Keap 1 knockdown increases markers of metabolic syndrome after long - term fat diet feeding

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. & 2013 Elsevier Inc. All rights reserved. 67 68 69 70 71 72 73 74 75 76 77 78 79 Metabolic syndrome is described as a cluster of risk factors that increase the risk for developing cardiovascular disease [1]. Some of the risk factors include central obesity, atherogenic dyslipidemia (elevated triglycerides and low HDL cholesterol), insulin resistance (with or without glucose intolerance), and a proinflammatory state. In 2003–2009, in an analytic sample that consisted of 3423 adults 20 years of age and over, 34% of American adults met the criteria for metabolic syndrome [2]. Nuclear factor E2-related factor-2 (Nrf2) is a basic leucine zipper transcription factor that regulates basal and inducible expression of multiple antioxidant and biotransformation genes 80 81 82 83 84 85 86 87 88 89 90 ll rights reserved. cluster of differentiation 36; thase; Gclc, glutamate– ipoprotein; Irs1, insulin d protein 1; Lpl, lipoprotein qo1, NAD(P)H dehydrogen-