Proposed model of the interaction of leucine, metformin, and sildenafil on the AMPK/Sirt1/eNOS network. AMPK, Sirt1, and eNOS are nutrient sensors responsive to caloric restriction, regulating energy metabolism in an interacting network. In addition, they prevent inflammation and reduce oxidative stress and proliferation, the key factors for the progression of NAFLD to NASH. Leucine and metformin synergistically activate the AMPK/Sirt1 pathway while sildenafil contributes to further stimulation through activation of eNOS. Moreover, sildenafil’s inhibition of PDE5 results in concomitant activation of the cGMP-dependent protein kinases (PKGs). These integrated effects result in reduction of hepatic lipid accumulation, hepatic inflammation and injury, and subsequently reduction of fibrosis.