Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet

Journal Article · Tue Jun 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.03.016· OSTI ID:21460178

Zhang, Yu-Kun Jennifer; Yeager, Ronnie L; Tanaka, Yuji ^[1]

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1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2-Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione and exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gst{alpha}1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities.

• OSTI ID: 21460178
• Journal Information: Toxicology and Applied Pharmacology, Vol. 245, Issue 3; Other Information: DOI: 10.1016/j.taap.2010.03.016; PII: S0041-008X(10)00113-4; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIOXIDANTS
CHOLINE
DIET
GLUTATHIONE
LIVER
METHIONINE
MICE
OXYGEN
STRESSES
ALCOHOLS
AMINO ACIDS
AMMONIUM COMPOUNDS
ANIMALS
BODY
CARBOXYLIC ACIDS
DIGESTIVE SYSTEM
DRUGS
ELEMENTS
GLANDS
HYDROXY COMPOUNDS
LIPOTROPIC FACTORS
MAMMALS
NONMETALS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
PEPTIDES
POLYPEPTIDES
PROTEINS
QUATERNARY AMMONIUM COMPOUNDS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RODENTS
VERTEBRATES