RESUMEN
OBJECTIVE: States of insulin resistance, hyperinsulinemia, and hepatic steatosis are associated with increased secretion of triglycerides (TG) and apolipoprotein B (apoB), even though insulin targets apoB for degradation. We used hepatic-specific "phosphatase and tensin homologue deleted on chromosome 10" (Pten) knockout (hPten-ko) mice, with increased hepatic insulin signaling, to determine the relative roles of insulin signaling and hepatic TG in regulating apoB secretion. METHODS AND RESULTS: TG and apoB secretion was elevated in hPten-ko mice. When hepatic TG was reduced by inhibition of diacylglycerol acyltransferase 1/diacylglycerol acyltransferase 2 or sterol regulatory element-binding protein-1c, both TG secretion and apoB secretion fell without changes in hepatic insulin signaling. Acute reconstitution of hPten reduced hepatic TG content, and both TG and apoB secretion fell within 4 days despite decreased hepatic insulin signaling. Acute depletion of hepatic Pten by adenoviral introduction of Cre into Pten floxed mice caused steatosis within 4 days, and secretion of both TG and apoB increased despite increased hepatic insulin signaling. Even when steatosis after acute Pten depletion was prevented by pretreatment with SREBP-1c antisense oligonucleotides, apoB secretion was not reduced after 4 days. Ex vivo results were in primary hepatocytes were similar. CONCLUSIONS: Either hepatic TG is the dominant regulator of apoB secretion or any inhibitory effects of hepatic insulin signaling on apoB secretion is very short-lived.
Asunto(s)
Apolipoproteínas B/metabolismo , Insulina/metabolismo , Hígado/metabolismo , Transducción de Señal/fisiología , Triglicéridos/metabolismo , Animales , Diacilglicerol O-Acetiltransferasa/deficiencia , Diacilglicerol O-Acetiltransferasa/genética , Hígado Graso/metabolismo , Lipogénesis/fisiología , Masculino , Ratones , Ratones Noqueados , Modelos Animales , Fosfohidrolasa PTEN/deficiencia , Fosfohidrolasa PTEN/genéticaRESUMEN
A real tonic: In a conceptually new approach to controlled release, the natural daily insulin profile in response to three meals is mimicked (see graph) with release of an insulin conjugate from a matrix, triggered by quinine, a component of tonic water.
Asunto(s)
ADN/química , Portadores de Fármacos/química , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Quinina/química , Administración Oral , Secuencia de Aminoácidos , Secuencia de Bases , Portadores de Fármacos/síntesis química , Hipoglucemiantes/química , Insulina/química , Datos de Secuencia Molecular , Resonancia por Plasmón de SuperficieRESUMEN
Uridine diphosphoglucose pyrophosphorylase (UDPGP) is a developmentally regulated enzyme in Dictyostelium discoideum, which is involved in trehalose, cellulose, and glycogen synthesis. Two independent UDPGP proteins are believed to be responsible for this activity. To determine the relative contributions of each protein, the genes encoding them were disrupted individually. Cells lacking the udpgp1 gene exhibit normal growth and development and make normal levels of cellulose. In agreement with these phenotypes, udpgp1(-) cells still have UDPGP activity, although at a reduced level. This supports the importance of the second UDPGP gene. This newly identified gene, ugpB, encodes an active UDPGP as determined by complementation in Escherichia coli. When this gene is disrupted, cells undergo aberrant differentiation and development ending with small, gnarled fruiting bodies. These cells also have decreased spore viability and decreased levels of glycogen, whose production requires UDPGP activity. These phenotypes suggest that UgpB constitutes the major UDPGP activity produced during development. Sequence analysis of the two UDPGP genes shows that UgpB has higher homology to other eukaryotic UDPGPs than does UDPGP1. This includes the presence of 5 conserved lysine residues. Udpgp1 only has 1 of these lysines.