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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 secretion and AMPK signaling. Overexpression of VASP in hepatocytes increased AMPK phosphorylation, fatty acid oxidation, and reduced hepatocyte triglyceride (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 (AICAR) in Vasp mice reduced hepatic steatosis and normalized fatty acid oxidation and VLDL-TG secretion. Activation of VASP by the phosphodiesterase-5 (PDE5