VASP Increases Hepatic Fatty Acid Oxidation by Activating AMPK in Mice

Abstract

Activation of AMP-activated protein kinase (AMPK) signaling reduces hepatic steatosis and hepatic insulin resistance; however, its regulatory mechanisms are not fully understood. In this study, we sought to determine whether vasodilator-stimulated phosphoprotein (VASP) signaling improves lipid metabolism in the liver and, if so, whether VASP's effects are mediated by AMPK. We show that disruption of VASP results in significant hepatic steatosis as a result of significant impairment of fatty acid oxidation, VLDL-triglyceride (TG) secretion, and AMPK signaling. Overexpression of VASP in hepatocytes increased AMPK phosphorylation and fatty acid oxidation and reduced hepatocyte TG accumulation; however, these responses were suppressed in the presence of an AMPK inhibitor. Restoration of AMPK phosphorylation by administration of 5-aminoimidazole-4-carboxamide riboside in Vasp(-/-) mice reduced hepatic steatosis and normalized fatty acid oxidation and VLDL-TG secretion. Activation of VASP by the phosphodiesterase-5 inhibitor, sildenafil, in db/db mice reduced hepatic steatosis and increased phosphorylated (p-)AMPK and p-acetyl CoA carboxylase. In Vasp(-/-) mice, however, sildendafil treatment did not increase p-AMPK or reduce hepatic TG content. These studies identify a role of VASP to enhance hepatic fatty acid oxidation by activating AMPK and to promote VLDL-TG secretion from the liver.

DOI: 10.2337/db12-0325

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@inproceedings{Tateya2013VASPIH, title={VASP Increases Hepatic Fatty Acid Oxidation by Activating AMPK in Mice}, author={Sanshiro Tateya and Norma Rizzo-De Leon and Priya Handa and Andrew M. Cheng and Vicki L. Morgan-Stevenson and Kayoko Ogimoto and Jenny E. Kanter and Karin E . Bornfeldt and Guenter Daum and Alexander W . Clowes and Alan Chait and Francis Y. Kim}, booktitle={Diabetes}, year={2013} }