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Constitutive activation of AMPK ?1 in vascular endothelium promotes high-fat diet-induced fatty liver injury: role of COX-2 induction.


ABSTRACT:

Background and purpose

AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, comprises three (?, ? and ?) subunits, each with a unique tissue distribution. As AMPK has a wide range of protein and gene targets, defining its role has been difficult. Here, we have studied a transgenic mouse model overexpressing the constitutively active ?1 subunit of AMPK in endothelial cells (EC-AMPK) to elucidate its role in energy homeostasis.

Experimental approach

Wild-type and EC-AMPK mice were fed with a high fat diet for 16 weeks. Drugs (or vehicles) were given daily by oral gavage. Body weight, fat mass composition, glucose and lipid levels were monitored regularly. Tissues including aortae and liver were collected for quantitative RT-PCR, Western blotting, elisa, histological and biochemical evaluations.

Key results

Compared with wild-type animals, high fat diet caused more severe metabolic defects in EC-AMPK mice, which exhibited increased body weight and fat mass, elevated blood pressure, augmented glucose and lipid levels, impaired glucose tolerance, hepatomegaly and steatohepatitis. Constitutive activation of AMPK ?1 in endothelial cells induced COX-2 expression and arterial inflammation. Genes involved in lipid metabolism were down-regulated in aortae and livers of EC-AMPK mice. Chronic treatment with selective COX-2 inhibitors, celecoxib or nimesulide, significantly ameliorated arterial inflammation, steatohepatitis and hyperlipidaemia in EC-AMPK mice, without altering their blood pressure or clotting.

Conclusions and implications

Constitutive activation of endothelial AMPK ?1 promotes vascular inflammation and the development of obesity-induced fatty livers largely via induction of COX-2.

SUBMITTER: Liang Y 

PROVIDER: S-EPMC3904267 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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