title: Chronic NOS inhibition accelerates NAFLD progression in an obese rat model.
abstract: 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.
authors.affiliation: Research Service, Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri;
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Sheldon
authors.affiliation: 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;
authors.forename: Jaume
authors.initials: J
authors.lastname: Padilla
authors.affiliation: Department of Kinesiology, University of Georgia, Athens, Georgia.
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Jenkins
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri; Department of Biomedical Sciences, University of Missouri, Columbia, Missouri; Department of Medical Physiology and Pharmacology, University of Missouri, Columbia, Missouri;
authors.forename: M Harold
authors.initials: MH
authors.lastname: Laughlin
authors.affiliation: Research Service, Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; Department of Medicine-Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri; and rectors@health.missouri.edu.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Rector
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology; D018450:Disease Progression; D004435:Eating; D004791:Enzyme Inhibitors / Q000633:toxicity*; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000209:etiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D020334:Rats, Inbred OLETF; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D008055:Lipids; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
keywords: Nω-nitro-l-arginine methyl ester; liver; nitric oxide; obese Otsuka Long-Evans Tokushima fatty rat