Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome

Guan, Youfei

doi:10.1097/01.asn.0000139067.83419.46

Cited by 157 publications

(138 citation statements)

References 177 publications

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“…PPARs heterodimerize with the retinoid X receptor (RXR) and bind to PPAR responsive element (PPRE) in the regulatory region of target genes that function in diverse biological processes, such as lipid metabolism, adipogenesis, insulin sensitivity, immune response, and cell growth and differentiation [1, 2]. PPARs also participate in the pathogenesis of a cluster of human diseases, for example, metabolic syndrome that includes insulin resistance, glucose intolerance, obesity, dyslipidemia, hypertension, atherosclerosis, and microalbuminuria [3–6]. …”

Section: Introductionmentioning

confidence: 99%

PPARs Integrate the Mammalian Clock and Energy Metabolism

2014

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Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of numerous target genes. PPARs play an essential role in various physiological and pathological processes, especially in energy metabolism. It has long been known that metabolism and circadian clocks are tightly intertwined. However, the mechanism of how they influence each other is not fully understood. Recently, all three PPAR isoforms were found to be rhythmically expressed in given mouse tissues. Among them, PPARα and PPARγ are direct regulators of core clock components, Bmal1 and Rev-erbα, and, conversely, PPARα is also a direct Bmal1 target gene. More importantly, recent studies using knockout mice revealed that all PPARs exert given functions in a circadian manner. These findings demonstrated a novel role of PPARs as regulators in correlating circadian rhythm and metabolism. In this review, we summarize advances in our understanding of PPARs in circadian regulation.

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Section: Introductionmentioning

confidence: 99%

PPARs Integrate the Mammalian Clock and Energy Metabolism

2014

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“…Molecules known to regulate ACC function (PPAR␣, PPAR␥, AMPK, SREBP-1, and ChREBP) have been studied in the experimental diabetic kidney, albeit in a context not specifically inclusive of effects on FA oxidation and ACC regulation (33)(34)(35). For example, evidence for the role of AMPK on kidney function is developing.…”

Section: Fa Metabolism and The Acc Enzymementioning

confidence: 99%

Lipotoxicity in Diabetic Nephropathy

Murea

Freedman²,

Parks³

et al. 2010

Clinical Journal of the American Society of Nephrology

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Cellular toxicity mediated by lipids (lipotoxicity) has been implicated in the pathophysiology of metabolic syndrome and diabetes mellitus. Genetic analyses now implicate lipotoxicity in susceptibility to type 2 diabetes mellitus-associated nephropathy (T2DN), a pathway that had previously been unexplored. A genome-wide association study in Japanese patients identified a single nucleotide polymorphism in the acetyl-CoA carboxylase ␤ (ACACB) gene associated with T2DN. Replication analyses suggest that this same polymorphism may be a diabetic nephropathy risk allele in other ethnic groups. The ACACB gene (also called ACC2 or acetyl-CoA carboxylase 2) plays a critical role in intracellular fatty acid (FA) oxidation. This manuscript reviews the physiology of FA metabolism and adverse cellular effects that can result from dysregulation of this process. It is hypothesized that glomerular and tubular dysfunction can be induced by increases in intracellular FA concentrations, a process that may be enabled by genetic risk variants. This novel glucolipotoxicity hypothesis in T2DN warrants further investigation. Clin J Am Soc Nephrol 5: 2373-2379, 2010. doi: 10.2215 O ver the last decade, dysregulated fatty acid (FA) oxidation has been implicated as an effector pathway in the pathophysiology of metabolic syndrome, atherosclerosis, cardiomyopathy, and diabetes mellitus (1). An imbalance between circulating and cytosolic FA levels resulting in excessive intracellular accumulation of FAs and their derivatives (diacylglycerol, ceramides) underlies the spectrum of insulin-deficient states, including insulin resistance in metabolic syndrome, insulin resistance and relative insulin deficiency in type 2 diabetes (T2D), and absolute insulin deficiency in type 1 diabetes (T1D) (2).Diabetic nephropathy (DN) is a serious complication that develops in a significant yet limited proportion of patients with T1D and T2D. Glycemic control and genetic predisposition have been explored as major pathogenic determinants. To determine how DN develops, the long-held theory that glomerular and tubular toxicity result from hyperglycemia (glucotoxicity) has been evaluated extensively at the molecular level for contributing factors, including generation of advanced glycation end products; activation of protein kinase C, TGF␤-Smad, and mitogen-activated protein kinase pathways; enhanced production of reactive oxygen species; increased extracellular matrix deposition, and increased tubulointerstitial fibrosis (3,4). Despite these investigations, the renal pathology in animal models of glucotoxicity does not reliably replicate what occurs in human DN, and specific factors that cause, propagate, or predict DN remain elusive.DN is believed to be a complex polygenic trait; that is, the clinical and histopathologic phenotype depends on alleles in multiple genes. On the basis of this hypothesis, scientists have taken full advantage of unbiased genetic studies as human genome-wide association studies have been used in large diabetic cohorts. Although several ...

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“…PPARs have attracted enormous attention in the past decade as a result of their therapeutic roles in metabolic diseases such as diabetes and obesity. 22,23 There are three isoforms of PPARs: PPAR-␣, PPAR-␤/␦, and PPAR-␥. PPAR-␥ has been a large focus of PPAR study because it is a key factor in adipogenesis, insulin sensitivity, cell cycle regulation, and cell differentiation.…”

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confidence: 99%

Transcription Factors Krüppel-Like Factor 6 and Peroxisome Proliferator-Activated Receptor-γ Mediate High Glucose-Induced Thioredoxin-Interacting Protein

Chen

Holian

et al. 2009

The American Journal of Pathology

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We demonstrated recently that thioredoxin-interacting protein (Txnip) and the transcription factor Krüp-pel-like factor 6 (KLF6) were up-regulated in both in vivo and in vitro models of diabetic nephropathy, thus promoting renal injury. Conversely, peroxisome proliferator-activated receptor-␥ (PPAR-␥) agonists have been shown to be renoprotective. Hence, this study was undertaken to determine whether Txnip expression is regulated by the transcription factors KLF6 and PPAR-␥. By using siRNAs and overexpressing constructs, the role of KLF6 and PPAR-␥ in Txnip transcriptional regulation was determined in human kidney proximal tubule cells and in streptozocin-induced diabetes mellitus in Sprague-Dawley rats, in vitro and in vivo models of diabetic nephropathy, respectively. KLF6 overexpression increased Txnip expression and promoter activity, which was inhibited by concurrent exposure to PPAR-␥ agonists. In contrast, reduced expression of KLF6 by siRNA or exposure to PPAR-␥ agonists attenuated high glucoseinduced Txnip expression and promoter activity. KLF6-Txnip promoter binding was decreased in KLF6-silenced cells, whereas PPAR-␥ agonists increased PPAR-␥-Txnip promoter binding. Indeed, silencing of KLF6 increased PPAR-␥ expression, suggesting endogenous regulation of PPAR-␥ expression by KLF6. Moreover, renal KLF6 and Txnip expression increased in rats with diabetes mellitus and was inhibited by PPAR-␥ agonist treatment; however, KLF6 expression did not change in HK-2 cells exposed to PPAR-␥ agonists. Hence, Txnip expression and promoter activity are mediated via divergent effects of KLF6 and PPAR-␥ transcriptional regulation.

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Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome

Cited by 157 publications

References 177 publications

PPARs Integrate the Mammalian Clock and Energy Metabolism

PPARs Integrate the Mammalian Clock and Energy Metabolism

Lipotoxicity in Diabetic Nephropathy

Transcription Factors Krüppel-Like Factor 6 and Peroxisome Proliferator-Activated Receptor-γ Mediate High Glucose-Induced Thioredoxin-Interacting Protein

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