Sheldon 2015 Am J Physiol Gastrointest Liver Physiol

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Sheldon RD, Padilla J, Jenkins NT, Laughlin MH, Rector RS (2015) Chronic NOS inhibition accelerates NAFLD progression in an obese rat model. Am J Physiol Gastrointest Liver Physiol 308:G540-9.

» PMID:25573175

Sheldon RD, Padilla J, Jenkins NT, Laughlin MH, Rector RS (2015) Am J Physiol Gastrointest Liver Physiol

Abstract: The progression in nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is a serious health concern, but the underlying mechanisms remain unclear. To address this, we hypothesized that chronic inhibition of NO synthase (NOS) via Nω-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 either control or L-NAME (65-70 mg/kg/day) containing drinking water for 4-wks. L-NAME treatment significantly (p<0.05) reduced serum NO metabolites and food intake in both groups. Remarkably, despite no change in body weight, L-NAME treatment increased hepatic triacylglycerol (TAG) content (+40%; p<0.05) versus 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 pro-inflammatory 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 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 TAG accumulation, and increased hepatic inflammation. These findings suggest an important role for proper nitric oxide metabolism in the hepatic adaptation to obesity.

Copyright © 2014, American Journal of Physiology- Gastrointestinal and Liver Physiology.

Keywords: L-NAME, OLETF, Nitric oxide, Liver

O2k-Network Lab: US MO Columbia Rector RS

Labels: MiParea: Respiration  Pathology: Diabetes, Obesity 

Organism: Rat  Tissue;cell: Liver  Preparation: Isolated mitochondria 

Regulation: Fatty acid  Coupling state: LEAK, OXPHOS, ET  Pathway: N, NS  HRR: Oxygraph-2k