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Nitric oxide synthase inhibition exacerbates liver injury in an obese rat model of NAFLD (1115.3)
Author(s) -
Sheldon Ryan,
Padilla Jaume,
Jenkins Nathan,
Laughlin M.,
Rector R.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1115.3
Subject(s) - medicine , endocrinology , insulin resistance , nitric oxide synthase , cd68 , cd163 , nonalcoholic fatty liver disease , fatty liver , liver injury , nitric oxide , obesity , fibrosis , chemistry , macrophage , immunohistochemistry , disease , biochemistry , in vitro
We tested the hypothesis that chronic disruption of constitutive nitric oxide (NO) production via the non‐selective NO synthase (NOS) inhibitor N ω ‐nitro‐L‐arginine methyl ester (L‐NAME) would intensify liver injury in a rat model of obesity, insulin resistance, and nonalcoholic fatty liver disease (NAFLD). Obese Otsuka Long‐Evans Tokushima Fatty (OLETF) and lean Long‐Evans Tokushima Otsuka (LETO) rats (16‐wks) received either control or L‐NAME (65‐70 mg/kg/d) containing drinking water (n=10/group) for 4‐wks. L‐NAME treated OLETF and LETO rats had significantly (p < 0.05) reduced serum NO metabolites (NO X ) and food intake. Despite reducing % body fat (‐2.5%; p < 0.05) in OLETF rats, L‐NAME treatment increased hepatic triacylglycerol (TAG) content (+40%; p < 0.05) compared to control OLETF rats. In addition, L‐NAME treatment caused a shift toward M1 macrophage polarity as indicated by elevated CD11c (p<0.05) and IL‐1β (p=0.07) mRNA in the OLETF rats. Markers of total and resident macrophages (CD68 and CD163 mRNA, respectively), fibrosis (TGFβ mRNA), and cell adhesion (MCP‐1 and ICAM mRNA) were unaffected by L‐NAME treatment in both groups. In conclusion, chronic NOS inhibition appears to aggravate liver injury by increasing expression of macrophage activation‐related genes associated with insulin resistance and by accelerating hepatic TAG accumulation in obese, insulin resistant rats. Grant Funding Source : Supported by a Life Sciences Fellowship (RDS), NIH HL‐36088 (MHL), and VHA‐CDA2 BX001299‐02 (RSR)