Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present evidence of a link between low-density lipoprotein (LDL) receptor binding and activation of a platelet G-coupled protein. LDL stimulation induced cytosolic [Ca2+]i mobilization, increase in inositol 1,4,5-triphosphate (IP3) formation and a rapid cytosol-to-membrane translocation of protein kinase C (PKC) enzymatic activity. Pertussis toxin inhibited all the stimulatory effects, whereas cholera toxin had no effect. Using ligand-binding assays, we demonstrated that exposing platelet LDL receptors to high concentrations of LDL (1.5 g/l) caused a rapid down-regulation and desensitization, as shown by the reduction in the Bmax, intracellular [Ca2+]i mobilization and IP3 formation to 65, 73 and 63%, respectively. The inhibitory effects were reversible and dose and time dependent. Furthermore, VLDL (0.2 g/l) and IDL (0.07 g/l) induced similar desensitization effects. However, HDL3 (up to 1.5 g/l), chylomicrons (up to 0.5 g/l) and cyclohexandione-modified LDL (which does not bind to platelets) had no significant effects. Protein kinase C inhibitors (150 nmol/l staurosporine, 100 micromol/l H-7, and 10 nmol/l bisindolylmaleimide) inhibited desensitization to 71%, on average. Sequestration blocking agents (0.30 g/l, concanavalin A) had no significant effect if phosphorylation was operative. However, there was a complete blockade with the concurrent inhibition of both pathways. In contrast, cAMP-dependent protein kinase inhibitors (PKI, 1 micromol/l) or beta2-adrenergic receptor kinase inhibitors (100 nmol/l, heparin), had no effect. Overall results indicate that LDL binds to a pertussis sensitive G-protein coupled receptor and that high levels of lipoproteins down-regulate the number of receptors and desensitize its mediated response by a mechanism that involves PKC-phosphorylation and sequestration of binding sites. This new regulatory mechanism may have implications for the thrombogenicity in hyperlipidemia and for effects of lipid lowering therapy.
 ...
PMID:Low-density lipoprotein (LDL) binds to a G-protein coupled receptor in human platelets. Evidence that the proaggregatory effect induced by LDL is modulated by down-regulation of binding sites and desensitization of its mediated signaling. 1122 31

Recently, adipose triglyceride lipase (ATGL, also called desnutrin and calcium-independent phospholipase A2 [iPLA(2)] zeta) was isolated as a novel adipose-expressed triglyceride lipase which is downregulated in obesity and may contribute to obesity-associated metabolic disorders such as hyperlipidemia and insulin resistance. To clarify expression and regulation of this fat-derived lipase, ATGL mRNA was measured in 3T3-L1 adipocytes by quantitative real-time reverse transcription-polymerase chain reaction after treatment with isoproterenol, tumor necrosis factor (TNF) alpha, insulin, and growth hormone (GH) which have been shown to influence lipolysis and insulin sensitivity profoundly. Interestingly, treatment of adipocytes with 100 nM isoproterenol, 30 ng/ml TNF alpha, and 100 nM insulin for 16 h significantly decreased ATGL mRNA to 74%, 17%, and 49% of control levels, respectively. GH did not influence ATGL synthesis. The effect of isoproterenol, TNFalpha, and insulin on ATGL expression was time- and dose-dependent. Similarly, HSL mRNA was downregulated by the three hormones. Furthermore, signaling studies suggested that activation of Gs-protein-coupled pathways by forskolin and cholera toxin is sufficient to significantly downregulate ATGL mRNA. Moreover, p44/42 mitogen-activated protein kinase appears to partly mediate the negative effect of insulin but not TNFalpha on ATGL. Taken together, downregulation of ATGL by isoproterenol, TNFalpha, and insulin might contribute to dysregulated expression and function of this lipase in obesity, hyperlipidemia, and insulin resistance.
 ...
PMID:Isoproterenol, TNFalpha, and insulin downregulate adipose triglyceride lipase in 3T3-L1 adipocytes. 1600 85

Efficient entry of synthetic polymers inside cells is a central issue in polymeric drug delivery. Though polymers are widely believed to interact nonspecifically with plasma membrane, we present unexpected evidence that amphiphilic block copolymers, depending on their aggregation state, can distinguish between caveolae- and clathrin-mediated endocytosis. A block copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), Pluronic P85 (P85), below critical micelle concentration (CMC) exists as single molecule coils (unimers) and above CMC forms 14.6 nm aggregated micelles with a hydrophobic PPO core and hydrophilic PEO shell. The internalization pathways of P85 in mammalian cells were elucidated using endocytosis inhibitors and colocalization with endocytosis markers (clathrin-specific antibodies and transferrin for clathrin and caveolin-1-specific antibodies and cholera toxin B for caveolae). Altogether, our results indicate that P85 unimers internalize through caveolae-mediated endocytosis, while P85 micelles internalize through clathrin-mediated endocytosis. Furthermore, at concentrations above 0.01% P85 inhibits caveolae-mediated endocytosis (cholera toxin B), while having little or no effect on the clathrin-mediated endocytosis (transferrin). Selective interaction of Pluronic with caveolae may explain its striking pharmacological activities including inhibition of drug efflux transport, activation of gene expression, and dose-dependent hyperlipidemia.
 ...
PMID:Different internalization pathways of polymeric micelles and unimers and their effects on vesicular transport. 1872 94