Linked Life Data

17919187

Source:http://linkedlifedata.com/resource/pubmed/id/17919187

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:dateCreated
2007-10-8
pubmed:abstractText
It has long been known that excess intracellular fatty acids cause impaired insulin secretion, referred to as beta-cell lipotoxicity. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls hepatic fatty acid synthesis. Activation of SREBP-1c by overnutrition also inhibits insulin receptor substrate-2 (IRS-2) and induces insulin resistance in the liver. As SREBP-1c is also expressed in beta cells, we hypothesized that activation of SREBP-1c could be a part of the mechanism by which saturated fatty acids induce beta-cell lipotoxicity. We found that nuclear SREBP-1c has a negative impact on both glucose- and potassium-stimulated insulin secretion as determined in islets from beta-cell-specific SREBP-1c transgenic mice as well as SREBP-1c knockout mice. This effect of SREBP-1c involves multiple functional pathways required for insulin secretion from beta cells: (i) decreased ATP caused by energy consumption through lipogenesis and uncoupling protein-2 (UCP-2) activation; (ii) repressed IRS-2 and pancreas duodenum homeobox 1 (PDX1) expression, leading to impaired beta-cell mass; and (iii) impaired post-ATP membrane voltage-dependent steps of the insulin secretion pathway caused by upregulated granuphilin and other ion channel proteins. Saturated fatty acids, such as palmitic acid (PA), impair insulin secretion through SREBP-1c activation, whereas polyunsaturated fatty acids including eicosapentaenoic acid (EPA) restore PA-suppressed insulin secretion through suppression of SREBP-1c. These data implicate a therapeutic potential of EPA against insulin secretion defects caused by lipotoxicity.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1462-8902
pubmed:author
pubmed:issnType
Print
pubmed:volume
9 Suppl 2
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
133-9
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Sterol regulatory element-binding protein-1c and pancreatic beta-cell dysfunction.
pubmed:affiliation
Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan. hshimano@md.tsukuba.ac.jp
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't