Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-Imidazolide

Shin, Soona; Wakabayashi, Junko; Yates, Melinda S.; Wakabayashi, Nobunao; Dolan, Patrick; Aja, Susan; Liby, Karen T.; Sporn, Michael B.; Yamamoto, Masayuki; Kensler, Thomas W.

doi:10.1016/j.ejphar.2009.08.022

Cited by 254 publications

(237 citation statements)

References 21 publications

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“…In mice fed a high-fat diet, the bardoxolone methyl analogue CDDO-Im prevented increases in body weight, adipose mass, and hepatic lipid accumulation and increased energy expenditure. 51 These effects were not observed in Nrf2 knockout mice, suggesting that activation of Nrf2 has perceived positive effects on lipid and energy metabolism. Bardoxolone methyl-associated changes in body mass composition are being further evaluated in patients with type 2 diabetes and CKD.…”

Section: Discussionmentioning

confidence: 91%

Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney

Reisman

Chertow

Hebbar

et al. 2012

Journal of the American Society of Nephrology

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Inflammation and oxidative stress are hallmarks and mediators of the progression of CKD. Bardoxolone methyl, a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant and anti-inflammatory response, increases estimated GFR and decreases BUN, serum phosphorus, and uric acid concentrations in patients with moderate to severe CKD. However, it also increases albuminuria, which is associated with inflammation and disease progression. Therefore, we investigated whether this bardoxolone methyl-induced albuminuria may result from the downregulation of megalin, a protein involved in the tubular reabsorption of albumin and lipid-bound proteins. Administration of bardoxolone methyl to cynomolgus monkeys significantly decreased the protein expression of renal tubular megalin, which inversely correlated with the urine albuminto-creatinine ratio. Moreover, daily oral administration of bardoxolone methyl to monkeys for 1 year did not lead to any adverse effects on renal histopathologic findings but did reduce serum creatinine and BUN, as observed in patients with CKD. Finally, the bardoxolone methyl-induced decrease in megalin corresponded with pharmacologic induction of renal Nrf2 targets, including NAD(P)H:quinone oxidoreductase 1 enzyme activity and glutathione content. This result indicates that Nrf2 may have a role in megalin regulation. In conclusion, these data suggest that the increase in albuminuria that accompanies bardoxolone methyl administration may result, at least in part, from reduced expression of megalin, which seems to occur without adverse effects and with strong induction of Nrf2 targets. 23: 166323: -167323: , 201223: . doi: 10.1681 Pathogenic stimuli in patients with CKD and type 2 diabetes, including hypertension, obesity, heightened renin-angiotensin activity, and albuminuria, activate oxidative stress-mediated inflammation. [1][2][3][4][5] Indeed, oxidative stress and impaired antioxidant capacity intensify with progression of CKD, 6,7 and production of reactive oxygen species and oxidative stress result in activation of the transcription factor nuclear factor kB (NFkB). NFkB regulates expression of proinflammatory cytokines and chemokines, and its pathologic activation is a hallmark of many inflammatory disorders, including CKD. Activated NFkB is present in the kidneys of patients with diabetic nephropathy but is undetectable in normal healthy kidneys. 8 Thus, oxidative stress facilitates proinflammatory signaling, which frequently results in further oxidative stress, thereby creating a destructive feedback loop and, often, perturbation of normal physiologic processes and disease progression. J Am Soc NephrolTo respond to oxidative and electrophilic stimuli, organisms have developed elaborate cytoprotective pathways that are directly regulated by the

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Section: Discussionmentioning

confidence: 91%

Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney

Reisman

Chertow

Hebbar

et al. 2012

Journal of the American Society of Nephrology

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“…The role of Nrf2 in regulating whole body weight and obesity has been investigated recently by our group and others. Oltipraz and oleanolic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole (CDDO-Im), two known activators of Nrf2, were shown to prevent HFD-induced increase of body weight, adipose mass and hepatic lipid accumulation [15,57] . Importantly, the effects of CDDO-Im were dependent on the Nrf2 system, while no such responses were observed in Nrf2-disrupted mice [57] .…”

Section: Role Of the Nrf2 System In Regulating Insulin Signaling Andmentioning

confidence: 99%

Role of nuclear factor (erythroid-derived 2)-like 2 in metabolic homeostasis and insulin action: A novel opportunity for diabetes treatment?

Zhong

Li²,

Liu³

et al. 2012

WJD

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Redox balance is fundamentally important for physiological homeostasis. Pathological factors that disturb this dedicated balance may result in oxidative stress, leading to the development or aggravation of a variety of diseases, including diabetes mellitus, cardiovascular diseases, metabolic syndrome as well as inflammation, aging and cancer. Thus, the capacity of endogenous free radical clearance can be of patho-physiological importance; in this regard, the major reactive oxygen species defense machinery, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system needs to be precisely modulated in response to pathological alterations. While oxidative stress is among the early events that lead to the development of insulin resistance, the activation of Nrf2 scavenging capacity leads to insulin sensitization. Furthermore, Nrf2 is evidently involved in regulating lipid metabolism. Here we summarize recent findings that link the Nrf2 system to metabolic homeostasis and insulin action and present our view that Nrf2 may serve as a novel drug target for diabetes and its complications.

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“…Recent studies revealed that Nrf2 also contributes to lipid metabolism (10,35). The genetic deletion of Nrf2 results in the rapid onset and progression of hepatic steatosis induced by a methionine-choline-deficient diet (3,46,56) and in differential gene expression of hepatic metabolism (49), while Nrf2 activation ameliorates high-fat diet-induced fatty liver (42).…”

mentioning

confidence: 99%

NF-E2-Related Factor 1 (Nrf1) Serves as a Novel Regulator of Hepatic Lipid Metabolism through Regulation of the Lipin1 and PGC-1β Genes

Hirotsu

Hataya

Katsuoka

et al. 2012

Molecular and Cellular Biology

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112

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Hepatic lipid metabolism is under elaborate regulation, and perturbations in this regulatory process at the transcriptional level lead to pathological conditions. NF-E2-related factor 1 (Nrf1) is a member of the cap'n'collar (CNC) transcription factor family. Hepatocyte-specific Nrf1 gene conditional-knockout mice are known to develop hepatic steatosis, but it remains unclear how Nrf1 contributes to the lipid homeostasis. Therefore, in this study we examined the gene expression profiles of Nrf1-deficient mouse livers. A pathway analysis based on the profiling results revealed that the levels of expression of the genes related to lipid metabolism, amino acid metabolism, and mitochondrial respiratory function were decreased in Nrf1-deficient mouse livers, indicating the profound effects that the Nrf1 deficiency conferred to various metabolic pathways. We discovered that the Nrf1 deficiency leads to the reduced expression of the transcriptional coactivator genes Lipin1 and PGC-1␤ (for peroxisome proliferator-activated receptor ␥ coactivator 1␤). Chromatin immunoprecipitation analyses showed that Nrf1 binds to the antioxidant response elements (AREs) in regulatory regions of the Lipin1 and PGC-1␤ genes and the binding of Nrf1 to the AREs activates reporter gene transcription. These results thus identified Nrf1 to be a novel regulator of the Lipin1 and PGC-1␤ genes, providing new insights into the Nrf1 function in hepatic lipid metabolism.

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Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-Imidazolide

Cited by 254 publications

References 21 publications

Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney

Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney

Role of nuclear factor (erythroid-derived 2)-like 2 in metabolic homeostasis and insulin action: A novel opportunity for diabetes treatment?

NF-E2-Related Factor 1 (Nrf1) Serves as a Novel Regulator of Hepatic Lipid Metabolism through Regulation of the Lipin1 and PGC-1β Genes

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