ENOS Deficiency Increases Susceptibility to Western Diet Induced Hepatic Mitochondrial Dysfunction

Abstract

Nitric oxide produced by endothelial nitric oxide synthase (eNOS) can influence mitochondrial biogenesis and electron transport chain activity. Hepatic mitochondrial dysfunction is a hallmark feature of nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms remain elusive. Here, we tested the hypothesis that eNOS plays an important role in sustaining hepatic mitochondrial function in NAFLD. Wild‐type (WT) and eNOS knockout (eNOS‐/‐) mice received either control (CON; 10% fat, 3.5% sucrose) or a western diet high in fat (45%), sucrose (17%), and cholesterol (1%; HFC) for 18‐weeks. HFC diet feeding induced histological NAFLD and increased weight gain and % body fat in both genotypes compared to CON diet. Complete hepatic mitochondrial palmitate oxidation to CO2 was elevated in both eNOS‐/‐ groups compared with WT mice(p<0.05), while incomplete acid‐soluble metabolite production was elevated only in eNOS‐/‐‐CON compared to other groups. In addition, maximal FCCP‐uncoupled mitochondrial respiration tended to be elevated in eNOS‐/‐‐CON compared to WT‐CON (+24%; p=0.08) but was significantly reduced with HFC feeding in eNOS‐/‐ mice (‐37% vs eNOS‐/‐‐CON; p<0.05). Finally, HFC feeding dramatically reduced hepatic mRNA expression of the putative control for mitochondrial biogenesis, PGC‐1α, in WT (‐33%) and eNOS‐/‐ (‐58%) compared with WT‐CON (p<0.05). These results support the hypothesis that eNOS limits susceptibility to western diet‐induced hepatic mitochondrial dysfunction and highlights a potential role for eNOS in hepatic mitochondrial biogenesis. Supported by:HL036088 (MHL) and VHA‐CDA2 1299‐03(RSR).