Peroxisome proliferator-binding protein: identification and partial characterization of nafenopin-, clofibric acid-, and ciprofibrate-binding proteins from rat liver.

Lalwani, Narendra D.; Alvares, Keith; Reddy, M. K.; Reddy, M N; Parikh, Indu; Reddy, Janardan K.

doi:10.1073/pnas.84.15.5242

Cited by 72 publications

(34 citation statements)

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“…In an effort to address this issue, we have undertaken studies to identify and characterize peroxisome proliferator binding protein(s) (PPbPs) in rat liver with the anticipation that such proteins might shed some light on the mechanism of tissue-specific induction of peroxisome proliferation. A PPbP from rat liver cytosol was isolated by affinity chromatography using three different affinity ligands-clofibric acid, ciprofibrate, and nafenopin-each bound to Sepharose (11). The present study demonstrates that the PPbP is identical with the constitutively expressed member (P72, HSC72) of the heat shock protein HSP70 family.…”

mentioning

confidence: 83%

“…Using the affinity chromatographic approach, we have previously described the purification of a PPbP from rat liver cytosol (11). This involved the coupling of the -COOH group ofthe ligand clofibric acid with the -NH2 group on AH-Sepharose 4B beads by the carbodiimide reaction (12).…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Under ether anesthesia, the liver was perfused via the portal vein with ice-cold saline and homogenized in 4 vol of 10 mM Hepes, pH 7.5/1 mM EDTA/1 mM dithiothreitol/ 10% glycerol (HEDG buffer) containing 0.3 mM phenylmethylsulfonyl fluoride, 1 mM benzamidine hydrochloride, 0.4 M KCI, and the 100,000 x g supernatant prepared as described earlier (9,11). The clofibric acid binding protein from liver cytosol was prepared as described (11), with minor modifications. The protein eluted from the clofibric acid-Sepharose column was diluted with HEDG buffer so as to reduce the KCl concentration to 0.2 M. The eluate was then passed through an anti-albumin-Sepharose column, to remove traces of albumin present in the eluate, as albumin is known to bind nonspecifically to clofibric acid and certain other compounds.…”

Section: Methodsmentioning

confidence: 99%

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Identification of cytosolic peroxisome proliferator binding protein as a member of the heat shock protein HSP70 family.

Alvares

Vicente-Carrillo

Yuan

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Clofibrate and many of its structural analogues induce proliferation of peroxisomes in the hepatic parenchymal cells of rodents and certain nonrodent species including primates. This induction is tissue specific, occurring mainly in the liver parenchymal cells and to a lesser extent in the kidney cortical epithelium. The induction of peroxisomes is associated with a predictable pleiotropic response, characterized by hepatomegaly, and increased activities and mRNA levels of certain peroxisomal enzymes. Using affinity chromatography, we had previously isolated a protein that binds to clofibric acid. We now show that this protein is homologous with the heat shock protein HSP70 family by analysis of amino acid sequences of isolated peptides from trypsin-treated clofibric acid binding protein and by cross-reactivity with a monoclonal antibody raised against the conserved region of the 70-kDa heat shock proteins. The clofibric acid-Sepharose column could bind HSP70 proteins isolated from various species, which could then be eluted with either clofibric acid or ATP. Conversely, when a rat liver cytosol containing multiple members of the HSP70 family was passed through an ATP-agarose column, and eluted with clofibric acid, only P72 (HSC70) was eluated. These results suggest that clofibric acid, a peroxisome proliferator, preferentially interacts with P72 at or near the ATP binding site.

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mentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Identification of cytosolic peroxisome proliferator binding protein as a member of the heat shock protein HSP70 family.

Alvares

Vicente-Carrillo

Yuan

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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“…The exact mechanism by which the structurally diverse chemicals induce peroxisome proliferation is not clear. The present experimental evidence indicates that the hypolipidaemic compounds most likely act through a cytosolic receptor-mediated mechanism Reddy & Rao, 1986;Lalwani et al, 1987).…”

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confidence: 97%

Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofibrate, a hypolipidaemic compound

Rao

Dwivedi²,

Subbarao³

et al. 1988

Br J Cancer

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Summary The hepatic effects of ciprofibrate, a potent peroxisome proliferator, were evaluated in male C57BL/6N mice, a mouse strain with very low incidence of spontaneous liver tumour development. Dietary feeding of ciprofibrate (0.0125% or 0.025% w/w) for 2 weeks resulted in a marked proliferation of peroxisomes (9-fold increase) and several-fold increase (8-to 10-fold) in the activity of peroxisomal /3-oxidation enzymes. Feeding ciprofibrate at 0.025% concentration for 15 months followed by a 0.0125% for 6 months led to the development of hepatic adenomas in 8/14 (57%) and hepatocellular carcinomas (HCC) in 3/14 (21%) mice. In mice given 0.0125% ciprofibrate for 18 months 5 of 8 (62%) and 3 of 8 (37%) developed adenomas and HCC respectively. Similar to the findings observed in rats, both the adenomas and HCC were negative for y-glutamyltranspeptidase. These results in C57BL/6N mice of hepatocarcinogenic effect of ciprofibrate, a non-genotoxic chemical, indicate that peroxisome proliferation can be used as a reliable parameter to evaluate the carcinogenicity of hypolipidaemic compounds.

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Lack of stereoselectivity of the peroxisome proliferation induced by 2‐phenylpropionic acid: Evidence against a role for lipid disturbance in peroxisome proliferation

Ahmad

Caldwell

1994

Chirality

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The significance of disturbances of lipid metabolism caused by xenobiotic acyl-CoAs as possible causes of peroxisomal proliferation has been studied with the enantiomers of 2-phenylpropionic acid (2-PPA), the (R)-enantiomer of which is converted to the acyl-CoA in rats while its (S)-antipode is not. rac-2-PPA (250 mg/kg/day ip x 3) was shown to be an hepatic peroxisomal proliferator in male Sprague-Dawley rats on the basis of increases in microsomal cytochrome P-450 content and lauric acid hydroxylation and hepatic CN(-)-insensitive palmitoyl-CoA oxidation, a peroxisomal marker activity, while electron microscopy revealed a rise in the peroxisome/mitochondria ratio in hepatocytes. Further studies established the dose-response relationships for these biochemical changes. The (R)- and (S)-enantiomers were administered at a dose of 50 mg/kg/day ip x 3 and both were peroxisome proliferators of very similar potency. The effects of 100 mg/kg/day ip x 3 of the racemate, a dose giving ca. 75% of maximal response, were essentially additive of those of 50 mg/kg/day ip x 3 of its two component isomers. The stereoselectivity of acyl-CoA formation from the enantiomers of 2-PPA was confirmed by their differential inhibition of microsomal palmitoyl-CoA synthesis. Taken together, these data indicate that it is very unlikely that the acyl-CoA of 2-PPA plays any role in the peroxisomal proliferation which this compound causes in the rat.

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Peroxisome proliferator-binding protein: identification and partial characterization of nafenopin-, clofibric acid-, and ciprofibrate-binding proteins from rat liver.

Cited by 72 publications

References 21 publications

Identification of cytosolic peroxisome proliferator binding protein as a member of the heat shock protein HSP70 family.

Identification of cytosolic peroxisome proliferator binding protein as a member of the heat shock protein HSP70 family.

Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofibrate, a hypolipidaemic compound

Lack of stereoselectivity of the peroxisome proliferation induced by 2‐phenylpropionic acid: Evidence against a role for lipid disturbance in peroxisome proliferation

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