Toxicological consequences of altered peroxisome proliferator-activated receptor γ (PPARγ) expression in the liver: insights from models of obesity and type 2 diabetes11Abbreviations: PPAR, peroxisome proliferator-activated receptor; 15d-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; NEFA, non-esterified fatty acid; T2DM, type 2 (non-insulin-dependent) diabetes mellitus; LPS, lipopolysaccharide; NSAIDs, nonsteroidal anti-inflammatory drugs; IL, interleukin; TNF α, tumor necrosis factor-α; TRAIL, tumor necrosis fa

Boelsterli, Urs A.; Bedoucha, Marc

doi:10.1016/s0006-2952(01)00817-6

Cited by 94 publications

(16 citation statements)

References 76 publications

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“…In the present study, we noticed the corresponding changes in the expressions of PPARs and UCP2, ATP and the fat content, in ob/ob livers treated with cerulenin, which support our hypothesis. In fact, treatment of obese and diabetic mice with the selective PPARγ activator thiazolidinediones has been reported to result in centrilobular steatosis in the liver [55], and disruption of PPARγ in ob/ob mice has been shown to be beneficial to the liver [56]. In our experiments, we found that with fat depletion, the expression of PPARα, PPARγ, and UCP2 were decreased, accompanied by increased ATP content and improved hepatic function.…”

Section: Discussionsupporting

confidence: 53%

Cerulenin Blockade of Fatty Acid Synthase Reverses Hepatic Steatosis in ob/ob Mice

et al. 2013

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Fatty liver or hepatic steatosis is a common health problem associated with abnormal liver function and increased susceptibility to ischemia/reperfusion injury. The objective of this study was to investigate the effect of the fatty acid synthase inhibitor cerulenin on hepatic function in steatotic ob/ob mice. Different dosages of cerulenin were administered intraperitoneally to ob/ob mice for 2 to 7 days. Body weight, serum AST/ALT, hepatic energy state, and gene expression patterns in ob/ob mice were examined. We found that cerulenin treatment markedly improved hepatic function in ob/ob mice. Serum AST/ALT levels were significantly decreased and hepatic ATP levels increased in treated obese mice compared to obese controls, accompanied by fat depletion in the hepatocyte. Expression of peroxisome proliferator-activated receptors α and γ and uncoupling protein 2 were suppressed with cerulenin treatment and paralleled changes in AST/ALT levels. Hepatic glutathione content were increased in some cases and apoptotic activity in the steatotic livers was minimally changed with cerulenin treatment. In conclusion, these results demonstrate that fatty acid synthase blockade constitutes a novel therapeutic strategy for altering hepatic steatosis at non-stressed states in obese livers.

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Section: Discussionsupporting

confidence: 53%

Cerulenin Blockade of Fatty Acid Synthase Reverses Hepatic Steatosis in ob/ob Mice

et al. 2013

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“…Ectopic fat deposition in the liver is a common feature of obesity and type 2 diabetes that may render this organ less sensitive to insulin. 32 In stark contrast to animals treated with the PPARγ ligand, which showed increased liver lipid accumulation, a side-effect of thiazolidinediones in rodents, 33 obese-diabetic mice treated chronically with WWL113 displayed complete clearance of the excess lipids that normally accrue in the liver of these animals ( Fig. 3d ).…”

Section: Resultsmentioning

confidence: 96%

Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes

et al. 2013

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Phenotypic screening is making a comeback in drug discovery as the maturation of chemical proteomics methods has facilitated target identification for bioactive small molecules. A limitation of these approaches is that time-consuming genetic methods or other means is often required to determine the biologically relevant target(s) from among multiple protein-compound interactions that are typically detected. Here, we have combined phenotypic screening of a directed small-molecule library with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits. Using this approach, we identify carboxylesterase 3 (Ces3 or Ces1d) as a primary molecular target of bioactive compounds that promote lipid storage in adipocytes. We further show that Ces3 activity is dramatically elevated during adipocyte differentiation. Treatment of two mouse models of obesity-diabetes with a Ces3 inhibitor ameliorates multiple features of metabolic syndrome, illustrating the power of the described strategy to accelerate the identification and pharmacologic validation of new therapeutic targets.

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“…Although the exact mechanism involved in the activation of PPAR γ in the liver remains unknown, it has been postulated that a circulating factor might be responsible for the stimulation of hepatic total PPAR γ transcription during a state of increased energy availability [29]. The upregulation of hepatic total PPAR γ would in turn activate several genes such as adipocyte fatty acid-binding protein (aP2) and fatty acid translocase (FAT/CD36), previously present only in trace amounts in the liver of lean mice.…”

Section: Discussionmentioning

confidence: 99%

Effects of Glycyrrhizic Acid on Peroxisome Proliferator-Activated Receptor Gamma (PPARγ), Lipoprotein Lipase (LPL), Serum Lipid and HOMA-IR in Rats

Yin

Kadir

2010

PPAR Research

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Studies on ligand binding potential of glycyrrhizic acid, a potential agonist to PPARγ, displayed encouraging results in amelioration of metabolic syndrome. The regulation of gene cassettes by PPARγ affects glucose homeostasis, lipid, lipoprotein metabolism and adipogenesis. This study was performed to determine the effects of GA on total PPARγ and LPL expression levels, lipid parameters and HOMA-IR. Oral administration of 100 mg/kg GA for 24 hours resulted in an increase in insulin sensitivity with decreases in blood glucose, serum insulin and HOMA-IR. Improvement in serum lipid parameters was also observed with a decrease in triacylglycerol, total cholesterol and LDL-cholesterol and an elevation in HDL-cholesterol. GA administration also resulted in up-regulation of total PPARγ and LPL expression levels in the visceral and subcutaneous adipose tissues, abdominal and quadriceps femoris muscles, as well as liver and kidney, with a significant up-regulation only in the visceral adipose tissue, abdominal and quadriceps femoris muscles. Thus, oral administration of 100 mg/kg GA for 24 hours improved insulin sensitivity and lipid profiles and induced upregulation of total PPARγ and LPL expression levels in all studied tissues.

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Cited by 94 publications

References 76 publications

Cerulenin Blockade of Fatty Acid Synthase Reverses Hepatic Steatosis in ob/ob Mice

Cerulenin Blockade of Fatty Acid Synthase Reverses Hepatic Steatosis in ob/ob Mice

Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes

Effects of Glycyrrhizic Acid on Peroxisome Proliferator-Activated Receptor Gamma (PPARγ), Lipoprotein Lipase (LPL), Serum Lipid and HOMA-IR in Rats

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