Impaired liver glucose production in a murine model of steatosis and endotoxemia: protection by inducible nitric oxide synthase.
This study hypothesized that upregulation of inducible nitric oxide synthase (iNOS) would preserve the metabolic status of the liver under conditions of steatosis and acute inflammation. Wild-type C57BL/6J and C57BL/6 iNOS-knockout (-/-) mice were fed a choline-deficient ethionine-supplemented diet (CDE). Mice were also injected with 5 mg/kg lipopolysaccharide (LPS) to induce endotoxemia. Consumption of the CDE diet led to steatosis of the liver and decreased expression of the gluconeogenic genes compared with controls. LPS treatment exacerbated these effects because of inhibition of PGC-1alpha expression, which resulted in hypoglycemia. In steatotic livers, LPS-induced iNOS expression was enhanced. Comparison between wild-type and iNOS-knockout mice under these conditions demonstrated a protective role of iNOS against fatal hypoglycemia. Nitric oxide (NO) signaling effects were confirmed by treatment of hepatocytes in culture with an NO donor, which resulted in increased expression of PGC-1alpha and gluconeogenic genes. In conclusion, iNOS was found to act as a protective protein and provides a possible mechanism by which the liver preserves glucose homeostasis under stress.
Tirosh
Oren
O
The School of Nutritional Sciences, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel. otirosh@agri.huji.ac.il
Artan
Avital
A
Aharoni-Simon
Michal
M
Ramadori
Giuliano
G
Madar
Zecharia
Z
D000818:Animals; D002796:Choline Deficiency / Q000378:metabolism; D019587:Dietary Supplements; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005001:Ethionine / Q000008:administration & dosage; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000096:biosynthesis*; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*
D008070:Lipopolysaccharides; D052247:Nitric Oxide Synthase Type II; D005947:Glucose; D005001:Ethionine