title: A Western diet induced NAFLD in LDLR(-/)(-) mice is associated with reduced hepatic glutathione synthesis.
abstract: Oxidative stress plays a key role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Glutathione is the major anti-oxidant involved in cellular oxidative defense, however there are currently no simple non-invasive methods for assessing hepatic glutathione metabolism in patients with NAFLD. As a primary source of plasma glutathione, liver plays an important role in interorgan glutathione homeostasis. In this study, we have tested the hypothesis that measurements of plasma glutathione turnover could be used to assess the hepatic glutathione metabolism in LDLR(-/)(-) mice, a mouse model of diet-induced NAFLD. Mice were fed a standard low fat diet (LFD) or a high fat diet containing cholesterol (a Western type diet (WD)). The kinetics of hepatic and plasma glutathione were quantified using the (2)H2O metabolic labeling approach. Our results show that a WD leads to reduced fractional synthesis rates (FSR) of hepatic (25%/h in LFD vs. 18%/h in WD, P<0.05) and plasma glutathione (43%/h in LFD vs. 21%/h in WD, P<0.05), without any significant effect on their absolute production rates (PRs). WD-induced concordant changes in both hepatic and plasma glutathione turnover suggest that the plasma glutathione turnover measurements could be used to assess hepatic glutathione metabolism. The safety, simplicity, and low cost of the (2)H2O-based glutathione turnover approach suggest that this method has the potential for non-invasive probing of hepatic glutathione metabolism in patients with NAFLD and other diseases.
authors.affiliation: Department of Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Guo-Fang
authors.initials: GF
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Kwangwon
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Rocio
authors.initials: R
authors.lastname: Lopez
authors.affiliation: Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Previs
authors.affiliation: Department of Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.affiliation: Department of Hepatology and Gastroenterology, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: McCullough
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA; Department of Hepatology and Gastroenterology, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: tkasumov@neomed.edu.
authors.forename: Takhar
authors.initials: T
authors.lastname: Kasumov
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D066273:Diet, Western / Q000009:adverse effects; D004195:Disease Models, Animal; D005978:Glutathione / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000235:genetics* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D011973:Receptors, LDL / Q000097:blood / Q000235:genetics* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D011973:Receptors, LDL; D005978:Glutathione
keywords: Flux; Glutathione; Heavy water; Mass spectrometer; NAFLD; NASH; Oxidative stress; Western Diet