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

Autor: Yuji Tanaka, Curtis D. Klaassen, Yu-Kun Jennifer Zhang, Ronnie L. Yeager
Rok vydání: 2010
Předmět:
Male
CD36
Toxicology
medicine.disease_cause
Severity of Illness Index
environment and public health
Lipid peroxidation
Mice
chemistry.chemical_compound
Methionine
NAD(P)H Dehydrogenase (Quinone)
Glutathione Transferase
Mice
Knockout
Kelch-Like ECH-Associated Protein 1
Fatty Acids
Fatty liver
Organ Size
respiratory system
Glutathione
Choline Deficiency
Isoenzymes
Phenotype
Liver
Signal Transduction
medicine.medical_specialty
Genotype
NF-E2-Related Factor 2
Biology
digestive system
Article
Internal medicine
medicine
Animals
RNA
Messenger
Adaptor Proteins
Signal Transducing
Pharmacology
Fatty acid metabolism
Body Weight
Lipid metabolism
Lipid Metabolism
medicine.disease
Fatty Liver
Mice
Inbred C57BL
Cytoskeletal Proteins
Disease Models
Animal
Endocrinology
chemistry
biology.protein
Lipid Peroxidation
Oxidative stress
Zdroj: Toxicology and Applied Pharmacology. 245:326-334
ISSN: 0041-008X
DOI: 10.1016/j.taap.2010.03.016
Popis: 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 Gstalpha1/2 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.
Databáze: OpenAIRE
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