VASP increases hepatic fatty acid oxidation by activating AMPK in mice.
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.
Department of Medicine, University of Washington, Seattle, Washington, USA. tateya@u.washington.edu
Sanshiro
S
Tateya
Norma
N
Rizzo-De Leon
Priya
P
Handa
Andrew M
AM
Cheng
Vicki
V
Morgan-Stevenson
Kayoko
K
Ogimoto
Jenny E
JE
Kanter
Karin E
KE
Bornfeldt
Guenter
G
Daum
Alexander W
AW
Clowes
Alan
A
Chait
Francis
F
Kim
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012263:Ribonucleosides / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D005227:Fatty Acids; D008840:Microfilament Proteins; D010750:Phosphoproteins; D012263:Ribonucleosides; D000098662:Vasodilator-Stimulated Phosphoprotein; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D055372:AMP-Activated Protein Kinases