Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver.


Autoria(s): Foretz M.; Ancellin N.; Andreelli F.; Saintillan Y.; Grondin P.; Kahn A.; Thorens B.; Vaulont S.; Viollet B.
Data(s)

2005

Resumo

AMP-activated protein kinase (AMPK) is a major therapeutic target for the treatment of diabetes. We investigated the effect of a short-term overexpression of AMPK specifically in the liver by adenovirus-mediated transfer of a gene encoding a constitutively active form of AMPKalpha2 (AMPKalpha2-CA). Hepatic AMPKalpha2-CA expression significantly decreased blood glucose levels and gluconeogenic gene expression. Hepatic expression of AMPKalpha2-CA in streptozotocin-induced and ob/ob diabetic mice abolished hyperglycemia and decreased gluconeogenic gene expression. In normal mouse liver, AMPKalpha2-CA considerably decreased the refeeding-induced transcriptional activation of genes encoding proteins involved in glycolysis and lipogenesis and their upstream regulators, SREBP-1 (sterol regulatory element-binding protein-1) and ChREBP (carbohydrate response element-binding protein). This resulted in decreases in hepatic glycogen synthesis and circulating lipid levels. Surprisingly, despite the inhibition of hepatic lipogenesis, expression of AMPKalpha2-CA led to fatty liver due to the accumulation of lipids released from adipose tissue. The relative scarcity of glucose due to AMPKalpha2-CA expression led to an increase in hepatic fatty acid oxidation and ketone bodies production as an alternative source of energy for peripheral tissues. Thus, short-term AMPK activation in the liver reduces blood glucose levels and results in a switch from glucose to fatty acid utilization to supply energy needs.

Identificador

http://serval.unil.ch/?id=serval:BIB_AD2F12020C42

isbn:0012-1797

pmid:15855317

doi:10.2337/diabetes.54.5.1331

isiid:000228701000010

Idioma(s)

en

Fonte

Diabetes, vol. 54, no. 5, pp. 1331-1339

Palavras-Chave #AMP-Activated Protein Kinases; Animals; Base Sequence; Blood Glucose; Cloning, Molecular; DNA Primers; Enzyme Activation; Fatty Acids; Fatty Liver; Hepatocytes; Hypoglycemia; Kinetics; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Multienzyme Complexes; Protein-Serine-Threonine Kinases; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Transfection
Tipo

info:eu-repo/semantics/article

article