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)

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a phytol-derived branched-chain fatty acid present in dietary products. Phytanic acid increased uncoupling protein-1 (UCP1) mRNA expression in brown adipocytes differentiated in culture. Phytanic acid induced the expression of the UCP1 gene promoter, which was enhanced by co-transfection with a retinoid X receptor (RXR) expression vector but not with other expression vectors driving peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma or a form of RXR devoid of ligand-dependent sensitivity. The effect of phytanic acid on the UCP1 gene required the 5' enhancer region of the gene and the effects of phytanic acid were mediated in an additive manner by three binding sites for RXR. Moreover, phytanic acid activates brown adipocyte differentiation: long-term exposure of brown preadipocytes to phytanic acid promoted the acquisition of the brown adipocyte morphology and caused a co-ordinate induction of the mRNAs for gene markers of brown adipocyte differentiation, such as UCP1, adipocyte lipid-binding protein aP2, lipoprotein lipase, the glucose transporter GLUT4 or subunit II of cytochrome c oxidase. In conclusion, phytanic acid is a natural product of phytol metabolism that activates brown adipocyte thermogenic function. It constitutes a potential nutritional signal linking dietary status to adaptive thermogenesis.
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PMID:Phytanic acid, a novel activator of uncoupling protein-1 gene transcription and brown adipocyte differentiation. 1182 40

The cAMP-response element-binding protein-binding protein (CBP) and p300 are common coactivators for several transcriptional factors. It has been reported that both CBP and p300 are significant for the activation of peroxisome proliferator-activated receptor gamma (PPARgamma), which is a crucial nuclear receptor in adipogenesis. However, it remains unclear whether CBP and/or p300 is physiologically essential to the activation of PPARgamma in adipocytes and adipocyte differentiation. In this study, we investigated the physiological significance of CBP/p300 in NIH3T3 cells transiently expressing PPARgamma and CBP and in 3T3-L1 preadipocytes stably expressing CBP- or p300-specific ribozymes. In PPARgamma-transfected NIH3T3 cells, induction of expression of PPARgamma target genes such as adipocyte fatty acid-binding protein (aP2) and lipoprotein lipase (LPL) by adding thiazolidinedione was enhanced, depending on the amount of a CBP expression plasmid transfected. Expression of aP2 and LPL genes, as well as glycerol-3-phosphate dehydrogenase activity and triacylglyceride accumulation after adipogenic induction, was largely suppressed in 3T3-L1 adipocytes expressing either the CBP- or p300-specific active ribozyme, but not in inactive ribozyme-expressing cells. These data suggest that both CBP and p300 are indispensable for the full activation of PPARgamma and adipocyte differentiation and that CBP and p300 do not mutually complement in the process.
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PMID:Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma. 1188 4

Disruption of the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene causes embryonic lethality due to placental dysfunction. To circumvent this, a PPAR gamma conditional gene knockout mouse was produced by using the Cre-loxP system. The targeted allele, containing loxP sites flanking exon 2 of the PPAR gamma gene, was crossed into a transgenic mouse line expressing Cre recombinase under the control of the alpha/beta interferon-inducible (MX) promoter. Induction of the MX promoter by pIpC resulted in nearly complete deletion of the targeted exon, a corresponding loss of full-length PPAR gamma mRNA transcript and protein, and marked reductions in basal and troglitazone-stimulated expression of the genes encoding lipoprotein lipase, CD36, LXR alpha, and ABCG1 in thioglycolate-elicited peritoneal macrophages. Reductions in the basal levels of apolipoprotein E (apoE) mRNA in macrophages and apoE protein in total plasma and high-density lipoprotein (HDL) were also observed in pIpC-treated PPAR gamma-MXCre(+) mice. Basal cholesterol efflux from cholesterol-loaded macrophages to HDL was significantly reduced after disruption of the PPAR gamma gene. Troglitazone selectively inhibited ABCA1 expression (while rosiglitazone, ciglitazone, and pioglitazone had little effect) and cholesterol efflux in both PPAR gamma-deficient and control macrophages, indicating that this drug can exert paradoxical effects on cholesterol homeostasis that are independent of PPAR gamma. Together, these data indicate that PPAR gamma plays a critical role in the regulation of cholesterol homeostasis by controlling the expression of a network of genes that mediate cholesterol efflux from cells and its transport in plasma.
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PMID:Conditional disruption of the peroxisome proliferator-activated receptor gamma gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux. 1190 55

Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist which regulates the transcription of genes encoding proteins involved in triglyceride (TG)-rich lipoproteins and lipoprotein lipase (LPL) metabolism. The aim of the present study was to investigate the relation between TG-related parameters considered in different clinical guidelines used in industrialized countries for the management of lipid disorders (namely fasting plasma TG, high density-lipoprotein cholesterol (HDL-C), non-HDL-C concentrations and total-C/HDL-C ratio) and the presence of LPL-null (P207L), LPL-defective (D9N), PPARalpha -L162V, apolipoprotein (apo) E and PPARgamma-P12A gene mutations, in a sample of 292 hypertriglyceridemic subjects treated with fenofibrate for 3 months. Although fenofibrate induced a decrease in plasma TG level and an increase in HDL-C level in all studied genotypes, mutation-specific differences were observed. After adjustment for age, gender, body mass index and the presence of apo E2 genotype, the LPL-P207L mutation was associated with residual post-treatment hypertriglyceridemia [TG > 2.0 mmol/l, odds ratio (OR) = 3.07, P = 0.005] and total-C/HDL-C ratio > 5 (OR = 2.68; P = 0.03). This effect was significantly related to higher plasma TG concentrations at baseline among carriers of a LPL-null mutation. Compared to apo E3 and E4 variants, the apo E2 allele was associated with a better response to fenofibrate on all lipid parameter, especially among PPARalpha -L162V carriers, whereas the simultaneous presence of apo E2 and PPARalpha -L162V tended to improve fenofibrate response among LPL-P207L heterozygotes. Finally, the LPL-D9N and PPARgamma -P12A mutations did not affect fenofibrate lipid-lowering action. This study suggests that frequent genetic variations in genes encoding proteins involved in TG-rich lipoprotein metabolism could modulate the response to fenofibrate treatment, as defined in clinical guidelines.
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PMID:Effect of apolipoprotein E, peroxisome proliferator-activated receptor alpha and lipoprotein lipase gene mutations on the ability of fenofibrate to improve lipid profiles and reach clinical guideline targets among hypertriglyceridemic patients. 1204 69

Protein tyrosine phosphatase 1B (PTP1B) has been implicated as a negative regulator of insulin action. Overexpression of PTP1B protein has been observed in insulin-resistant states associated with obesity. Mice lacking a functional PTP1B gene exhibit increased insulin sensitivity and are resistant to weight gain. To investigate the role of PTP1B in adipose tissue from obese animals, hyperglycemic obese (ob/ob) mice were treated with PTP1B antisense oligonucleotide (ISIS-113715). A significant reduction in adiposity correlated with a decrease of PTP1B protein levels in fat. Antisense treatment also influenced the triglyceride content in adipocytes, correlating with a downregulation of genes encoding proteins involved in lipogenesis, such as sterol regulatory element-binding protein 1 and their downstream targets spot14 and fatty acid synthase, as well as other adipogenic genes, lipoprotein lipase, and peroxisome proliferator-activated receptor gamma. In addition, an increase in insulin receptor substrate-2 protein and a differential regulation of the phosphatidylinositol 3-kinase regulatory subunit (p85alpha) isoforms expression were found in fat from antisense-treated animals, although increased insulin sensitivity measured by protein kinase B phosphorylation was not observed. These results demonstrate that PTP1B antisense treatment can modulate fat storage and lipogenesis in adipose tissue and might implicate PTP1B in the enlargement of adipocyte energy stores and development of obesity.
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PMID:Protein tyrosine phosphatase 1B reduction regulates adiposity and expression of genes involved in lipogenesis. 1214 51

In adipose tissue, the ability of cells to respond to insulin and to express genes such as those encoding fatty-acid-binding protein (422/aP2), lipoprotein lipase (LPL), adipsin and glucose transporter 4 (GLUT4) is acquired during their differentiation into mature adipocytes. It has been recognized that peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding proteins (C/EBPs) play critical roles in adipocyte differentiation. However, it remained uncertain whether PPARgamma or which C/EBP is involved in the acquisition of these characteristics. We introduced PPARgamma2 into C/EBPbeta/delta-double deficient mouse embryonic fibroblasts (MEFs), followed by stimulation with its ligands, in order to define the roles of C/EBPbeta and C/EBPdelta in phenotypic acquisition during adipocyte differentiation. This procedure resulted in differentiation of these MEFs into mature adipocytes morphologically similar to wild-type MEFs. However, the adipocytes derived from the C/EBPbeta/delta-deficient MEFs showed lower expression of GLUT4 and adipsin mRNA than those derived from wild-type MEFs, although aP2 and LPL mRNA levels were similar in both types. The C/EBPbeta/delta-deficient adipocytes also expressed lower amounts of insulin receptor substrate 2 (IRS-2) than the adipocytes derived from wild-type MEFs, whereas the amounts of insulin receptor and IRS-1 were similar. Finally, insulin-responsive 2-deoxyglucose uptake was lower in the C/EBPbeta/delta-deficient cells. It could thus be demonstrated that C/EBPbeta and C/EBPdelta are involved in the acquisition of IRS-2 and GLUT4 expression as well as in insulin-sensitive glucose uptake during adipocyte differentiation.
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PMID:Reduced IRS-2 and GLUT4 expression in PPARgamma2-induced adipocytes derived from C/EBPbeta and C/EBPdelta-deficient mouse embryonic fibroblasts. 1218 46

The current study examined the acute effects of intravenous propionate infusion on plasma hormones and metabolites and the expression of adipose tissue lipogenic genes. Four yearling rams were assigned to one oftwo groups (saline or propionate infusion) in a crossover design. All sheep were cannulated in both jugular veins and infused with 1.2 M propionate at a rate of 64 micromol x mix(-1) x kg BW(-1) for 30 min. Blood samples were collected at -10, 0, 5, 10, 20, 30, 60, and 120 min after initiation of infusion. Subcutaneous adipose tissue biopsies were obtained from the tailhead at 0 and 2 h after propionate infusion and analyzed for gene expressions of lipoprotein lipase, acetyl CoA carboxylase, fatty acid synthase, peroxisome proliferator-activated receptor gamma, leptin, and uncoupling protein-2 using a nonisotopic ribonuclease protection assay. The partial cDNA of the enoyl reductase region of ovine fatty acid synthase was cloned and sequenced from s.c. adipose tissue of sheep. The deduced amino acid sequence (210 amino acids) was 86% identical to human, 88% identical to rat, 88% identical to mouse, and 72% identical to chicken. Plasma glucose and insulin concentrations abruptly increased 5 min after beginning propionate infusion and further increased up until 30 min but were unaffected in saline-infused sheep (P < 0.05). Plasma concentration of NEFA decreased (P < 0.05) during propionate infusion, whereas IGF-I levels were unaltered. The amounts of lipoprotein lipase, acetyl CoA carboxylase, fatty acid synthase, peroxisome proliferator-activated receptor gamma, and leptin mRNA increased (P < 0.05) in s.c. adipose tissue of propionate-infused sheep compared with those of saline-infused sheep. However, uncoupling protein-2 mRNA decreased (P < 0.05) in propionate-infused sheep. This study demonstrates that an acute nutrient challenge, in the form of i.v. propionate, can stimulate or inhibit the expression of various adipose tissue genes involved with lipogenesis and adipose tissue metabolism.
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PMID:Coordinate regulation of ovine adipose tissue gene expression by propionate. 1246 51

Estrogen deficiency in the aromatase knockout (ArKO) mouse leads to the development of obesity by as early as 3 months of age, which is characterized by a marked increase in the weights of gonadal and infrarenal fat pads. Humans with natural mutations of the aromatase gene also develop a metabolic syndrome. In the present study cellular and molecular parameters were investigated in gonadal adipose tissue from 10-wk-old wild-type (WT) and ArKO female mice treated with 17beta-estradiol or placebo to identify the basis for the increase in intraabdominal obesity. Stereological examination revealed that adipocytes isolated from ArKO mice were significantly larger and more abundant than adipocytes isolated from WT mice. Upon treatment with estrogen, the volume of these adipocytes was greatly reduced, whereas the reduction in the number of adipocytes was much less pronounced. Transcriptional analysis using real-time PCR revealed concomitant changes with adipocyte volume in the levels of transcripts encoding leptin and lipoprotein lipase, whereas peroxisome proliferator-activated receptor gamma levels followed a pattern closer to that of adipocyte number. Little change was observed in levels of transcripts for factors involved in de novo fatty acid synthesis, beta-oxidation, and lipolysis, suggesting that changes in the uptake of lipids from the circulation are the main mechanisms by which estrogen regulates lipid metabolism in these mice.
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PMID:Cellular and molecular characterization of the adipose phenotype of the aromatase-deficient mouse. 1263 31

The trans-10,cis-12 isomer of conjugated linoleic acid (CLA) has been shown to reduce body fat gain in mice. However, the underlying molecular mechanism is not well characterized. Here we report evidence that trans-10,cis-12 (t10c12) CLA inhibits preadipocyte differentiation. Treating differentiating 3T3-L1 preadipocytes with t10c12 CLA and conjugated nonadecadienoic acid (CNA, a 19-carbon CLA cognate) resulted in decreased intracellular triglyceride accumulation and mRNA levels of the adipogenic gene fatty acid synthase and adipocyte lipid binding protein. T10c12 CLA and CNA also reduced protein levels of adipocyte transcription factors, peroxisome proliferator-activated receptor gamma and CCAAT/enhancer binding protein alpha. Similarly, CLA reduced body fat gain and significantly inhibited the expression of PPAR gamma and its downstream target lipoprotein lipase in mouse adipose tissue. These observations indicate that CLA decreases body fat gain in part by inhibiting the differentiation of preadipocytes.
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PMID:trans-10,cis-12 CLA inhibits differentiation of 3T3-L1 adipocytes and decreases PPAR gamma expression. 1267 Apr 81

The aim was to study the effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene on the expression of PPARgamma target genes in adipose tissue. Adipose tissue samples were collected from 30 massively obese subjects (10 men and 20 women) from omental, sc abdominal, and femoral depots. The mRNA expression of PPARgamma1, PPARgamma2, lipoprotein lipase, p85alpha phosphatidylinositol 3-kinase, and uncoupling protein 2 were quantified by reverse transcription-competitive PCR. The genotypes of Pro12Ala polymorphism were determined by single-strand conformation polymorphism analysis. The frequency of the Ala12 allele was 13.3% (8 Pro12Ala and 22 Pro12Pro). There were no differences in body weight, fat mass, and fasting serum leptin between the genotypes. The mRNA expression of p85alpha phosphatidylinositol 3-kinase was significantly lower in the omental fat of the Pro12Ala carriers than the Pro12Pro carriers (P < 0.01). It also appeared that PPARgamma2 expression was higher in men with Ala12 allele (P < 0.01). Interestingly, particularly in women, the expression of both PPARgamma splice variants was lower in omental than sc fat independently of the genotype (P < 0.05-0.01). The common Pro12Ala polymorphism of the PPARgamma2 gene has minor influence on mRNA expression of PPARgamma target genes in adipose tissue of obese subjects. Expression of both PPARgamma splice variants is dependent on fat depot: omental fat shows lower mRNA levels, compared with sc fat depots.
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PMID:Effect of the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma2 gene on the expression of PPARgamma target genes in adipose tissue of massively obese subjects. 1267 63


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