title: Keap1 knockdown increases markers of metabolic syndrome after long-term high fat diet feeding.
abstract: The nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway upregulates antioxidant and biotransformation enzyme expression to counter cellular oxidative stress. The contributions of Nrf2 to other cellular functions, such as lipid homeostasis, are emerging. This study was conducted to determine how enhanced Nrf2 activity influences the progression of metabolic syndrome with long-term high-fat diet (HFD) feeding. C57BL/6 and Keap1-knockdown (Keap1-KD) mice, which exhibit enhanced Nrf2 activity, were fed a HFD for 24 weeks. Keap1-KD mice had higher body weight and white adipose tissue mass compared to C57BL/6 mice on HFD, along with increased inflammation and lipogenic gene expression. HFD feeding increased hepatic steatosis and inflammation to a greater extent in Keap1-KD mice compared to C57BL/6 mice, which was associated with increased liver Cd36, fatty acid-binding protein 4, and monocyte chemoattractant protein 1 mRNA expression, as well as increased acetyl-CoA carboxylase 1 and stearoyl-CoA desaturase-1 protein expression. The HFD altered short-term glucose homeostasis to a greater degree in Keap-KD mice compared to C57BL/6 mice, which was accompanied by downregulation of insulin receptor substrate 1 mRNA expression in skeletal muscle. Together, the results indicate that Keap1 knockdown, on treatment with HFD, increases certain markers of metabolic syndrome.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Vijay R
authors.initials: VR
authors.lastname: More
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Jialin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Prajakta C
authors.initials: PC
authors.lastname: Shimpi
authors.affiliation: Pathology and Laboratory Medicine, Providence VA Medical Center, Providence, RI 02908, USA.
authors.forename: Clyde
authors.initials: C
authors.lastname: Belgrave
authors.affiliation: Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.affiliation: Division of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA. Electronic address: aslitt@uri.edu.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Slitt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D003598:Cytoskeletal Proteins / Q000502:physiology*; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000209:etiology; D005947:Glucose / Q000378:metabolism; D007249:Inflammation / Q000209:etiology; D000072019:Kelch-Like ECH-Associated Protein 1; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D005947:Glucose
keywords: Free radicals; Keap1; Metabolic syndrome; Nrf2; Steatosis