Specificity in beta cell expression of L-3-hydroxyacyl-CoA dehydrogenase, short chain, and potential role in down-regulating insulin release.
A loss-of-function mutation of the mitochondrial beta-oxidation enzyme l-3-hydroxyacyl-CoA dehydrogenase, short chain (HADHSC), has been associated with hyperinsulinemic hypoglycemia in man. It is still unclear whether loss of glucose homeostasis in these patients (partly) results from a dysregulation of beta cells. This study examines HADHSC expression in purified rat beta cells and investigates whether its selective suppression elevates insulin release. Beta cells expressed the highest levels of HADHSC mRNA and protein of all examined tissues, including those with high rates of mitochondrial beta-oxidation. On the other hand, beta cells expressed relatively low levels of other beta-oxidation enzymes (acyl-CoA dehydrogenase short, medium, and long chain and acetyl-coenzyme A acyltransferase 2). HADHSC expression was sequence-specifically silenced by RNA interference, and the effects were examined on glucose-stimulated insulin secretion following 48-72 h of suppression. In both rat beta cells and in the beta cell line INS1 832-13, HADHSC silencing resulted in elevated insulin release at low and at high glucose concentrations, which appeared not to be caused by increased rates of glucose metabolism or an inhibition in fatty acid oxidation. These data indicate that the normal beta cell phenotype is characterized by a high expression of HADHSC and a low expression of other beta-oxidation enzymes. Down-regulation of HADHSC causes an elevated secretory activity suggesting that this enzyme protects against inappropriately high insulin levels and hypoglycemia.
Martens
Geert A
GA
Diabetes Research Center, Brussels Free University-VUB, Laarbeeklaan 103, B-1090 Brussels.
Vervoort
Annelies
A
Van de Casteele
Mark
M
Stangé
Geert
G
Hellemans
Karine
K
Van Thi
Hong Vien
HV
Schuit
Frans
F
Pipeleers
Daniël
D
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000096:biosynthesis*; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D010084:Oxidation-Reduction; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D014018:Tissue Distribution
D007328:Insulin; D008055:Lipids; D034741:RNA, Small Interfering; D015094:3-Hydroxyacyl CoA Dehydrogenases; D005947:Glucose