Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.34 (lipoprotein lipase)
 7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Whereas the role of thyroid hormone is clearly established in the regulation of cholesterol homeostasis, its involvement in the control of serum triglyceride (TG) levels remains largely debated. Angiopoietin-like proteins 3 and 4 have recently been characterized as potent lipoprotein lipase inhibitors and therefore as important components of plasma triglyceride homeostasis. In the present study, the role of thyroid hormone in the regulation of both ANGPTL4 and ANGPTL3 gene expression was investigated. In vivo studies revealed that thyroid hormone down-regulates ANGPTL3 but not ANGPTL4 gene expression in hypothyroid rats. Using thyroid hormone receptor (TR)-deficient mice, we show that thyroid hormone regulates ANGPTL3 gene expression in a TRbeta-dependent manner. Transfection studies revealed that this inhibition occurs at the transcriptional level in a DNA binding-independent fashion and requires the proximal (-171 to +66) region of the ANGPTL3 gene promoter. Moreover, site-directed mutagenesis experiments indicate that the HNF1 site within this proximal region mediates this TRbeta-dependent repression. Finally, co-transfection studies and electrophoretic mobility shift assays suggest that TRbeta antagonizes the HNF1alpha signaling pathway by inhibiting its transcriptional activity without interfering with its DNA-binding capacity. Taken together, our results lead to the identification of ANGPTL3 as a novel TRbeta target gene and provide a new potential mechanism to explain the hypotriglyceridemic properties of TRbeta agonists in vivo.
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PMID:The lipoprotein lipase inhibitor ANGPTL3 is negatively regulated by thyroid hormone. 1650 86

Chondrocytes and adipocytes are two differentiated cell types which are both derived from mesenchymal cells. The purpose of this study was to investigate whether peroxisome proliferator-activated receptor-gamma (PPARgamma), a transcription factor involved in lineage determination during adipogenesis, is able to induce adipogenic differentiation in growth plate chondrocytes. Isolated epiphyseal chondrocytes were infected with a PPARgamma adenovirus or treated with the PPARgamma agonist ciglitazone. Both of these treatments resulted in lipid droplet accumulation and expression of the adipogenic markers aP2, lipoprotein lipase, and adipsin in chondrocytes. Proteoglycan matrix synthesis was decreased in the PPARgamma-infected cells, as was the expression of the chondrogenic genes Col2a1 and aggrecan. Growth plate cells transfected with a PPARgamma expression plasmid under the control of the collagen alpha1(II) promoter also demonstrated a similar adipogenic changes. Terminal differentiation of growth plate chondrocytes induced by thyroid hormone was also inhibited by overexpression of PPARgamma and ciglitazone treatment, with decreased expression of alkaline phosphatase and Runx2/Cbfa1 genes. These in vitro data suggest that PPARgamma is able to promote adipogenic differentiation in growth plate chondrocytes, while negatively regulating chondrogenic differentiation and terminal differentiation.
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PMID:Peroxisome Proliferator-Activated Receptor-gamma Promotes Adipogenic Changes in Growth Plate Chondrocytes In Vitro. 1725 68

The effects of thyroid hormone (TH) status on energy metabolism and tissue-specific substrate supply in vivo are incompletely understood. To study the effects of TH status on energy metabolism and tissue-specific fatty acid (FA) fluxes, we used metabolic cages as well as (14)C-labeled FA and (3)H-labeled triglyceride (TG) infusion in rats treated with methimazole and either 0 (hypothyroidism), 1.5 (euthyroidism), or 16.0 (thyrotoxicosis) microg per 100 g/d T(4) for 11 d. Thyrotoxicosis increased total energy expenditure by 38% (P = 0.02), resting energy expenditure by 61% (P = 0.002), and food intake by 18% (P = 0.004). Hypothyroidism tended to decrease total energy expenditure (10%; P = 0.064) and resting energy expenditure (12%; P = 0.025) but did not affect food intake. TH status did not affect spontaneous physical activity. Thyrotoxicosis increased fat oxidation (P = 0.006), whereas hypothyroidism decreased glucose oxidation (P = 0.035). Plasma FA concentration was increased in thyrotoxic but not hypothyroid rats. Thyrotoxicosis increased albumin-bound FA uptake in muscle and white adipose tissue (WAT), whereas hypothyroidism had no effect in any tissue studied, suggesting mass-driven albumin-bound FA uptake. During thyrotoxicosis, TG-derived FA uptake was increased in muscle and heart, unaffected in WAT, and decreased in brown adipose tissue. Conversely, during hypothyroidism TG-derived FA uptake was increased in WAT in association with increased lipoprotein lipase activity but unaffected in oxidative tissues and decreased in liver. In conclusion, TH status determines energy expenditure independently of spontaneous physical activity. The changes in whole-body lipid metabolism are accompanied by tissue-specific changes in TG-derived FA uptake in accordance with hyper- and hypometabolic states induced by thyrotoxicosis and hypothyroidism, respectively.
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PMID:Thyroid hormone effects on whole-body energy homeostasis and tissue-specific fatty acid uptake in vivo. 2002 77

To understand the roles of thyroid hormone receptors (TRs) in adipogenesis, we adopted a loss-of-function approach. We generated 3T3-L1 cells stably expressing either TRalpha1 mutant (TRalpha1PV) or TRbeta1 mutant (TRbeta1PV). TRalpha1PV and TRbeta1PV are dominant negative mutations with a frameshift in the C-terminal amino acids. In control cells, the thyroid hormone, tri-iodothyronine (T(3)), induced a 2.5-fold increase in adipogenesis in 3T3-L1 cells, as demonstrated by increased lipid droplets. This increase was mediated by T(3)-induced expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha), which are master regulators of adipogenesis at both the mRNA and protein levels. In 3T3-L1 cells stably expressing TRalpha1PV (L1-alpha1PV cells) or TRbeta1PV (L1-beta1PV cells), adipogenesis was reduced 94 or 54% respectively, indicative of differential inhibitory activity of mutant TR isoforms. Concordantly, the expression of PPARgamma and C/EBPalpha at the mRNA and protein levels was more repressed in L1-alpha1PV cells than in L1-beta1PV cells. In addition, the expression of PPARgamma downstream target genes involved in fatty acid synthesis - the lipoprotein lipase (Lpl) and aP2 involved in adipogenesis - was more inhibited by TRalpha1PV than by TRbeta1PV. Chromatin immunoprecipitation assays showed that TRalpha1PV was more avidly recruited than TRbeta1PV to the promoter to preferentially block the expression of the C/ebpalpha gene. Taken together, these data indicate that impaired adipogenesis by mutant TR is isoform dependent. The finding that induction of adipogenesis is differentially regulated by TR isoforms suggests that TR isoform-specific ligands could be designed for therapeutic intervention for lipid abnormalities.
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PMID:Adipogenesis is differentially impaired by thyroid hormone receptor mutant isoforms. 2008 Sep 85


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