Peroxisomes

Barth et al. (2001) identified AUTIO as a novel gene required for both the cytoplasm to vacuole targeting of proaminopeptidase I and starvation-induced autophagy. 

Rhodin described in 1954 a newcellular organelle that he discovered in the proximal tubular epithelium of the kidney and called a microbody [263]. At first microbodies were believed to exist only in a few tissues such as liver kidney, and tetrahymina. It is now apparent that they exist almost in every vertebrate tissue and in many plants. 

One characteristic of many, but not all peroxisomes, is the presence of a nucleoid and, therefore, three different types of microbodies have been distinguished those with one crystalloid nucleoid, those with several smaller nucleoids (subcrystalloids), and those without nucleoid. The physiological meaning of the presence or absence of nucleoid is not clear except for the fact that the nucleoid contains urate oxidase. Apparently those microbodies which do not contain urate oxidase are also devoid of nucleoid. 

Microbodies cannot be seen with the light microscope on electron micrographs they appear like small round bodies (5 p in diameter in liver) with a single membrane surrounding a homogeneous electron-dense mass. 

It has been shown that these organelles contain peroxidase, catalase, uricase, and a number of other oxidases, such as D amino oxidase, L-hydroxy acid oxidase, and even isocitrate dehydrogenase [264]. Because of their content in peroxidase, microbodies have been renamed peroxisomes. Nothing is known of their role in cellular physiology. Usually on the basis of circumstantial evidence they have been suspected to play a role in purine (because of the presence of xanthine oxidase and allantoinase in the kidney and liver of chicken microbodies), cholesterol, lipid, and steroid metabolisms, gluconeogenesis, photosynthesis, and respiration. 

Among organelles, microbodies have an unusually short half life 1 to 5 days or about /lo of that of mitochondria. The reasons for the rapid turnover of microbodies are not known. The enzymes found in microbodies are synthesized in the endoplasmic reticulum. The mechanism of transfer of the enzymes from endoplasmic reticulum to microbodies has not been discovered. In view of their rapid turnover, microbodies must constantly be eliminated from the cell. Although entrapment in areas of focal cytoplasmic degradation is certainly involved, it appears that other still unknown mechanisms of degradation exist. 

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On the basis of these differences in species response it was concluded that phthalates do not pose a significant health hazard to humans. This view is home out by the EU Commission decision of July 25, 1990 which states that DEHP shall not be classified or labeled as a carcinogenic or an irritant substance (42). This has been reaffirmed in a comprehensive review (43) which concludes that "peroxisome proliferators constitute a discrete class of nongenotoxic rodent hepatocarcinogens and that the relevance of thek hepatocarcinogenic effects for human hazard assessment is considered to be negligible."... 

Golgi apparatus, endoplasmic reticulum, ribosomes, lysosomes, peroxisomes, and cytoskeleton... 

Peroxisomal /3-Oxidation Requires FAD-Dependent Acyl-CoA Oxidase... 

The thiazolidinediones have also been reported to act as inhibitors of the respiratory chain at high concentrations, and this appears to account for their ability to activate AMGPK in cultured cells. However, the primary target of the thiazolidinediones appears to be the peroxisome proliferator-activated receptor-y ( PPAR-y), a member of the nuclear receptor superfamily expressed in adipocytes. One of the major effects of stimulation of PPAR-y in adipocytes is the release ofthe... 

Antidiabetic Drugs other than Insulin. Table 2 Tissue expression, ligands, genes activated, and biological actions of the peroxisome proliterator-activated receptor-y (PPARy)... 

HMG-CoA-Reductase-Inhibitors Peroxisome Proliferator-Activated Recqrtors (PPARs) ACE Inhibitors Antiplatelet Drugs... 

Thiazolidinediones (PPARy-agonists) Thiazolidine-diones ( pioglitazone, rosiglitazone) lower blood glucose levels in animal models of insulin resistance and also in insulin resistant patients. They are agonists of the peroxisome proliferator-activated receptor y (PPARy). Because they enhance the effect of insulin and reduce serum insulin levels in insulin resistant patients, thiazolidinediones are usually referred to as insulin sensitizers . 

A peroxisome proliferator-activated receptor (PPAR) binding site was identified in the murine FATP1 promoter. Several reports have shown a positive regulation of mouse FATPs by ligands that activate PPAR-a, PPAR-y, or PPAR-y/RXR heterodimers. 

Peroxisome Proliferator-Activated Receptor (PPARs) HMG-CoA Reductase Inhibitors... 

Thiazolidinediones (synonyms glitazones, insulin sensitizers rosiglitazone, pioglitazone) are a novel class of oral antidiabetic drugs that activate the transcription factor peroxisome proliferator-activated receptor (PPARy). Thiazolidinediones ameliorate insulin resistance in obese animal models and in individuals... 

Peroxisome Proliferator-Activated Receptors (PPARs) Diabetes Mellitus... 

The synthesis of virtually all proteins in a cell begins on ribosomes in the cytosol (except a few mitochondrial, and in the case of plants, a few chloroplast proteins that are synthesized on ribosomes inside these organelles). The fate of a protein molecule depends on its amino acid sequence, which can contain sorting signals that direct it to its corresponding organelle. Whereas proteins of mitochondria, peroxisomes, chloroplasts and of the interior of the nucleus are delivered directly from the cytosol, all other organelles receive their set of proteins indirectly via the ER. These proteins enter the so-called secretory pathway (Fig. 1). 

Finally, it has to be mentioned that LPA also has an intracellular target site, which is the nuclear transcription factor, peroxisome proliferator-activated receptor-y (PPARy). LPA competes for thiazolidinedione binding and activates PPARy-dependent gene transcription. Thereby, LPA induced neointima formation in a rat carotid artery model. 

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

Peraza MA, Burdick AD, Marin HE et al (2006) The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR). Toxicol Sci 90 269-295... 

Peroxisome Proliferator-Activated Receptors. Figure 1 Common structural and functional features of nuclear receptor transcription factors. Consistent with other members of the nuclear receptor superfamily, the PPARs have a modular domain structure consisting of domains A/B, C, D, and E. Each domain is associated with specific functions. 

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