Sheldon Ryan D, Padilla Jaume, Jenkins Nathan T, Laughlin M Harold, Rector R Scott
Research Service, Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri;
Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; Department of Child Health, University of Missouri, Columbia, Missouri; Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri;
Am J Physiol Gastrointest Liver Physiol. 2015 Mar 15;308(6):G540-9. doi: 10.1152/ajpgi.00247.2014. Epub 2015 Jan 8.
The progression in nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis is a serious health concern, but the underlying mechanisms remain unclear. We hypothesized that chronic inhibition of nitric oxide (NO) synthase (NOS) via N(ω)-nitro-L-arginine methyl ester (L-NAME) would intensify liver injury in a rat model of obesity, insulin resistance, and NAFLD. Obese Otsuka Long-Evans Tokushima fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats received control or L-NAME (65-70 mg·kg(-1)·day(-1))-containing drinking water for 4 wk. L-NAME treatment significantly (P < 0.05) reduced serum NO metabolites and food intake in both groups. Remarkably, despite no increase in body weight, L-NAME treatment increased hepatic triacylglycerol content (+40%, P < 0.05) vs. control OLETF rats. This increase was associated with impaired (P < 0.05) hepatic mitochondrial state 3 respiration. Interestingly, the opposite effect was found in LETO rats, where L-NAME increased (P < 0.05) hepatic mitochondrial state 3 respiration. In addition, L-NAME induced a shift toward proinflammatory M1 macrophage polarity, as indicated by elevated hepatic CD11c (P < 0.05) and IL-1β (P = 0.07) mRNA in OLETF rats and reduced expression of the anti-inflammatory M2 markers CD163 and CD206 (P < 0.05) in LETO rats. Markers of total macrophage content (CD68 and F4/80) mRNA were unaffected by L-NAME in either group. In conclusion, systemic NOS inhibition in the obese OLETF rats reduced hepatic mitochondrial respiration, increased hepatic triacylglycerol accumulation, and increased hepatic inflammation. These findings suggest an important role for proper NO metabolism in the hepatic adaptation to obesity.
非酒精性脂肪性肝病（NAFLD）进展为非酒精性脂肪性肝炎是一个严重的健康问题，但其潜在机制仍不清楚。我们假设，通过N（ω）-硝基-L-精氨酸甲酯（L-NAME）对一氧化氮（NO）合酶（NOS）进行慢性抑制会加重肥胖、胰岛素抵抗和NAFLD大鼠模型的肝损伤。肥胖的大冢长-埃文斯-德岛肥胖（OLETF）大鼠和瘦的大冢长-埃文斯-德岛（LETO）大鼠饮用含对照或L-NAME（65 - 70 mg·kg⁻¹·天⁻¹）的饮用水4周。L-NAME处理显著（P < 0.05）降低了两组大鼠的血清NO代谢产物和食物摄入量。值得注意的是，尽管体重没有增加，但与对照OLETF大鼠相比，L-NAME处理使肝脏三酰甘油含量增加了40%（P < 0.05）。这种增加与肝脏线粒体状态3呼吸受损（P < 0.05）有关。有趣的是，在LETO大鼠中发现了相反的效果，L-NAME增加了（P < 0.05）肝脏线粒体状态3呼吸。此外，L-NAME诱导了向促炎性M1巨噬细胞极性的转变，OLETF大鼠肝脏中CD11c（P < 0.05）和IL-1β（P = 0.07）mRNA升高以及LETO大鼠中抗炎性M2标志物CD163和CD206的表达降低（P < 0.05）表明了这一点。两组中巨噬细胞总含量（CD68和F4/80）mRNA的标志物均不受L-NAME影响。总之，肥胖的OLETF大鼠全身NOS抑制降低了肝脏线粒体呼吸，增加了肝脏三酰甘油积累，并增加了肝脏炎症。这些发现表明适当的NO代谢在肝脏适应肥胖过程中起重要作用。
