Linked Life Data

19759400

Source:http://linkedlifedata.com/resource/pubmed/id/19759400

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
46
pubmed:dateCreated
2009-11-9
pubmed:abstractText
The regulation of lipid homeostasis by insulin is mediated in part by the enhanced transcription of the gene encoding sterol regulatory element-binding protein-1c (SREBP-1c). The nascent SREBP-1c is embedded in the endoplasmic reticulum (ER) and must be transported to the Golgi where two sequential cleavages generate its NH(2)-terminal fragment, nSREBP-1c. We have shown recently that in primary cultures of rat hepatocytes, insulin rapidly and selectively stimulates proteolytic processing of the nascent SREBP-1c by enhancing the affinity of the SREBP cleavage-activating protein (SCAP).SREBP-1c complex for coatomer protein complex II (COPII) vesicles. The SCAP.SREBP complex is retained in the ER by Insig proteins. We report here that insulin persistently stimulates controlled proteolysis of the nascent SREBP-1c by selectively reducing the level of Insig-2a protein via accelerated degradation of its cognate mRNA. Insulin enhanced the rate of turnover of Insig-2a mRNA via its 3'-untranslated region. Insulin-induced depletion of Insig-2a promotes association of the SCAP.SREBP-1c complex with COPII vesicles and subsequent migration to the Golgi where site-1 and site-2 proteases process the nascent SREBP-1c. Consistent with this mechanism, experimental knockdown of Insig-2a expression with small interfering RNA mimicked insulin-induced proteolysis of the nascent SREBP-1c, whereas exogenous expression of Insig-2a in hepatocytes led to reduced intramembrane proteolysis of the newly synthesized SREBP-1c. The action of insulin on the processing of the nascent SREBP-1c via Insig-2a was highly selective, as proteolysis of the newly synthesized SREBP-2 remained unchanged under identical conditions. On the basis of these data, we propose that the stimulation of SREBP-1c processing by insulin is mediated by a selective depletion of Insig-2a protein by promoting decay of its cognate mRNA. Thus, insulin-induced reduction in Insig-2a protein leads to an enhanced export of the SCAP.SREBP-1c complex from ER to the Golgi.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
13
pubmed:volume
284
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
31726-34
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:19759400-Animals, pubmed-meshheading:19759400-Cell Nucleus, pubmed-meshheading:19759400-Cells, Cultured, pubmed-meshheading:19759400-Down-Regulation, pubmed-meshheading:19759400-Hepatocytes, pubmed-meshheading:19759400-Hypoglycemic Agents, pubmed-meshheading:19759400-Insulin, pubmed-meshheading:19759400-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:19759400-Liver, pubmed-meshheading:19759400-Male, pubmed-meshheading:19759400-Membrane Proteins, pubmed-meshheading:19759400-Microsomes, Liver, pubmed-meshheading:19759400-RNA Processing, Post-Transcriptional, pubmed-meshheading:19759400-Rats, pubmed-meshheading:19759400-Rats, Sprague-Dawley, pubmed-meshheading:19759400-Sterol Regulatory Element Binding Protein 1, pubmed-meshheading:19759400-Sterol Regulatory Element Binding Protein 2, pubmed-meshheading:19759400-Transfection
pubmed:year
2009
pubmed:articleTitle
Insulin enhances the biogenesis of nuclear sterol regulatory element-binding protein (SREBP)-1c by posttranscriptional down-regulation of Insig-2A and its dissociation from SREBP cleavage-activating protein (SCAP).SREBP-1c complex.
pubmed:affiliation
Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. cyellatu@utmem.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural