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R Hertz

Publications and source records attributed to R Hertz.

At least 19 recordsLinked to original sources
PubMed2002

Modulation by nutrients and drugs of liver acyl-CoAs analyzed by mass spectrometry.

The profile of liver acyl-CoAs induced by dietary fats of variable compositions or by xenobiotic hypolipidemic amphipathic carboxylates was evaluated in vivo using a novel electrospray ionization tandem mass spectrometry methodology of high resolution, sensitivity, and reliability. The composition of liver fatty acyl-CoAs was found to reflect the composition of dietary fat. Treatment with hypolipidemic carboxylates resulted in liver dominant abundance of their respective acyl-CoAs accompanied by an increase in liver fatty acyl-CoAs. Cellular effects exerted by dietary fatty acids and/or xenobiotic carboxylic drugs may be transduced in vivo by their respective acyl-CoAs.

Acyl Coenzyme A↗
PubMed2001

Suppression of hepatocyte nuclear factor-4alpha by acyl-CoA thioesters of hypolipidemic peroxisome proliferators.

Hepatocyte nuclear factor-4alpha (HNF-4alpha) modulates the expression of liver-specific genes that control the production (e.g. apolipoprotein [apo] A-I and apo B) and clearance (e.g. apo C-III) of plasma lipoproteins. We reported that the CoA thioesters of amphipathic carboxylic hypolipidemic drugs (e.g. clofibric acid analogues currently used for treating hyperlipidemia in humans and substituted long-chain dicarboxylic acids) were formed in vivo, bound to HNF-4alpha, inhibited its transcriptional activity, and suppressed the expression of HNF-4alpha-responsive genes. Hypolipidemic PPARalpha (peroxisome proliferator-activated receptor alpha) activators that were not endogenously thioesterified into their respective acyl-CoAs were shown to be effective in rats but not in humans, implying that the hypolipidemic activity transduced by PPARalpha in rats was PPARalpha-independent in humans. The suppressed acyl-CoA synthase of PPARalpha knockout mice left unresolved the contribution made by the acyl-CoA/HNF-4alpha pathway to the hypolipidemic effect of PPARalpha agonists in rodents. Hence, suppression of HNF-4alpha activity by the CoA thioesters of hypolipidemic "peroxisome proliferators" may account for their hypolipidemic activity independently of PPARalpha activation by their respective free carboxylates. The hypolipidemic activity of peroxisome proliferators is mediated in rats and humans by the PPARalpha and HNF-4alpha pathways, respectively.

Animals↗
PubMed1998

Peroxisome proliferator-activated receptor (PPAR) alpha activation and its consequences in humans.

Amphipathic carboxylates collectively defined as peroxisome proliferators (PP) induce in rodents a pleiotropic effect, mediated by the peroxisome proliferator-activated receptor alpha (PPAR alpha). Treatment with PP results in rodents in hypolipidemia, peroxisome proliferation and liver hypertrophy and hyperplasia leading to non-genotoxic hepatocarcinogenesis. In contrast to rodents, the hypolipidemic effect exerted by PP in humans is not accompanied by peroxisome proliferation nor by induction of peroxisomal beta-oxidation or other activities induced by PP in rodents. Non-responsiveness in humans may be ascribed to a missing liver component in the PPAR alpha transduction pathway specifically involved with transcriptional modulation of chromosomal PPAR alpha responsive genes. Hence, biological effects exerted by PP in the human liver are likely to be mediated by a transduction pathway independent of PPAR alpha.

Animals↗
PubMed1998

Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha.

Dietary fatty acids specifically modulate the onset and progression of various diseases, including cancer, atherogenesis, hyperlipidaemia, insulin resistances and hypertension, as well as blood coagulability and fibrinolytic defects; their effects depend on their chain length and degree of saturation. Hepatocyte nuclear factor-4alpha (HNF-4alpha) is an orphan transcription factor of the superfamily of nuclear receptors and controls the expression of genes that govern the pathogenesis and course of some of these diseases. Here we show that long-chain fatty acids directly modulate the transcriptional activity of HNF-4alpha by binding as their acyl-CoA thioesters to the ligand-binding domain of HNF-4alpha. This binding may shift the oligomeric-dimeric equilibrium of HNF-4alpha or may modulate the affinity of HNF-4alpha for its cognate promoter element, resulting in either activation or inhibition of HNF-4alpha transcriptional activity as a function of chain length and the degree of saturation of the fatty acyl-CoA ligands. In addition to their roles as substrates to yield energy, as an energy store, or as constituents of membrane phospholipids, dietary fatty acids may affect the course of a disease by modulating the expression of HNF-4alpha-controlled genes.

Acyl Coenzyme A↗
PubMed1998

Analgesic effect of bupivacaine on extraperitoneal laparoscopic hernia repair.

UNLABELLED: Local anesthetics decrease postoperative pain when placed at the surgical site. Patients benefit from laparoscopic extraperitoneal hernia repair because this allows earlier mobilization than the more classical open surgical approach. The purpose of this study was to determine the pain-sparing efficacy of local anesthetics placed in the preperitoneal fascial plane during extraperitoneal laparoscopic inguinal hernia surgery. Forty-two outpatients were included in a double-blind, randomized, placebo-controlled, institutional review board-approved study. At the conclusion of a standardized general anesthetic, 21 patients received 60 mL of 0.125% bupivacaine into the preperitoneal fascial plane before incisional closure, whereas the other 21 patients received 60 mL of the isotonic sodium chloride solution placebo. Postoperative pain was assessed 1, 4, 8, 24, and 72 h postoperatively. In addition, postoperative fentanyl and outpatient acetaminophen 500 mg/hydrocodone 5 mg requirements were recorded. All hernia repairs were performed by the same surgeon. Appropriate statistical analyses were used. There were no significant differences between the bupivacaine and isotonic sodium chloride solution groups with regard to postoperative pain scores, length of postanesthesia care unit stay, or analgesic requirements. Furthermore, neither unilateral versus bilateral repair nor operative time affected the measured parameters. The addition of 60 mL of 0.125% bupivacaine into the preperitoneal fascial plane during extraperitoneal laparoscopic hernia repair did not significantly alter pain scores, supplementary analgesic requirements, or recovery room length of stay. IMPLICATIONS: The placement of 60 mL of 0.125% bupivacaine into the preperitoneal fascial plane during extraperitoneal laparoscopic hernia repair did not significantly alter pain scores, supplementary analgesic requirements, or recovery room length of stay.

Anesthetics, Local↗
PubMed1996

Thyromimetic mode of action of peroxisome proliferators: activation of 'malic' enzyme gene transcription.

Peroxisome proliferators induce thyroid-hormone-dependent liver activities, e.g. 'malic' enzyme, mitochondrial glycerol-3-phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, S14[Hertz, Aurbach, Hashimoto and Bar-Tana (1991) Biochem. J. 274, 745-751]. Here we report that the thyromimetic effect of peroxisome proliferators with respect to 'malic' enzyme result from transcriptional activation of the 'malic' enzyme gene, mediated by binding of the peroxisome proliferator activated receptor (PPAR alpha)/retinoid X receptor (RXR alpha) heterodimer to a 5'-flanking enhancer of the 'malic' enzyme promoter. The enhancer involved is distinct from the thyroid hormone response element of the 'malic' enzyme promoter and is partly homologous with that which mediates transcriptional activation of peroxisomal acyl-CoA oxidase by peroxisome proliferators. Hence transcriptional activation of thyroid-hormone-dependent liver genes by xenobiotic or endogenous amphipathic carboxylates collectively defined as peroxisome proliferators is mediated by a transduction pathway similar to that involved in transcriptional activation of peroxisomal beta-oxidative genes and distinct from that which mediates thyroid hormone action.

Animals↗
PubMed1996

Activation of gene transcription by prostacyclin analogues is mediated by the peroxisome-proliferators-activated receptor (PPAR).

Xenobiotic amphipathic carboxylates, known collectively as hypolipidemic peroxisome proliferators (e.g., aryloxyalkanoic acids), or native long-chain fatty acids induce liver peroxisome proliferation and other biological activities. This broad spectrum of effects results from modulation of transcription of specific genes mediated by binding of peroxisome-proliferators-activated receptors (PPAR) to respective sequence-specific promoter elements (PPRE). The broad specificity and relatively low potency of reported hypolipidemic peroxisome proliferators prompted us to search for specific highly potent peroxisome proliferators. Here we report that stable prostacyclin analogues may act in such a manner. mPPAR alpha-mediated expression of a reporter gene linked to the peroxisomal rat acyl-CoA oxidase promoter was dose-dependently induced by carbaprostacyclin and iloprost. The ED50 for carbaprostacyclin was 25 nM, and carbaprostacyclin was therefore 25-fold and 200-fold more effective than the most potent xenobiotic (5,18,11,14-eicosatetraynoic acid) and native (arachidonic acid) inducers, respectively. Induction was further increased by cotransfecting the cells with mPPAR alpha and an expression vector for retinoic acid-X-receptor. PPAR-mediated activation of gene expression by prostacyclin analogues was specific for PPAR and was not observed using other members of the superfamily. No activation of gene expression was induced by other prostaglandins or leukotrienes at concentrations 100-fold higher than those of the prostacyclin analogues. Induction of gene expression by prostacyclin analogues was inhibited in cells transfected with the long-chain-acyl-CoA synthase, indicating that the acidic form of prostacyclin, rather than the respective CoA derivative or a metabolite derived thereof, serves as the activator of the PPAR/PPRE transduction pathway. Hence, PPAR-mediated modulation of gene transcription by prostacyclins may form the basis for their novel role as regulators of gene expression. Xenobiotic hypolipidemic peroxisome proliferators and native long-chain fatty acids seem to exploit the PPAR/PPRE transduction pathway used by prostacyclin.

Animals↗
PubMed1996

Transcriptional suppression of the transferrin gene by hypolipidemic peroxisome proliferators.

Activation of gene expression by hypolipidemic peroxisome proliferators (e.g. native and substituted long chain fatty acids, aryloxyalkanoic fibrate drugs) is accompanied by transcriptional suppression of liver transferrin gene in treated animals or human hepatoma cell line. Transcriptional suppression of liver transferrin by hypolipidemic peroxisome proliferators results from (a) displacement of hepatic nuclear factor (HNF)-4 from the transferrin promoter by nonproductive binding of the peroxisome proliferator-activated receptor-retinoic acid X receptor heterodimer to the (-76/-52) PRI promoter element of the human transferrin gene and (b) suppression of liver HNF-4 gene expression by hypolipidemic peroxisome proliferators with a concomitant decrease in its availability for binding to the transferrin PRI promoter element. HNF-4 gene suppression and its displacement from the transferrin promoter result in eliminating HNF-4-enhanced transcription of transferrin. Liver transferrin suppression by hypolipidemic peroxisome proliferators may result in reduced iron availability as well as modulation of transferrin-induced differentiation processes. Transcriptional suppression of HNF-4-enhanced liver genes (e.g. apolipoprotein C-III, transferrin) may complement the pleiotropic biological effect exerted by hypolipidemic peroxisome proliferators.

Animals↗
PubMed1995

Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III.

The hypolipidemic effect exerted by beta,beta'-tetramethyl-hexadecanedioic acid (Medica 16) is accounted for by enhanced catabolism of plasma triglyceride-rich lipoproteins due to a decrease in plasma apolipoprotein C-III (Frenkel, B., Mayorek, N., Hertz, R., and Bar-Tana, J. (1988) J. Biol. Chem. 263, 8491-8497; Frenkel, B., Bishara-Shieban, J., and Bar-Tana, J. (1994) Biochem. J. 298, 409-414). Decrease in apolipoprotein C-III exerted by peroxisome proliferators/hypolipidemic amphipathic carboxylates (e.g. Medica 16, fibrate drugs) is shown here to result from suppression of apolipoprotein C-III gene expression. Transcriptional suppression of apolipoprotein C-III is due to transcriptional suppression of hepatic nuclear factor (HNF)-4 as well as displacement of HNF-4 from the apolipoprotein C-III promoter. HNF-4 displacement exerted by peroxisome proliferators/hypolipidemic amphipathic carboxylates is mediated by the peroxisome proliferators activated receptor (PPAR). Transcriptional suppression of HNF-4-enhanced genes (e.g. apolipoprotein C-III) along with transcriptional activation of peroxisomal and other genes by hypolipidemic drugs may account for their broad spectrum pharmacological effect.

Animals↗
PubMed1995

Treatment of vulvar vestibulitis syndrome with electromyographic biofeedback of pelvic floor musculature.

Thirty-three women diagnosed as suffering from vulvar vestibulitis syndrome, marked by a significant history of long-term moderate to severe chronic introital dyspareunia and tenderness of the vulvar vestibule, were selected for treatment. Patients were given a computerized electromyographic evaluation of the pelvic floor muscles and were then provided with portable electromyographic biofeedback instrumentation and instructions on the conduct of daily, at-home, biofeedback-assisted pelvic floor muscle rehabilitation exercises. They received intermittent evaluations of pelvic floor muscles to ensure compliance and monitor their progress and symptom changes. The results show that after an average of 16 weeks of practice, pelvic floor muscle contractions increased 95.4%, resting tension levels decreased 68%, and the instability of the muscle at rest decreased by 62%. Subjective reports of pain decreased an average of 83%. Twenty-eight patients had abstained from intercourse for an average of 13 months. Twenty-two of these 28 patients resumed intercourse by the end of the treatment period. Six month follow-up indicated maintenance of therapeutic benefits.

Adult↗
PubMed1994

Transcriptional activation by amphipathic carboxylic peroxisomal proliferators is induced by the free acid rather than the acyl-CoA derivative.

Most peroxisomal proliferators consist of a carboxylic group attached to a hydrophobic backbone yielding an amphipathic carboxylate molecule. The respective CoA derivatives of peroxisomal proliferators, formed by ATP-dependent CoA thioesterification catalyzed by long-chain-acyl-CoA synthase, have been repeatedly considered as the immediate inducers of peroxisome and other genes. In this study, the putative requirement for prior CoA thioesterification of peroxisomal proliferators was evaluated by analyzing the induced expression of a reporter plasmid promoted by the peroxisomal acyl-CoA-oxidase promoter in cells transiently cotransfected with expression vectors for the peroxisome-proliferator-activated receptor and the long-chain-acyl-CoA synthase. Transcriptional activation of peroxisomal acyl-CoA oxidase by peroxisomal proliferators was inhibited in the presence of transfected functional acyl-CoA synthase. The inhibitory effect was negatively correlated with the capacity of the acyl-CoA synthase to catalyze CoA thioesterification of the respective proliferator. Hence, the immediate inducer is the peroxisomal proliferator free acid rather than the respective CoA derivative or a metabolite derived from the peroxisomal-proliferator-CoA intermediate.

Acyl Coenzyme A↗
PubMed1993

Thyromimetic effect of peroxisome proliferators.

Xenobiotic amphipathic carboxylates of varying hydrophobic backbones, known collectively as 'peroxisome proliferators' (PP), affect lipoprotein metabolism, calorigenesis, liver redox and phosphate potentials and adipose conversion. Some biological effects exerted by PP are strikingly similar to those exerted by thyroid hormones (TH). Furthermore, similarly to TH, these compounds have been recently found to induce in euthyroid as well as thyroidectomized rats or in rat hepatocytes cultured in TH-free media, liver activities classically considered as TH-dependent, eg malic enzyme (ME) and S14. The thyromimetic effect of PP could be accounted for by transcriptional activation of TH-dependent genes as verified by run-on transcription assays. The thyromimetic effect of PP was found not to be mediated by the TH nuclear receptor. Moreover, in contrast to TH, PP were ineffective as thyromimetic agents in the rat heart or pituitary cells, suggesting a tissue specificity different from that of TH. The overall thyromimetic effect of PP appears to involve transcriptional activation of TH-dependent genes, yet being mediated by a novel transduction pathway.

Animals↗
PubMed1992

Induction of peroxisomal beta-oxidation genes by retinoic acid in cultured rat hepatocytes.

Retinoic acid is reported here to induce peroxisomal beta-oxidation activities in cultured rat hepatocytes, with a concomitant increase in respective peroxisomal mRNAs. The concentrations of retinoic acid required for inducing liver peroxisomal acyl-CoA oxidase were similar to those required for inducing liver transglutaminase. A putative 5'-flanking response element for retinoic acid may be found within the enhancer region involved in the induction of peroxisomal genes by xenobiotic amphipathic carboxylates.

Acetyl-CoA C-Acetyltransferase↗
PubMed1992

Effect of thyroid hormone treatment on redox and phosphate potentials in rat liver.

In the present study rat liver cytosolic/mitochondrial redox and phosphate potentials were evaluated as a function of thyroid hormone status. T3 treatment resulted in a dose-dependent 2-fold decrease in the cytosolic redox potential, as reflected by the liver lactate/pyruvate ratio, with a concomitant increase in the liver capacity of handling an ethanol load. The effect of T3 on liver cytosolic redox potential was correlated with a T3-induced increase in mitochondrial glycerol-3-phosphate dehydrogenase activity. The apparent liver cytosolic phosphate potential was calculated from the glycerol-3-phosphate/3-phosphoglyceric acid ratio, using 31P-nmr under conditions of rapid equilibrium within the glycerol-3-phosphate/3- phosphoglyceric acid metabolic section and was found to be essentially unaffected by T3 treatment. The apparent total cellular phosphate potential measured by 31P-nmr, however, was decreased in T3-treated animals, reflecting a decrease in the apparent liver mitochondrial phosphate potential induced by T3 treatment. Also, while the apparent cellular phosphate potential of euthyroid rats was independent of ethanol administration, the reduced cellular phosphate potential of T3-treated rats was normalized by ethanol treatment. In conclusion, thyroid hormone treatment induces in vivo a dramatic decrease in the liver cytosolic redox potential, with a concomitant increase in the liver oxidizing capacity. The decrease in cytosolic redox potential induced by thyroid hormone treatment is accompanied by a decrease in mitochondrial phosphate potential. Liver mitochondrial ATP production in thyroid hormone-treated animals appears to be rate limited by the availability of cytosolic reducing equivalents.

Animals↗
PubMed1992

Tissue selective modulation of redox and phosphate potentials by beta,beta'-methyl-substituted hexadecanedioic acid.

beta,beta'-Methyl-substituted hexadecanedioic acid (MEDICA 16) shares some of the calorigenic-hypolipidemic characteristics of thyroid hormones. In light of this similarity, MEDICA 16 was further evaluated here as a modulator of rat liver redox and phosphate potentials as well as an effector of cardiac high energy intermediates level in comparison to thyroid hormone. 1) Similarly to thyroid hormone, MEDICA 16 treatment resulted in 3.5-fold decrease in cytosolic redox potential. With both treatment modes, the induced decrease in cytosolic redox potential resulted in a concomitant increase in the liver capacity of handling an ethanol or xylitol load. 2) The apparent liver cytosolic phosphate potential calculated from the glycerol-3-phosphate 3-phosphoglyceric acid ratio evaluated under conditions of rapid equilibrium within the glycerol-3 phosphate/3-phosphoglyceric acid metabolic section was found to remain unaffected by either MEDICA 16 or T3 treatment. However, the apparent cellular phosphate potential was substantially decreased by both treatment modes, thus reflecting a decrease in the apparent liver mitochondrial phosphate potential. 3) Similarly to thyroid hormone, the effect of MEDICA 16 on liver redox and phosphate potentials could be accounted for by induction of mitochondrial glycerol-3-phosphate dehydrogenase. 4) In contrast to liver, heart high energy intermediates were affected by thyroid hormone but not by MEDICA 16 treatment. 5) The effect of T3 and MEDICA 16 with respect to liver redox and phosphate potentials may partially account for the calorigenic-hypolipidemic effect of both. MEDICA 16 may however serve as a selective liver thyromimetic agent lacking the cardiac affect induced by thyroid hormone.

Animals↗
PubMed1991

Thyromimetic effect of peroxisomal proliferators in rat liver.

Amphipathic carboxylates, of varying hydrophobic backbones, which act as peroxisomal proliferators (aryloxyalkanoic acids, methyl-substituted dicarboxylic acid) induce in euthyroid or thyroidectomized rats, as well as in rat hepatocytes cultured in 3,5,3'-tri-iodo-L-thyronine (T3)-free media, liver enzyme activities that are classically considered to be thyroid-hormone-dependent (malic enzyme, mitochondrial alpha-glycerophosphate dehydrogenase, glucose-6-phosphate dehydrogenase and S14). The dose required in vivo for the thyromimetic effect of peroxisomal proliferators was 10(3)-fold higher than the dose of T3 required. Similarly, peroxisomal proliferators were active in culture in the range 1-100 microM compared with 1 nM for T3. Their maximal inductive capacities were, however, similar to or greater than that of T3. The thyromimetic effect of peroxisomal proliferators was only partially correlated with their capacities as inducers of liver peroxisomal enzymes. The thyromimetic effect with respect to liver malate dehydrogenase and S14 resulted from an increase in their mRNA contents. The increase in liver S14 mRNA was accounted for by transcriptional activation of the S14 gene. T3 binding to isolated liver nuclei or nuclear extract was competitively displaced by some but not all of the non-thyroidal inducers of the above liver activities. In contrast with the thyromimetic effect induced in liver cells, no increase in growth hormone mRNA was observed in cultured GH1 pituitary cells incubated in the presence of non-thyroidal amphipathic carboxylates. The characteristics of the thyromimetic effect of amphipathic carboxylic peroxisomal proliferators indicate that these agents may act as transcriptional activators of thyroid-hormone-dependent genes in the rat liver.

Animals↗
PubMed1989

Synthesis and hypolipidemic and antidiabetogenic activities of beta,beta,beta',beta'-tetrasubstituted, long-chain dioic acids.

beta,beta,beta',beta'-Tetrasubstituted, long-chain dioic acids of the general formula HOOC-C(XY)-C(R2)-Q-C-(R2)-C(XY)-COOH have been synthesized and evaluated as hypotriglyceridemic-hypocholesterolemic agents in rats and as antidiabetogenic agents in ob/ob diabetic mice. The free carboxyl function of analogues of the series was mandatory for their hypolipidemic-antidiabetogenic effect while nonhydrolyzable diesters were inactive. Other structure-activity relationships were determined as a function of the overall chain length (C12-C22), alpha,alpha'-substitutions (X, Y = H, F, Cl, Br, OH, CN), beta, beta'-substitutions (R = CH3, C6H5), and core substitutions [Q = (CH2)10, (CH2)4CH = CH(CH2)4, 1,4-C6H10[(CH2)3]2, 1,4-C6H4[(CH2)3]2, 1,4-C6H4(CH = CHCH2)2, CH2(OCH2CH2)3OCH2)]. The most effective hypolipidemic-antidiabetogenic members of the series were alpha,alpha'-nonsubstituted, beta,beta'-methyl-substituted analogues of 14-18-carbon chains having either a saturated aliphatic core or a 1,4-bis(propenyl)benzene core in the cis/trans configuration. The hypotriglyceridemic rather than the hypocholesterolemic capacity of members of the series was found to correlate with their respective capacities as liver peroxisomal proliferators in rats.

Animals↗