Acyl-CoAs are functionally channeled in liver: potential role of acyl-CoA synthetase

2000 ◽  
Vol 279 (6) ◽  
pp. E1366-E1373 ◽  
Author(s):  
Deborah M. Muoio ◽  
Tal M. Lewin ◽  
Petra Wiedmer ◽  
Rosalind A. Coleman
Keyword(s):  
Metabolic Pathways ◽  
Potential Role ◽  
De Novo ◽  
Specific Activity ◽  
Liver Microsomes ◽  
Rat Hepatocytes ◽  
Long Chain Fatty Acids ◽  
Intracellular Lipid ◽  
Triacsin C

Acyl-CoA synthetase (ACS) catalyzes the activation of long-chain fatty acids to acyl-CoAs, which can be metabolized to form CO2, triacylglycerol (TAG), phospholipids (PL), and cholesteryl esters (CE). To determine whether inhibiting ACS affects these pathways differently, we incubated rat hepatocytes with [14C]oleate and the ACS inhibitor triacsin C. Triacsin inhibited TAG synthesis 70% in hepatocytes from fed rats and 40% in starved rats, but it had little effect on oleate incorporation into CE, PL, or β-oxidation end products. Triacsin blocked [3H]glycerol incorporation into TAG and PL 33 and 25% more than it blocked [14C]oleate incorporation, suggesting greater inhibition of de novo TAG synthesis than reacylation. Triacsin did not affect oxidation of prelabeled intracellular lipid. ACS1 protein was abundant in liver microsomes but virtually undetectable in mitochondria. Refeeding increased microsomal ACS1 protein 89% but did not affect specific activity. Triacsin inhibited ACS specific activity in microsomes more from fed than from starved rats. These data suggest that ACS isozymes may be functionally linked to specific metabolic pathways and that ACS1 is not associated with β-oxidation in liver.

The Incorporation of [4-14C] δ-Aminolaevulic Acid into Urinary Porphyrins in Symptomatic Porphyria

1970 ◽  
Vol 39 (2) ◽  
pp. 159-168 ◽  
Author(s):  
P. Goldswain ◽  
E. Dowdle ◽  
Norma Spong ◽  
L. Eales
Keyword(s):  
Oral Dose ◽  
Control Subject ◽  
Single Oral Dose ◽  
Metabolic Pathways ◽  
Specific Activity ◽  
Specific Activities ◽  
Urinary Porphyrins

1. The specific activities of urinary uroporphyrin and coproporphyrin were measured as functions of time following the administration of a single oral dose of [4-14C] δ-aminolaevulic acid (ALA) to six patients with symptomatic porphyria and one control subject. 2. The peak specific activity of coproporphyrin preceded that of uroporphyrin in all subjects studied and exceeded that of uroporphyrin in the patients with symptomatic porphyria. 3. These results are interpreted as indicating the existence of two distinct metabolic pathways in the liver for the disposal of ALA, rather than as contradicting the generally accepted role of uroporphyrinogen as a precursor of coproporphyrinogen.

Glucose metabolism in the lactating beagle dog

1962 ◽  
Vol 202 (2) ◽  
pp. 329-333 ◽  
Author(s):  
Jack R. Luick ◽  
Arthur L. Black ◽  
Harold R. Parker ◽  
Mogens G. Simesen
Keyword(s):  
Plasma Glucose ◽  
Metabolic Pathways ◽  
Milk Fat ◽  
Specific Activity ◽  
Energy Requirement ◽  
Similar Data ◽  
Lactating Cows ◽  
Diabetic Dog ◽  
Oxidation Of Glucose

A study was made of the role of glucose as an oxidizable substrate and as a source of C for the synthesis of milk using lactating beagle dogs. Uniformly C14-labeled glucose was used as a tracer of these metabolic pathways. Our data indicate that the labeled glucose was completely eliminated from the dog's body within 24 hr after injection. Sixty percent of the injected dose appeared in the expired CO2, 40% in the various milk products. Comparison of the integrated specific activity of plasma glucose with that of expired CO2 indicates that 36% of the dog's energy requirement is met by the oxidation of glucose. This presumably means that the catabolism of noncarbohydrate substances must be of considerable importance to the energy metabolism of not only the fasted dog and the diabetic dog, as has been demonstrated earlier, but also of the fed dog. We have also shown that 68–100% of the C required for the synthesis of lactose is derived from plasma glucose. In addition, plasma glucose contributes 7.2–12% of milk protein C and 5.1–8.7% of milk fat C. These results are compared with similar data obtained earlier in our laboratory using lactating cows and sows.

scholarly journals SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP

2016 ◽  
Vol 113 (38) ◽  
pp. E5685-E5693 ◽  
Author(s):  
Masami Shimizu-Albergine ◽  
Brian Van Yserloo ◽  
Martin G. Golkowski ◽  
Shao-En Ong ◽  
Joseph A. Beavo ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Leydig Cells ◽  
De Novo ◽  
Regulatory Element ◽  
De Novo Synthesis ◽  
Intracellular Lipid ◽  
Element Binding Protein ◽  
Short Palindromic Repeat ◽  
Sterol Regulatory Element

Luteinizing hormone (LH) stimulates steroidogenesis largely through a surge in cyclic AMP (cAMP). Steroidogenic rates are also critically dependent on the availability of cholesterol at mitochondrial sites of synthesis. This cholesterol is provided by cellular uptake of lipoproteins, mobilization of intracellular lipid, and de novo synthesis. Whether and how these pathways are coordinated by cAMP are poorly understood. Recent phosphoproteomic analyses of cAMP-dependent phosphorylation sites in MA10 Leydig cells suggested that cAMP regulates multiple steps in these processes, including activation of the SCAP/SREBP pathway. SCAP [sterol-regulatory element-binding protein (SREBP) cleavage-activating protein] acts as a cholesterol sensor responsible for regulating intracellular cholesterol balance. Its role in cAMP-mediated control of steroidogenesis has not been explored. We used two CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 (CRISPR associated protein 9) knockout approaches to test the role of SCAP in steroidogenesis. Our results demonstrate that SCAP is required for progesterone production induced by concurrent inhibition of the cAMP phosphodiesterases PDE4 and PDE8. These inhibitors increased SCAP phosphorylation, SREBP2 activation, and subsequent expression of cholesterol biosynthetic genes, whereas SCAP deficiency largely prevented these effects. Reexpression of SCAP in SCAP-deficient cells restored SREBP2 protein expression and partially restored steroidogenic responses, confirming the requirement of SCAP–SREBP2 in steroidogenesis. Inhibitors of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase and isoprenylation attenuated, whereas exogenously provided cholesterol augmented, PDE inhibitor-induced steroidogenesis, suggesting that the cholesterol substrate needed for steroidogenesis is provided by both de novo synthesis and isoprenylation-dependent mechanisms. Overall, these results demonstrate a novel role for LH/cAMP in SCAP/SREBP activation and subsequent regulation of steroidogenesis.

scholarly journals Cell-autonomous role of TGFβ and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD

Blood ◽  
2012 ◽  
Vol 119 (23) ◽  
pp. 5575-5583 ◽  
Author(s):  
Norifumi Sawamukai ◽  
Atsushi Satake ◽  
Amanda M. Schmidt ◽  
Ian T. Lamborn ◽  
Priti Ojha ◽  
...  
Keyword(s):  
T Cells ◽  
Potential Role ◽  
Acute Gvhd ◽  
De Novo ◽  
Receptor Expression ◽  
Tgfβ Receptor ◽  
Bona Fide ◽  
Deficient Mice ◽  
Transplantation Recipient

Abstract FoxP3+ regulatory T cells (Tregs) suppress GVHD while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from the expansion of preexisting natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplantation recipient. Using an MHC-mismatched model of acute GVHD, in the present study we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wild-type and FoxP3-deficient mice suggested that both preexisting donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8+FoxP3+ T cells represented approximately 70% of the iTreg pool. These CD8+FoxP3+ T cells shared phenotypic markers with their CD4+ counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4+ and CD8+ Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFβ receptor expression for their generation. These data illustrate the complex makeup of the donor-derived FoxP3+ Treg pool in allogeneic recipients and their potential role in protection against GVHD.

scholarly journals Modulation of the hepatic malonyl-CoA–carnitine palmitoyltransferase 1A partnership creates a metabolic switch allowing oxidation of de novo fatty acids1

2009 ◽  
Vol 420 (3) ◽  
pp. 429-438 ◽  
Author(s):  
Marie Akkaoui ◽  
Isabelle Cohen ◽  
Catherine Esnous ◽  
Véronique Lenoir ◽  
Martin Sournac ◽  
...  
Keyword(s):  
De Novo ◽  
Glycogen Synthesis ◽  
Rat Hepatocytes ◽  
Carnitine Palmitoyltransferase ◽  
Long Chain Fatty Acids ◽  
Metabolic Switch ◽  
Triglyceride Accumulation ◽  
Malonyl Coa ◽  
Triacylglycerol Accumulation ◽  
Prime Target

Liver mitochondrial β-oxidation of LCFAs (long-chain fatty acids) is tightly regulated through inhibition of CPT1A (carnitine palmitoyltransferase 1A) by malonyl-CoA, an intermediate of lipogenesis stimulated by glucose and insulin. Moreover, CPT1A sensitivity to malonyl-CoA inhibition varies markedly depending on the physiopathological state of the animal. In the present study, we asked whether an increase in CPT1A activity solely or in association with a decreased malonyl-CoA sensitivity could, even in the presence of high glucose and insulin concentrations, maintain a sustained LCFA β-oxidation and/or protect from triacylglycerol (triglyceride) accumulation in hepatocytes. We have shown that adenovirus-mediated expression of rat CPT1wt (wild-type CPT1A) and malonyl-CoA-insensitive CPT1mt (CPT1AM593S mutant) in cultured fed rat hepatocytes counteracted the inhibition of oleate β-oxidation induced by 20 mM glucose/10 nM insulin. Interestingly, the glucose/insulin-induced cellular triacylglycerol accumulation was prevented, both in the presence and absence of exogenous oleate. This resulted from the generation of a metabolic switch allowing β-oxidation of de novo synthesized LCFAs, which occurred without alteration in glucose oxidation and glycogen synthesis. Moreover, CPT1mt expression was more effective than CPT1wt overexpression to counteract glucose/insulin effects, demonstrating that control of CPT1A activity by malonyl-CoA is an essential driving force for hepatic LCFA metabolic fate. In conclusion, the present study highlights that CPT1A is a prime target to increase hepatic LCFA β-oxidation and that acting directly on the degree of its malonyl-CoA sensitivity may be a relevant strategy to prevent and/or correct hepatic steatosis.

scholarly journals The Role of DJ-1 in Cellular Metabolism and Pathophysiological Implications for Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 347
Author(s):  
Pauline Mencke ◽  
Ibrahim Boussaad ◽  
Chiara D. Romano ◽  
Toshimori Kitami ◽  
Carole L. Linster ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Chronic Diseases ◽  
Metabolic Pathways ◽  
Potential Role ◽  
Current Knowledge ◽  
Cellular Metabolism ◽  
Metabolic Effects ◽  
Physiological Functions ◽  
Multifunctional Protein

DJ-1 is a multifunctional protein associated with pathomechanisms implicated in different chronic diseases including neurodegeneration, cancer and diabetes. Several of the physiological functions of DJ-1 are not yet fully understood; however, in the last years, there has been increasing evidence for a potential role of DJ-1 in the regulation of cellular metabolism. Here, we summarize the current knowledge on specific functions of DJ-1 relevant to cellular metabolism and their role in modulating metabolic pathways. Further, we illustrate pathophysiological implications of the metabolic effects of DJ-1 in the context of neurodegeneration in Parkinson´s disease.

scholarly journals Serine and one-carbon metabolisms bring new therapeutic venues in prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Carlo Ganini ◽  
Ivano Amelio ◽  
Riccardo Bertolo ◽  
Eleonora Candi ◽  
Angela Cappello ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Carbon Metabolism ◽  
Potential Role ◽  
De Novo ◽  
Cancer Pathogenesis ◽  
Gene And Protein Expression ◽  
Serine Pathway ◽  
One Carbon Metabolism ◽  
Serine Metabolism

AbstractSerine and one-carbon unit metabolisms are essential biochemical pathways implicated in fundamental cellular functions such as proliferation, biosynthesis of important anabolic precursors and in general for the availability of methyl groups. These two distinct but interacting pathways are now becoming crucial in cancer, the de novo cytosolic serine pathway and the mitochondrial one-carbon metabolism. Apart from their role in physiological conditions, such as epithelial proliferation, the serine metabolism alterations are associated to several highly neoplastic proliferative pathologies. Accordingly, prostate cancer shows a deep rearrangement of its metabolism, driven by the dependency from the androgenic stimulus. Several new experimental evidence describes the role of a few of the enzymes involved in the serine metabolism in prostate cancer pathogenesis. The aim of this study is to analyze gene and protein expression data publicly available from large cancer specimens dataset, in order to further dissect the potential role of the abovementioned metabolism in the complex reshaping of the anabolic environment in this kind of neoplasm. The data suggest a potential role as biomarkers as well as in cancer therapy for the genes (and enzymes) belonging to the one-carbon metabolism in the context of prostatic cancer.

Evidence for cAMP as a mediator of gonadotropin secretion from male pituitaries

1987 ◽  
Vol 253 (3) ◽  
pp. E296-E299
Author(s):  
G. A. Bourne ◽  
D. M. Baldwin
Keyword(s):  
Protein Synthesis ◽  
Potential Role ◽  
De Novo ◽  
Follicle Stimulating Hormone ◽  
Gonadotropin Releasing Hormone ◽  
Dibutyryl Camp ◽  
Camp Production ◽  
Gonadotropin Secretion ◽  
De Novo Protein Synthesis

The purpose of this study was to use sodium flufenamate, a compound that inhibits gonadotropin-releasing hormone (GnRH)-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production in the pituitary, to evaluate the potential role of cAMP as a mediator of GnRH-stimulated gonadotropin secretion from male pituitaries. Quartered male pituitaries were perifused at 37 degrees C and sequential effluent fractions collected every 10 min. Infusions of GnRH resulted in a twofold increase in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Cycloheximide, 5 microM, completely inhibited the GnRH-stimulated LH and FSH secretion. Infusions of 0.1 mM flufenamate had similar effects on gonadotropin secretion as cycloheximide, whereas the administration of 5 mM dibutyryl cAMP in combination with GnRH and flufenamate restored the secretory responses of both hormones. The flufenamate-inhibited GnRH stimulated LH and FSH release, which was restored by DBcAMP and appeared to be protein synthesis dependent and specific for cAMP. These results suggest an indirect role for cAMP as a mediator of gonadotropin secretion from male pituitaries. However, in contrast to female pituitaries, the secretion of these hormones from male pituitaries is completely dependent on cAMP and de novo protein synthesis.

scholarly journals 3-Iodothyronamine and 3,5,3′-triiodo-L-thyronine reduce SIRT1 protein expression in the HepG2 cell line

2020 ◽  
Vol 41 (1) ◽  
Author(s):  
Ginevra Sacripanti ◽  
Leonardo Lorenzini ◽  
Lavinia Bandini ◽  
Sabina Frascarelli ◽  
Riccardo Zucchi ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Viability ◽  
Cell Line ◽  
Potential Role ◽  
Colorimetric Assay ◽  
Tumor Cell Line ◽  
Rat Hepatocytes ◽  
Carcinoma Cells ◽  
Primary Rat Hepatocytes

AbstractBackground3-Iodothyronamine (T1AM) is an endogenous messenger chemically related to thyroid hormone. Recent results indicate significant transcriptional effects of chronic T1AM administration involving the protein family of sirtuins, which regulate important metabolic pathways and tumor progression. Therefore, the aim of this work was to compare the effect of exogenous T1AM and 3,5,3′-triiodo-L-thyronine (T3) chronic treatment on mammalian sirtuin expression in hepatocellular carcinoma cells (HepG2) and in primary rat hepatocytes at micromolar concentrations.Materials and methodsSirtuin (SIRT) activity and expression were determined using a colorimetric assay and Western blot analysis, respectively, in cells treated for 24 h with 1–20 μM T1AM or T3. In addition, cell viability was evaluated by the MTTtest upon 24 h of treatment with 0.1–20 μM T1AM or T3.ResultsIn HepG2, T1AM significantly reduced SIRT 1 (20 μM) and SIRT4 (10–20 μM) protein expression, while T3 strongly decreased the expression of SIRT1 (20 μM) and SIRT2 (any tested concentration). In primary rat hepatocytes, T3 decreased SIRT2 expression and cellular nicotinamide adenine dinucleotide (NAD) concentration, while on sirtuin activity it showed opposite effects, depending on the evaluated cell fraction. The extent of MTT staining was moderately but significantly reduced by T1AM, particularly in HepG2 cells, whereas T3 reduced cell viability only in the tumor cell line.ConclusionsT1AM and T3 downregulated the expression of sirtuins, mainly SIRT1, in hepatocytes, albeit in different ways. Differences in mechanisms are only observational, and further investigations are required to highlight the potential role of T1AM and T3 in modulating sirtuin expression and, therefore, in regulating cell cycle or tumorigenesis.

Regulation of annexin I in adipogenesis: cAMP-independent action of methylisobutylxanthine

1992 ◽  
Vol 262 (1) ◽  
pp. C91-C97 ◽  
Author(s):  
W. T. Wong ◽  
H. S. Nick ◽  
S. C. Frost
Keyword(s):  
Adrenergic Receptor ◽  
Cellular Differentiation ◽  
Culture Medium ◽  
Potential Role ◽  
De Novo ◽  
Second Messengers ◽  
Annexin I ◽  
Intracellular Second Messengers ◽  
Camp And Cgmp

The differentiation of 3T3-L1 fibroblasts to adipocytes can be accelerated by the addition of 1-methyl-3-isobutylxanthine (MIX), insulin, and dexamethasone to the culture medium. During differentiation, we have demonstrated that the level of both annexin I mRNA and protein decreases. The half-times for this reduction were 2 h and 10 h for annexin I mRNA and protein, respectively. Of the added agents in the differentiation medium, only MIX caused a decline in annexin I expression in 3T3-L1 fibroblasts. The MIX effect in fibroblasts was reversible and required de novo transcription but not protein synthesis. Although MIX could be replaced by high levels of theophylline, neither agonists of the beta-adrenergic receptor nor intracellular second messengers, cAMP and cGMP, were able to reduce annexin I. The potential role of annexin I in cellular differentiation is discussed.

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