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Papers by Michael Satre

American Journal of Physiology-gastrointestinal and Liver Physiology, Mar 1, 1997

Hepatic stellate cells (HSC) participate in liver fibrogenesis via myofibroblastic activation, th... more Hepatic stellate cells (HSC) participate in liver fibrogenesis via myofibroblastic activation, the extent of which appears to correlate with the loss of cellular vitamin A. The present study has tested a hypothesis that HSC activation is associated with diminished retinoic acid (RA) signaling. Pure HSC were isolated from rats with cholestatic liver fibrosis induced by bile duct ligation (BDL) and sham-operated animals (Sham). Northern blot analysis of HSC RNA from BDL confirmed fibrogenic activation of the cells with enhanced mRNA levels for procollagen-alpha1(I) and transforming growth factor-beta1 (TGF-beta1). Competitive polymerase chain reaction analysis showed selective reductions in the mRNA levels of RA receptor (RAR)-beta and retinoid X receptor (RXR)-alpha to 20 and 17% of the Sham HSC. The mRNA level for cellular retinol binding protein I, a gene with RA responsive element (RARE), was also suppressed by 78% in BDL. The concentrations of all-trans-RA and 9-cis-RA were decreased in HSC from BDL. Nuclear extracts of these cells showed diminished binding activity to the RARE, whereas activity of AP-1, a transcription factor known to be antagonized by RAR and RXR, was enhanced. These results demonstrate diminished RA signaling in HSC from cholestatic liver fibrosis, which appeared to have resulted from RA deficiency and suppressed expression of RAR-beta and RXR-alpha. Furthermore, the reciprocal enhancement of AP-1 activity and coordinately increased expression of an AP-1 responsive gene, TGF-beta1, suggest a permissive role of the diminished RA signaling in promoting AP-1 activity and TGF-beta1 expression.

Journal of Biological Chemistry, Jun 1, 1994

A novel human alcohol dehydrogenase (ADH) gene called ADH7 has been characterized and determined ... more A novel human alcohol dehydrogenase (ADH) gene called ADH7 has been characterized and determined to encode class IV ADH, an ADH isozyme which is very active as a retinol dehydrogenase. A nearly full-length cDNA for ADH7 was isolated from a human stomach cDNA library, and a 5' genomic clone containing exons 1 and 2 was isolated from a human genomic library. DNA sequence analysis of the cDNA and genomic clones revealed the complete coding region of the gene and the deduced full-length amino acid sequence of human class * This work was supported in part by National Institutes of Health Grant AA07261 and a grant from the Alcoholic Beverage Medical Research Foundation (to G. D). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "aduertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The nucleotide sequence(s) reported in this paper has been submitted to the GenBankmIEMBL Data Bank with accession numbeds) U07821.

Journal of Biological Chemistry, Mar 1, 1994

This is an Open Access article under the CC BY license. ADH3 Promoter Activity in Dansgenic Mouse... more This is an Open Access article under the CC BY license. ADH3 Promoter Activity in Dansgenic Mouse Embryos Characteristics of ADH3-lacZ transgenic founder embryos and TABLE I progeny Founder Passage Embryonic expression name to progeny characteristics 1144 1151' No Not applicable No Not applicable 1156 Yes Observed from 9.5 d.p.c. onward; expression in neural tube, limb buds, heart, kidney, eye, ear, craniofacial region in neural tube, limb buds, heart, kidney, eye, ear, craniofacial region highest in limb buds, but also in neural tube, kidney, eye, ear, craniofacial region 1162 Yes Observed from 9.5 d.p.c. onward; expression 1172 Yes Observed from 11.5 d.p.c. onward; expression

Journal of Biological Chemistry, 2001

Multiple retinoic acid responsive cDNAs were isolated from a high density cDNA microarray membran... more Multiple retinoic acid responsive cDNAs were isolated from a high density cDNA microarray membrane, which was developed from a cDNA library of human tracheobronchial epithelial cells. Five selected cDNA clones encoded the sequence of the same novel gene. The predicted open reading frame of the novel gene encoded a protein of 319 amino acids. The deduced amino acid sequence contains four motifs that are conserved in the short-chain alcohol dehydrogenase/reductase (SDR) family of proteins. The novel gene shows the greatest homology to a group of dehydrogenases that can oxidize retinol (retinol dehydrogenases). The mRNA of the novel gene was found in trachea, colon, tongue, and esophagus. In situ hybridization of airway tissue sections demonstrated epithelial cell-specific gene expression, especially in the ciliated cell type. Both all-trans-retinoic acid and 9-cis-retinoic acid were able to elevate the expression of the novel gene in primary human tracheobronchial epithelial cells in vitro. This elevation coincided with an enhanced retinol metabolism in these cultures. COS cells transfected with an expression construct of the novel gene were also elevated in the metabolism of retinol. The results suggested that the novel gene represents a new member of the SDR family that may play a critical role in retinol metabolism in airway epithelia as well as in other epithelia of colon, tongue, and esophagus.

The Journal of nutrition, 2006

When pyrroloquinoline quinone (PQQ) is added to an amino acid-based, but otherwise nutritionally ... more When pyrroloquinoline quinone (PQQ) is added to an amino acid-based, but otherwise nutritionally complete basal diet, it improves growth-related variables in young mice. We examined PQQ and mitochondrial function based on observations that PQQ deficiency results in elevated plasma glucose concentrations in young mice, and PQQ addition stimulates mitochondrial complex 1 activity in vitro. PQQ-deficient weanling mice had a 20-30% reduction in the relative amount of mitochondria in liver; lower respiratory control ratios, and lower respiratory quotients than PQQ-supplemented mice (2 mg PQQ/kg diet). In mice from dams fed a conventional laboratory diet, but switched at weaning to the basal diet, plasma glucose, Ala, Gly, and Ser concentrations were elevated at 4 wk (PQQ- vs. PQQ+), but not at 8 wk. The relative mitochondrial content (ratio of mtDNA to nuclear DNA) also tended (P<0.18) to be lower (PQQ- vs. PQQ+) at 4 wk, but not at 8 wk. PQQ also counters the mitochondrial complex 1 ...

The Journal of Nutritional Biochemistry, 2013

Biochemical Journal, 2010

PQQ (pyrroloquinoline quinone) improves energy utilization and reproductive performance when adde... more PQQ (pyrroloquinoline quinone) improves energy utilization and reproductive performance when added to rodent diets devoid of PQQ. In the present paper we describe changes in gene expression patterns and transcriptional networks that respond to dietary PQQ restriction or pharmacological administration. Rats were fed diets either deficient in PQQ (PQQ−) or supplemented with PQQ (approx. 6 nmol of PQQ/g of food; PQQ+). In addition, groups of rats were either repleted by administering PQQ to PQQ− rats (1.5 mg of PQQ intraperitoneal/kg of body weight at 12 h intervals for 36 h; PQQ−/+) or partially depleted by feeding the PQQ− diet to PQQ+ rats for 48 h (PQQ+/−). RNA extracted from liver and a Codelink® UniSet Rat I Bioarray system were used to assess gene transcript expression. Of the approx. 10000 rat sequences and control probes analysed, 238 were altered at the P<0.01 level by feeding on the PQQ− diet for 10 weeks. Short-term PQQ depletion resulted in changes in 438 transcripts (P...

American Journal of Physiology. Endocrinology and Metabolism, 2001

Destabilization of TNF-␣ mRNA by retinoic acid in hepatic macrophages: implications for alcoholic... more Destabilization of TNF-␣ mRNA by retinoic acid in hepatic macrophages: implications for alcoholic liver disease. Am J Physiol Endocrinol Metab 281: E420-E429, 2001.-Retinoic acid (RA) inhibits hepatic macrophage (HM) cytokine expression, and retinoids are depleted in alcoholic liver disease (ALD). However, neither the causal link between the two nor the mechanism underlying RA-mediated HM inhibition is known. The aim of the present study was to determine the mechanism of RA-induced inhibition of HM tumor necrosis factor (TNF)-␣ expression and the relevance of this regulation to ALD. Treatment with all-trans RA (500 nM) caused a 50% inhibition in lipopolysaccharide (LPS)-stimulated TNF-␣ expression by cultured normal rat HM. The mRNA levels for inducible nitric oxide synthase, interleukin (IL)-6, IL-1␣, and IL-1␤ were also reduced, whereas those for transforming growth factor-␤1, MMP-9, and membrane cofactor protein-1 were unaffected. The inhibitory effect on TNF-␣ expression was reproduced by LG268, a retinoid X receptor (RXR)-specific ligand, but not by TTNPB, an RA receptor (RAR)-specific ligand. RA did not alter LPS-stimulated NF-kB and activation protein-1 binding but significantly decreased TNF-␣ mRNA stability in HM. HM isolated from the ALD model showed significant decreases in all-trans RA (Ϫ48%) and 9-cis RA (Ϫ61%) contents, RA response element (RARE) binding, and mRNA levels for RAR␤, RXR␣, and cytosolic retinol binding protein-1, whereas TNF-␣ mRNA expression was induced. TNF-␣ mRNA stability was increased in these cells, and an ex vivo treatment with all-trans RA normalized both RAR␤ and TNF-␣ mRNA levels. These results demonstrate the RA-induced destabilization of TNF-␣ mRNA by cultured HM and the association of RA depletion with increased TNF-␣ mRNA stability in HM from experimental ALD. These findings suggest that RA depletion primes HM for proinflammatory cytokine expression in ALD, at least in part, via posttranscriptional regulation. Kupffer cells; tumor necrosis factor-␣ mRNA stability; retinoic acid receptors; retinoid X receptors; retinoic acid response element TUMOR NECROSIS FACTOR (TNF)-␣ is a pleiotropic cytokine with diverse biological effects on all mammalian cells.

The FASEB Journal, 2007

Pyrroloquinoline quinone (PQQ) added to purified diets devoid of PQQ improves indices of perinata... more Pyrroloquinoline quinone (PQQ) added to purified diets devoid of PQQ improves indices of perinatal development in rats and mice. Herein, PQQ nutritional status and lysine metabolism are described, prompted by a report that PQQ functions as a vitamin-like enzymatic cofactor important in lysine metabolism (Nature 422 [2003] 832). Alternatively, we propose that PQQ influences lysine metabolism, but by mechanisms that more likely involve changes in mitochondrial content. PQQ deprivation in both rats and mice resulted in a decrease in mitochondrial content. In rats, α-aminoadipic acid (αAA), which is derived from α-aminoadipic semialdehyde (αAAS) and made from lysine in mitochondria, and the plasma levels of amino acids known to be oxidized in mitochondria (e.g., Thr, Ser, and Gly) were correlated with changes in the liver mitochondrial content of PQQ-deprived rats, but not PQQ-supplemented rats. In contrast, the levels of NAD dependent α-aminoadipate-δsemialdehyde dehydrogenase (AASDH), a cytosolic enzyme important to αAA production from αAAS, was not influenced by PQQ dietary status. Moreover, the levels of U26 mRNA were not significantly changed even when diets differed markedly in PQQ and dietary lysine content. U26 mRNA levels were measured, because of U26's proposed, albeit questionable role as a PQQ-dependent enzyme involved in αAA formation.

When pyrroloquinoline quinone (PQQ) is added to an amino acid-based, but otherwise nutritionally ... more When pyrroloquinoline quinone (PQQ) is added to an amino acid-based, but otherwise nutritionally complete basal diet, it improves growth-related variables in young mice. We examined PQQ and mitochondrial function based on observations that PQQ deficiency results in elevated plasma glucose concentrations in young mice, and PQQ addition stimulates mitochondrial complex 1 activity in vitro. PQQ-deficient weanling mice had a 20– 30% reduction in the relative amount of mitochondria in liver; lower respiratory control ratios, and lower respiratory quotients than PQQ-supplemented mice (2 mg PQQ/kg diet). In mice from dams fed a conventional laboratory diet, but switched at weaning to the basal diet, plasma glucose, Ala, Gly, and Ser concentrations were elevated at 4 wk (PQQ vs. PQQ1), but not at 8 wk. The relative mitochondrial content (ratio of mtDNA to nuclear DNA) also tended (P , 0.18) to be lower (PQQ vs. PQQ1) at 4 wk, but not at 8 wk. PQQ also counters the mitochondrial complex 1 in...

American Journal of Physiology-Endocrinology and Metabolism

Retinoic acid (RA) inhibits hepatic macrophage (HM) cytokine expression, and retinoids are deplet... more Retinoic acid (RA) inhibits hepatic macrophage (HM) cytokine expression, and retinoids are depleted in alcoholic liver disease (ALD). However, neither the causal link between the two nor the mechanism underlying RA-mediated HM inhibition is known. The aim of the present study was to determine the mechanism of RA-induced inhibition of HM tumor necrosis factor (TNF)-α expression and the relevance of this regulation to ALD. Treatment with all- trans RA (500 nM) caused a 50% inhibition in lipopolysaccharide (LPS)-stimulated TNF-α expression by cultured normal rat HM. The mRNA levels for inducible nitric oxide synthase, interleukin (IL)-6, IL-1α, and IL-1β were also reduced, whereas those for transforming growth factor-β1, MMP-9, and membrane cofactor protein-1 were unaffected. The inhibitory effect on TNF-α expression was reproduced by LG268, a retinoid X receptor (RXR)-specific ligand, but not by TTNPB, an RA receptor (RAR)-specific ligand. RA did not alter LPS-stimulated NF-kB and act...

Developmental Biology, Jun 30, 1989

Retinoic acid, an endogenous metabolite of vitamin A (retinol), possesses striking biological act... more Retinoic acid, an endogenous metabolite of vitamin A (retinol), possesses striking biological activity akin to a morphogen in developing and regenerating vertebrate limbs. Systemic administration of retinoic acid (RA) to pregnant mammals during the period of limb organogenesis invariably results in dose-dependent dysmorphogenesis. In an attempt to uncover the mode of action of RA in the developing limb bud we analyzed, by HPLC methods, the levels of RA and its metabolic precursor, retinol, in embryonic mouse tissues prior to and following maternal exposure to a teratogenic dose of RA. Detectable levels of both RA and its isomer 13-cis-retinoic acid were found in the limb buds of Day 11 mouse embryos (40 +/- 2 somites). Although retinol was the major retinoid found in ethanolic extracts of either whole embryo or the limb buds, the latter is enriched in RA compared to the whole embryo. This indicated either a higher degree of retinol metabolism or a sequestration of RA in the limb bud compared to the rest of the embryo at this stage of development. A study of the time course of retinoid levels in treated embryos showed that changes occur rapidly, are stable for several hours, and then begin to return to pretreatment levels. After a maternal dose of 10 mg/kg RA, which resulted in a mild degree of limb anomalies, peak RA levels in the limb bud increased 50-fold over the endogenous level; a full 300-fold increase was found after a 100 mg/kg dose which results in 100% incidence of phocomelia. Interestingly, a dose-dependent depression in retinol levels was observed after RA treatment both in maternal plasma as well as the embryo. Studies are in progress to trace the intracellular disposition of both retinol and RA as well as any further active metabolite of RA in the limb buds and other embryonic tissues.

The Faseb Journal, Mar 1, 2006

The Faseb Journal, Apr 1, 2010

American Journal of Physiology-gastrointestinal and Liver Physiology, Mar 1, 1997

Hepatic stellate cells (HSC) participate in liver fibrogenesis via myofibroblastic activation, th... more Hepatic stellate cells (HSC) participate in liver fibrogenesis via myofibroblastic activation, the extent of which appears to correlate with the loss of cellular vitamin A. The present study has tested a hypothesis that HSC activation is associated with diminished retinoic acid (RA) signaling. Pure HSC were isolated from rats with cholestatic liver fibrosis induced by bile duct ligation (BDL) and sham-operated animals (Sham). Northern blot analysis of HSC RNA from BDL confirmed fibrogenic activation of the cells with enhanced mRNA levels for procollagen-alpha1(I) and transforming growth factor-beta1 (TGF-beta1). Competitive polymerase chain reaction analysis showed selective reductions in the mRNA levels of RA receptor (RAR)-beta and retinoid X receptor (RXR)-alpha to 20 and 17% of the Sham HSC. The mRNA level for cellular retinol binding protein I, a gene with RA responsive element (RARE), was also suppressed by 78% in BDL. The concentrations of all-trans-RA and 9-cis-RA were decreased in HSC from BDL. Nuclear extracts of these cells showed diminished binding activity to the RARE, whereas activity of AP-1, a transcription factor known to be antagonized by RAR and RXR, was enhanced. These results demonstrate diminished RA signaling in HSC from cholestatic liver fibrosis, which appeared to have resulted from RA deficiency and suppressed expression of RAR-beta and RXR-alpha. Furthermore, the reciprocal enhancement of AP-1 activity and coordinately increased expression of an AP-1 responsive gene, TGF-beta1, suggest a permissive role of the diminished RA signaling in promoting AP-1 activity and TGF-beta1 expression.

Journal of Biological Chemistry, Jun 1, 1994

A novel human alcohol dehydrogenase (ADH) gene called ADH7 has been characterized and determined ... more A novel human alcohol dehydrogenase (ADH) gene called ADH7 has been characterized and determined to encode class IV ADH, an ADH isozyme which is very active as a retinol dehydrogenase. A nearly full-length cDNA for ADH7 was isolated from a human stomach cDNA library, and a 5' genomic clone containing exons 1 and 2 was isolated from a human genomic library. DNA sequence analysis of the cDNA and genomic clones revealed the complete coding region of the gene and the deduced full-length amino acid sequence of human class * This work was supported in part by National Institutes of Health Grant AA07261 and a grant from the Alcoholic Beverage Medical Research Foundation (to G. D). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "aduertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The nucleotide sequence(s) reported in this paper has been submitted to the GenBankmIEMBL Data Bank with accession numbeds) U07821.

Journal of Biological Chemistry, Mar 1, 1994

This is an Open Access article under the CC BY license. ADH3 Promoter Activity in Dansgenic Mouse... more This is an Open Access article under the CC BY license. ADH3 Promoter Activity in Dansgenic Mouse Embryos Characteristics of ADH3-lacZ transgenic founder embryos and TABLE I progeny Founder Passage Embryonic expression name to progeny characteristics 1144 1151' No Not applicable No Not applicable 1156 Yes Observed from 9.5 d.p.c. onward; expression in neural tube, limb buds, heart, kidney, eye, ear, craniofacial region in neural tube, limb buds, heart, kidney, eye, ear, craniofacial region highest in limb buds, but also in neural tube, kidney, eye, ear, craniofacial region 1162 Yes Observed from 9.5 d.p.c. onward; expression 1172 Yes Observed from 11.5 d.p.c. onward; expression

Journal of Biological Chemistry, 2001

Multiple retinoic acid responsive cDNAs were isolated from a high density cDNA microarray membran... more Multiple retinoic acid responsive cDNAs were isolated from a high density cDNA microarray membrane, which was developed from a cDNA library of human tracheobronchial epithelial cells. Five selected cDNA clones encoded the sequence of the same novel gene. The predicted open reading frame of the novel gene encoded a protein of 319 amino acids. The deduced amino acid sequence contains four motifs that are conserved in the short-chain alcohol dehydrogenase/reductase (SDR) family of proteins. The novel gene shows the greatest homology to a group of dehydrogenases that can oxidize retinol (retinol dehydrogenases). The mRNA of the novel gene was found in trachea, colon, tongue, and esophagus. In situ hybridization of airway tissue sections demonstrated epithelial cell-specific gene expression, especially in the ciliated cell type. Both all-trans-retinoic acid and 9-cis-retinoic acid were able to elevate the expression of the novel gene in primary human tracheobronchial epithelial cells in vitro. This elevation coincided with an enhanced retinol metabolism in these cultures. COS cells transfected with an expression construct of the novel gene were also elevated in the metabolism of retinol. The results suggested that the novel gene represents a new member of the SDR family that may play a critical role in retinol metabolism in airway epithelia as well as in other epithelia of colon, tongue, and esophagus.

The Journal of nutrition, 2006

When pyrroloquinoline quinone (PQQ) is added to an amino acid-based, but otherwise nutritionally ... more When pyrroloquinoline quinone (PQQ) is added to an amino acid-based, but otherwise nutritionally complete basal diet, it improves growth-related variables in young mice. We examined PQQ and mitochondrial function based on observations that PQQ deficiency results in elevated plasma glucose concentrations in young mice, and PQQ addition stimulates mitochondrial complex 1 activity in vitro. PQQ-deficient weanling mice had a 20-30% reduction in the relative amount of mitochondria in liver; lower respiratory control ratios, and lower respiratory quotients than PQQ-supplemented mice (2 mg PQQ/kg diet). In mice from dams fed a conventional laboratory diet, but switched at weaning to the basal diet, plasma glucose, Ala, Gly, and Ser concentrations were elevated at 4 wk (PQQ- vs. PQQ+), but not at 8 wk. The relative mitochondrial content (ratio of mtDNA to nuclear DNA) also tended (P<0.18) to be lower (PQQ- vs. PQQ+) at 4 wk, but not at 8 wk. PQQ also counters the mitochondrial complex 1 ...

The Journal of Nutritional Biochemistry, 2013

Biochemical Journal, 2010

PQQ (pyrroloquinoline quinone) improves energy utilization and reproductive performance when adde... more PQQ (pyrroloquinoline quinone) improves energy utilization and reproductive performance when added to rodent diets devoid of PQQ. In the present paper we describe changes in gene expression patterns and transcriptional networks that respond to dietary PQQ restriction or pharmacological administration. Rats were fed diets either deficient in PQQ (PQQ−) or supplemented with PQQ (approx. 6 nmol of PQQ/g of food; PQQ+). In addition, groups of rats were either repleted by administering PQQ to PQQ− rats (1.5 mg of PQQ intraperitoneal/kg of body weight at 12 h intervals for 36 h; PQQ−/+) or partially depleted by feeding the PQQ− diet to PQQ+ rats for 48 h (PQQ+/−). RNA extracted from liver and a Codelink® UniSet Rat I Bioarray system were used to assess gene transcript expression. Of the approx. 10000 rat sequences and control probes analysed, 238 were altered at the P<0.01 level by feeding on the PQQ− diet for 10 weeks. Short-term PQQ depletion resulted in changes in 438 transcripts (P...

American Journal of Physiology. Endocrinology and Metabolism, 2001

Destabilization of TNF-␣ mRNA by retinoic acid in hepatic macrophages: implications for alcoholic... more Destabilization of TNF-␣ mRNA by retinoic acid in hepatic macrophages: implications for alcoholic liver disease. Am J Physiol Endocrinol Metab 281: E420-E429, 2001.-Retinoic acid (RA) inhibits hepatic macrophage (HM) cytokine expression, and retinoids are depleted in alcoholic liver disease (ALD). However, neither the causal link between the two nor the mechanism underlying RA-mediated HM inhibition is known. The aim of the present study was to determine the mechanism of RA-induced inhibition of HM tumor necrosis factor (TNF)-␣ expression and the relevance of this regulation to ALD. Treatment with all-trans RA (500 nM) caused a 50% inhibition in lipopolysaccharide (LPS)-stimulated TNF-␣ expression by cultured normal rat HM. The mRNA levels for inducible nitric oxide synthase, interleukin (IL)-6, IL-1␣, and IL-1␤ were also reduced, whereas those for transforming growth factor-␤1, MMP-9, and membrane cofactor protein-1 were unaffected. The inhibitory effect on TNF-␣ expression was reproduced by LG268, a retinoid X receptor (RXR)-specific ligand, but not by TTNPB, an RA receptor (RAR)-specific ligand. RA did not alter LPS-stimulated NF-kB and activation protein-1 binding but significantly decreased TNF-␣ mRNA stability in HM. HM isolated from the ALD model showed significant decreases in all-trans RA (Ϫ48%) and 9-cis RA (Ϫ61%) contents, RA response element (RARE) binding, and mRNA levels for RAR␤, RXR␣, and cytosolic retinol binding protein-1, whereas TNF-␣ mRNA expression was induced. TNF-␣ mRNA stability was increased in these cells, and an ex vivo treatment with all-trans RA normalized both RAR␤ and TNF-␣ mRNA levels. These results demonstrate the RA-induced destabilization of TNF-␣ mRNA by cultured HM and the association of RA depletion with increased TNF-␣ mRNA stability in HM from experimental ALD. These findings suggest that RA depletion primes HM for proinflammatory cytokine expression in ALD, at least in part, via posttranscriptional regulation. Kupffer cells; tumor necrosis factor-␣ mRNA stability; retinoic acid receptors; retinoid X receptors; retinoic acid response element TUMOR NECROSIS FACTOR (TNF)-␣ is a pleiotropic cytokine with diverse biological effects on all mammalian cells.

The FASEB Journal, 2007

Pyrroloquinoline quinone (PQQ) added to purified diets devoid of PQQ improves indices of perinata... more Pyrroloquinoline quinone (PQQ) added to purified diets devoid of PQQ improves indices of perinatal development in rats and mice. Herein, PQQ nutritional status and lysine metabolism are described, prompted by a report that PQQ functions as a vitamin-like enzymatic cofactor important in lysine metabolism (Nature 422 [2003] 832). Alternatively, we propose that PQQ influences lysine metabolism, but by mechanisms that more likely involve changes in mitochondrial content. PQQ deprivation in both rats and mice resulted in a decrease in mitochondrial content. In rats, α-aminoadipic acid (αAA), which is derived from α-aminoadipic semialdehyde (αAAS) and made from lysine in mitochondria, and the plasma levels of amino acids known to be oxidized in mitochondria (e.g., Thr, Ser, and Gly) were correlated with changes in the liver mitochondrial content of PQQ-deprived rats, but not PQQ-supplemented rats. In contrast, the levels of NAD dependent α-aminoadipate-δsemialdehyde dehydrogenase (AASDH), a cytosolic enzyme important to αAA production from αAAS, was not influenced by PQQ dietary status. Moreover, the levels of U26 mRNA were not significantly changed even when diets differed markedly in PQQ and dietary lysine content. U26 mRNA levels were measured, because of U26's proposed, albeit questionable role as a PQQ-dependent enzyme involved in αAA formation.

When pyrroloquinoline quinone (PQQ) is added to an amino acid-based, but otherwise nutritionally ... more When pyrroloquinoline quinone (PQQ) is added to an amino acid-based, but otherwise nutritionally complete basal diet, it improves growth-related variables in young mice. We examined PQQ and mitochondrial function based on observations that PQQ deficiency results in elevated plasma glucose concentrations in young mice, and PQQ addition stimulates mitochondrial complex 1 activity in vitro. PQQ-deficient weanling mice had a 20– 30% reduction in the relative amount of mitochondria in liver; lower respiratory control ratios, and lower respiratory quotients than PQQ-supplemented mice (2 mg PQQ/kg diet). In mice from dams fed a conventional laboratory diet, but switched at weaning to the basal diet, plasma glucose, Ala, Gly, and Ser concentrations were elevated at 4 wk (PQQ vs. PQQ1), but not at 8 wk. The relative mitochondrial content (ratio of mtDNA to nuclear DNA) also tended (P , 0.18) to be lower (PQQ vs. PQQ1) at 4 wk, but not at 8 wk. PQQ also counters the mitochondrial complex 1 in...

American Journal of Physiology-Endocrinology and Metabolism

Retinoic acid (RA) inhibits hepatic macrophage (HM) cytokine expression, and retinoids are deplet... more Retinoic acid (RA) inhibits hepatic macrophage (HM) cytokine expression, and retinoids are depleted in alcoholic liver disease (ALD). However, neither the causal link between the two nor the mechanism underlying RA-mediated HM inhibition is known. The aim of the present study was to determine the mechanism of RA-induced inhibition of HM tumor necrosis factor (TNF)-α expression and the relevance of this regulation to ALD. Treatment with all- trans RA (500 nM) caused a 50% inhibition in lipopolysaccharide (LPS)-stimulated TNF-α expression by cultured normal rat HM. The mRNA levels for inducible nitric oxide synthase, interleukin (IL)-6, IL-1α, and IL-1β were also reduced, whereas those for transforming growth factor-β1, MMP-9, and membrane cofactor protein-1 were unaffected. The inhibitory effect on TNF-α expression was reproduced by LG268, a retinoid X receptor (RXR)-specific ligand, but not by TTNPB, an RA receptor (RAR)-specific ligand. RA did not alter LPS-stimulated NF-kB and act...

Developmental Biology, Jun 30, 1989

Retinoic acid, an endogenous metabolite of vitamin A (retinol), possesses striking biological act... more Retinoic acid, an endogenous metabolite of vitamin A (retinol), possesses striking biological activity akin to a morphogen in developing and regenerating vertebrate limbs. Systemic administration of retinoic acid (RA) to pregnant mammals during the period of limb organogenesis invariably results in dose-dependent dysmorphogenesis. In an attempt to uncover the mode of action of RA in the developing limb bud we analyzed, by HPLC methods, the levels of RA and its metabolic precursor, retinol, in embryonic mouse tissues prior to and following maternal exposure to a teratogenic dose of RA. Detectable levels of both RA and its isomer 13-cis-retinoic acid were found in the limb buds of Day 11 mouse embryos (40 +/- 2 somites). Although retinol was the major retinoid found in ethanolic extracts of either whole embryo or the limb buds, the latter is enriched in RA compared to the whole embryo. This indicated either a higher degree of retinol metabolism or a sequestration of RA in the limb bud compared to the rest of the embryo at this stage of development. A study of the time course of retinoid levels in treated embryos showed that changes occur rapidly, are stable for several hours, and then begin to return to pretreatment levels. After a maternal dose of 10 mg/kg RA, which resulted in a mild degree of limb anomalies, peak RA levels in the limb bud increased 50-fold over the endogenous level; a full 300-fold increase was found after a 100 mg/kg dose which results in 100% incidence of phocomelia. Interestingly, a dose-dependent depression in retinol levels was observed after RA treatment both in maternal plasma as well as the embryo. Studies are in progress to trace the intracellular disposition of both retinol and RA as well as any further active metabolite of RA in the limb buds and other embryonic tissues.

The Faseb Journal, Mar 1, 2006

The Faseb Journal, Apr 1, 2010