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

Obesity is a principal risk factor for type 2 diabetes, and elevated fatty acids reduce beta-cell function and survival. An unbiased proteomic screen was used to identify targets of palmitate in beta-cell death. The most significantly altered protein in both human islets and MIN6 beta-cells treated with palmitate was carboxypeptidase E (CPE). Palmitate reduced CPE protein levels within 2 h, preceding endoplasmic reticulum (ER) stress and cell death, by a mechanism involving CPE translocation to Golgi and lysosomal degradation. Palmitate metabolism and Ca(2+) flux were also required for CPE proteolysis and beta-cell death. Chronic palmitate exposure increased the ratio of proinsulin to insulin. CPE null islets had increased apoptosis in vivo and in vitro. Reducing CPE by approximately 30% using shRNA also increased ER stress and apoptosis. Conversely, overexpression of CPE partially rescued beta-cells from palmitate-induced ER stress and apoptosis. Thus, carboxypeptidase E degradation contributes to palmitate-induced beta-cell ER stress and apoptosis. CPE is a major link between hyperlipidemia and beta-cell death pathways in diabetes.
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PMID:Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis. 1855 Aug 19

Type 2 diabetes occurs when the endocrine pancreas can no longer secrete enough insulin to maintain glucose and lipid homeostasis. This is likely due to cumulative defects in beta-cell fate and function, as well as insulin resistance. A number of recent studies, including ones from our group, have used unbiased proteomic, genomic and genetic approaches to unravel the mechanisms by which hyperlipidemia causes beta-cell apoptosis and dysfunction. It is clear from these studies and others, that there are multiple pathways by which fatty acids such as palmitate can lead to beta-cell dysfunction and death. In the present article, we highlight the role for dysfunction in the ER and secretory pathway in the toxic effects of free fatty acids. Recent work has shown that the rapid degradation of carboxypeptidase E plays a significant role in beta-cell death in response to the free fatty acid palmitate. These newly identified targets of beta-cell lipotoxicity present novel avenues for research and therapeutic intervention.
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PMID:Proteomic identification of carboxypeptidase E connects lipid-induced beta-cell apoptosis and dysfunction in type 2 diabetes. 1910 15