HDL metabolism lead to decreased reverse cholesterol transport and increased cholesterol delivery to immune cells. Oxidation of LDL and VLDL increases, whereas HDL becomes a proinflammatory molecule. Lipoproteins become enriched in ceramide, glucosylceramide, and sphingomyelin, enhancing uptake by macrophages. Thus, many of the changes in lipoproteins are proatherogenic. The molecular mechanisms underlying the decrease in many of the proteins during the APR involve coordinated decreases in several nuclear hormone receptors, including peroxisome proliferator-activated receptor, liver X receptor, farnesoid X receptor, and retinoid X receptor. APR-induced alterations initially protect the host from the harmful effects of bacteria, viruses, and parasites. However, if prolonged, these changes in the structure and function of lipoproteins will contribute to atherogenesis.
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PMID:Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. 1510 78

Interconversion of bone marrow osteoblasts and adipocytes has been reported previously. However, the osteogenic potential of extramedullary adipocytes is not known. Thus, we incubated a pure culture of human subcutaneous adipocytes in control medium for 1-2 weeks. Afterward, the cells were incubated in either osteoblast medium (OB medium) containing various combinations of calcitriol, dexamethasone, ascorbic acid, and beta-glycerophosphate or in adipocyte medium (AD medium) containing HEPES, biotin, pantothenate, insulin, triiodothyronine, dexamethasone, and isobutylmethylxanthine for 4 weeks. Expression of osteoblastic and adipocytic phenotypes was examined by determination of lineage-specific mRNA markers and in vitro adipocyte and osteoblast formation. Cells were also implanted, mixed with hydroxyapatite-tricalcium phosphate powder, in the subcutaneous tissue of immunodeficient mice in order to assess in vivo bone formation potential. One week after incubation in control medium, cells formed fusiform elongated fibroblast-like cells. In OB medium, cells stained positive for alkaline phosphatase (AP) and expressed mRNAs encoding Cbfa1/Runx2, AP, and osteocalcin. In AD medium cells reacquired adipocyte morphology with multilocular lipid-filled cells. Also, the cells expressed adipocyte-specific mRNA markers: lipoprotein lipase and peroxisome proliferator-activated receptor gamma2. Bone was formed only in the in vivo implants of cells incubated in OB medium. In conclusion, extramedullary adipocytes can transdifferentiate to bone-forming cells. Because of their ease of isolation, adipocytes may be good candidates for tissue-engineering protocols aimed at creating bone tissue for the repair of nonunion fractures and large bone defects.
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PMID:Subcutaneous adipocytes can differentiate into bone-forming cells in vitro and in vivo. 1516 55

This study analyzes the relationship between risk factors related to overweight/obesity, insulin resistance, lipid tolerance, hypertension, endothelial function and genetic polymorphisms associated with: i) appetite regulation (leptin, melanocortin-3-receptor (MCR-3), dopamine receptor 2 (D2R)); ii) adipocyte differentiation and insulin sensitivity (peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), tumor necrosis factor-alpha (TNF-alpha)); iii) thermogenesis and free fatty acid (FFA) transport/catabolism (uncoupling protein-1 (UCP1), lipoprotein lipase (LPL), beta2- and beta3-adrenergic receptor (beta2AR, beta3AR), fatty acid transport protein-1 (FATP-1) and iv) lipoproteins (apoliprotein E (apoE), apo CIII). The 122 members of 40 obese Caucasian families from southern Poland participated in the study. The genotypes were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) or by direct sequencing. Phenotypes related to obesity (body mass index (BMI), fat/lean body mass composition, waist-to-hip ratio (WHR)), fasting lipids, glucose, leptin and insulin, as well as insulin during oral glucose tolerance test (OGTT) (4 points within 2 hours) and during oral lipid tolerance test (OLTT) (5 points within 8 hours) were assessed. The insulin sensitivity indexes: homeostasis model assessment of insulin resistance, whole body insulin sensitivity index, hepatic insulin sensitivity and early secretory response to an oral glucose load (HOMA-IR, ISI-COMP, ISI-HOMA and DELTA) were calculated. The single gene mutations such as C105 T OB and Pro115 Gln PPAR-gamma2 linked to morbid obesity were not detected in our group. A weak correlation between obesity and certain gene polymorphisms was observed. Being overweight (25 < BMI > or = 30 kg/m2) significantly correlated with worse FFA tolerance in male PPAR-gamma2 12Pro, LPL-H (G) allele carriers. Insulin resistance was found in female PPAR-gamma2 Pro12, TNF-alpha (-308A) and LPL-H (G) allele carriers. Hypertension linked to the PPAR-gamma2 Pro allele carriers was characterized by high leptin output during OLTT. We conclude that the polymorphisms we investigated were weakly correlated with obesity but significantly modified the risk factors of the metabolic syndrome.
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PMID:Analysis of candidate genes in Polish families with obesity. 1520 83

Both rosiglitazone and metformin increase hepatic insulin sensitivity, but their mechanism of action has not been compared in humans. The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content, hepatic insulin sensitivity, insulin clearance, and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes. A total of 20 drug-naive patients with type 2 diabetes (age 48 +/- 3 years, fasting plasma glucose 152 +/- 9 mg/dl, BMI 30.6 +/- 0.8 kg/m2) were treated in a double-blind randomized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks. Both drugs similarly decreased HbA1c, insulin, and free fatty acid concentrations. Body weight decreased in the metformin (84 +/- 4 vs. 82 +/- 4 kg, P < 0.05) but not the rosiglitazone group. Liver fat (proton spectroscopy) was decreased with rosiglitazone by 51% (15 +/- 3 vs. 7 +/- 1%, 0 vs. 16 weeks, P = 0.003) but not by metformin (13 +/- 3 to 14 +/- 3%, NS). Rosiglitazone (16 +/- 2 vs. 20 +/- 1 ml.kg(-1).min(-1), P = 0.02) but not metformin increased insulin clearance by 20%. Hepatic insulin sensitivity in the basal state increased similarly in both groups. Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin. Serum adiponectin concentrations increased by 123% with rosiglitazone but remained unchanged during metformin treatment. The decrease of serum adiponectin concentrations correlated with the decrease in liver fat (r = -0.74, P < 0.001). Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-gamma, adiponectin, and lipoprotein lipase in adipose tissue. In conclusion, rosiglitazone but not metformin decreases liver fat and increases insulin clearance. The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations. Both agents increase hepatic insulin sensitivity, but only rosiglitazone increases peripheral glucose uptake.
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PMID:Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. 1527 3

The mechanism by which increased central adiposity causes hepatic insulin resistance is unclear. The "portal hypothesis" implicates increased lipolytic activity in the visceral fat and therefore increased delivery of free fatty acids (FFA) to the liver, ultimately leading to liver insulin resistance. To test the portal hypothesis at the transcriptional level, we studied expression of several genes involved in glucose and lipid metabolism in the fat-fed dog model with visceral adiposity vs. controls (n = 6). Tissue samples were obtained from dogs after 12 wk of either moderate fat (42% calories from fat; n = 6) or control diet (35% calories from fat). Northern blot analysis revealed an increase in the ratio of visceral to subcutaneous (v/s ratio) mRNA expression of both lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor-gamma (PPARgamma). In addition, the ratio for sterol regulatory element-binding transcription factor-1 (SREBP-1) tended to be higher in fat-fed dogs, suggesting enhanced lipid accumulation in the visceral fat depot. The v/s ratio of hormone-sensitive lipase (HSL) increased significantly, implicating a higher rate of lipolysis in visceral adipose despite hyperinsulinemia in obese dogs. In fat-fed dogs, liver SREBP-1 expression was increased significantly, with a tendency for increased fatty acid-binding protein (FABP) expression. In addition, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK) increased significantly, consistent with enhanced gluconeogenesis. Liver triglyceride content was elevated 45% in fat-fed animals vs. controls. Moreover, insulin receptor binding was 50% lower in fat-fed dogs. Increased gene expression promoting lipid accumulation and lipolysis in visceral fat, as well as elevated rate-limiting gluconeogenic enzyme expression in the liver, is consistent with the portal theory. Further studies will need to be performed to determine whether FFA are involved directly in this pathway and whether other signals (either humoral and/or neural) may contribute to the development of hepatic insulin resistance observed with visceral obesity.
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PMID:Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance. 1552 94

Suppressor of cytokine signaling-2 (SOCS2)-deficient (SOCS2-/-) mice grow significantly larger than their littermates, suggesting that SOCS2 is important in the negative regulation of the actions of GH and/or IGF-I. The aim of this study was to identify genes and metabolic parameters that might contribute to the SOCS2-/- phenotype. We demonstrate that although SOCS2 deficiency induces significant changes in hepatic gene expression, only a fraction of these overlap with known GH-induced effects in the liver, suggesting that SOCS2 might be an important regulator of other growth factors and cytokines acting on the liver. However, an important role of GH and IGF-I in the phenotype of these animals was demonstrated by an overexpression of IGF-binding protein-3 mRNA in the liver and increased levels of circulating IGF-binding protein-3. Other GH-like effects included diminished serum triglycerides and down-regulation of lipoprotein lipase in adipose tissue. Interestingly, SOCS2-/- mice did not differ from their wild-type littermates in glucose or insulin tolerance tests, which is in contrast with the known diabetogenic effects of GH. Furthermore, there was no evidence of impaired insulin signaling in primary hepatocytes isolated from SOCS2-/- mice. Moreover, increased expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha mRNA was detected in skeletal muscle, which might contribute to normal glycemic control despite the apparent overactivity of the GH/IGF-I axis. Our data indicate that SOCS2 deficiency partially mimics a state of increased GH activity, but also results in changes that cannot be related to known GH effects.
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PMID:Suppressor of cytokine signaling-2 deficiency induces molecular and metabolic changes that partially overlap with growth hormone-dependent effects. 1556 48

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

We have previously reported a hyperlipidemic state in two strains of Apc-deficient mice, Min and Apc(1309), associated with low expression levels of lipoprotein lipase (LPL) in the liver and small intestine, and enforced induction of LPL mRNA by peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma agonists clearly suppressed hyperlipidemia and intestinal polyp formation in these mice. Meanwhile, a compound, NO-1886, has been shown to increase LPL mRNA and protein levels but not to possess PPARalpha and PPARgamma agonistic activity. In this study, therefore, the effects of NO-1886 on hyperlipidemia and intestinal polyp formation were investigated in Min mice. Administration of 400 and 800 ppm NO-1886 in the diet for 13 weeks from 7 weeks of age caused a reduction of serum triglycerides to 39% and 31% of the untreated value, respectively, and the values for very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were improved almost to the wild-type level with a corresponding elevation of the LPL mRNA. Moreover, total numbers of intestinal polyps in the groups receiving NO-1886 at 400 and 800 ppm were decreased to 48% and 42% of the control value, respectively. We also found that NO-1886 suppressed cyclooxygenase-2 transcriptional promoter activity in a reporter gene assay and reduced cyclooxygenase-2 mRNA levels in the small intestine of Min mice. These results indicate that suppression of serum lipid levels by increasing LPL activity may contribute to a reduction of intestinal polyp formation with Apc-deficiency, and NO-1886 and its derivatives could be useful as chemopreventive agents for colon cancer.
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PMID:Concurrent suppression of hyperlipidemia and intestinal polyp formation by NO-1886, increasing lipoprotein lipase activity in Min mice. 1571 Aug 87


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