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At least 19 recordsLinked to original sources
PubMed2025

Targeting hepatocyte-specific SLC2A8 blocks hepatic steatosis and dissociates TCA cycle flux inhibition from glutamine anaplerosis.

BACKGROUND: Excess TCA cycle and glutamine anaplerosis are hallmarks of metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Blocking glutamine metabolism attenuates metabolic dysfunction-associated steatohepatitis. However, inhibiting TCA cycle flux by blocking plasma membrane carbohydrate transport is limited by the ubiquitous tissue distribution, function, and homology among the SLC2A family of facilitative carbohydrate transporters, and the potential for carbohydrate blockade to invoke or exacerbate glutamine anaplerosis. Here, we quantify alterations in hepatocyte carbon flux, define the broader metabolic consequences of hepatocyte-specific GLUT8/SLC2A8 inhibition, and delineate the antisteatotic efficacy of a novel small-molecule GLUT8-selective inhibitor. METHODS: We generated mice with floxed SLC2A8 alleles and expressed hepatocyte-specific Cre by breeding these mice with albumin-Cre transgenic mice, or by administering AAV8 encoding hepatocyte-specific iCre. We performed stable-isotope glucose, fructose, and glutamine metabolic labeling in isolated GLUT8WT and GLUT8LKO hepatocytes and performed metabolic phenotyping in lean and diet-induced obese GLUT8WT and GLUT8LKO mice. Finally, we performed high-throughput screening to identify a GLUT8-selective inhibitor, which we characterized using in vitro models of triglyceride accumulation. RESULTS: Hepatocyte-specific SLC2A8 deletion reduced diet-induced hepatic and peripheral fat accumulation and increased thermogenesis during ZT12-24 (eg, the dark phase). It also disrupted TCA cycle flux without inducing compensatory glutamine utilization. High-throughput screening identified a small-molecule, GLUT8-selective inhibitor, P20, which blocked hepatocyte TG accumulation and inflammation in in vitro steatotic and inflammatory models. CONCLUSIONS: Deleting the hepatocyte carbohydrate transporter GLUT8 suppresses TCA cycle flux without inducing compensatory glutamine anaplerosis. The net effect of this is liver protection against multiple forms of dietary insult. Given that selective pharmacological GLUT8 inhibition is feasible, GLUT8 may be a viable target to abate metabolic dysfunction-associated steatohepatitis and other complications of obesity.

Animals↗
PubMed1992

NMR determination of the TCA cycle rate and alpha-ketoglutarate/glutamate exchange rate in rat brain.

A mathematical model of cerebral glucose metabolism was developed to analyze the isotopic labeling of carbon atoms C4 and C3 of glutamate following an intravenous infusion of [1-13C]glucose. The model consists of a series of coupled metabolic pools representing glucose, glycolytic intermediates, tricarboxylic acid (TCA) cycle intermediates, glutamate, aspartate, and glutamine. Based on the rate of 13C isotopic labeling of glutamate C4 measured in a previous study, the TCA cycle rate in rat brain was determined to be 1.58 +/- 0.41 mumol min-1 g-1 (mean +/- SD, n = 5). Analysis of the difference between the rates of isotopic enrichment of glutamate C4 and C3 permitted the rate of exchange between alpha-ketoglutarate (alpha-KG) and glutamate to be assessed in vivo. In rat brain, the exchange rate between alpha-KG and glutamate is between 89 +/- 35 and 126 +/- 22 times faster than the TCA cycle rate (mean +/- SD, n = 4). The sensitivity of the calculated value of the TCA cycle rate to other metabolic fluxes and to concentrations of glycolytic and TCA cycle intermediates was tested and found to be small.

Animals↗
PubMed1992

Metabolism of [3-13C]pyruvate in TCA cycle mutants of yeast.

The utilization of pyruvate and acetate by Saccharomyces cerevisiae was examined using 13C and 1H NMR methodology in intact wild-type yeast cells and mutant yeast cells lacking Krebs tricarboxylic acid (TCA) cycle enzymes. These mutant cells lacked either mitochondrial (NAD) isocitrate dehydrogenase (NAD-ICDH1),alpha-ketoglutarate dehydrogenase complex (alpha KGDC), or mitochondrial malate dehydrogenase (MDH1). These mutant strains have the common phenotype of being unable to grow on acetate. [3-13C]-Pyruvate was utilized efficiently by wild-type yeast with the major intermediates being [13C]glutamate, [13C]acetate, and [13C]alanine. Deletion of any one of these Krebs TCA cycle enzymes changed the metabolic pattern such that the major synthetic product was [13C]galactose instead of [13C]glutamate, with some formation of [13C]acetate and [13C]alanine. The fact that glutamate formation did not occur readily in these mutants despite the metabolic capacity to synthesize glutamate from pyruvate is difficult to explain. We discuss the possibility that these data support the metabolon hypothesis of Krebs TCA cycle enzyme organization.

Acetates↗
PubMed2026

Exogenous lactate ameliorates Aβ-induced energy deficit and neurotoxicity with increased mitochondrial TCA cycle carbon flux in SH-SY5Y cells.

A growing body of evidence has demonstrated the existence of metabolic dysfunction in neurodegenerative diseases, including Alzheimer's disease (AD), suggesting that deprivation of energy substrates impairs cellular dynamics. As glucose utilization declines in patients with AD, the need for alternative energy sources becomes crucial to sustain neuronal activities and prevent cell death induced by neurotoxic proteins, such as amyloid beta (Aβ) aggregates. In this context, lactate has been investigated as a potential alternative brain energy substrate in several studies, yet its impact on neuronal cells under Aβ-induced toxicity remains unclear. We confirmed significant suppression of energy production-related biological pathways by analyzing brain transcriptomic data of patients with AD. In subsequent in vitro studies, exogenous lactate treatment ameliorated neuron-like cell death caused by Aβ aggregates. Using a 13C stable isotope tracer, we verified cellular lactate uptake and its incorporation into tricarboxylic acid (TCA) cycle in neurons under the neurotoxic condition. 13C metabolic flux analysis further supported these findings by revealing that lactate treatment restored Aβ-suppressed mitochondrial TCA cycle fluxes. These metabolic improvements were accompanied by increased expression of mitochondrial proteins. These findings support lactate shuttling as a mechanism for supplying lactate-derived carbon to mitochondrial energy metabolism, which may improve neuronal resilience under Aβ-induced metabolic stress.NEW & NOTEWORTHY This study shows that lactate treatment attenuates Aβ-induced cell death in neuron-like cells and supports mitochondrial carbon metabolism. Glycolytic hypometabolism was observed in human AD brain transcriptome and Aβ-treated neuron-like cells. We confirmed that lactate replenished mitochondrial energetics, making neurons more resilient to neurotoxicity. Using 13C tracing and metabolic flux analysis, we found that lactate-derived carbon was incorporated into the TCA cycle and that lactate treatment was associated with restoration of Aβ-suppressed mitochondrial fluxes.

Humans↗
PubMed1992

Effect of efferentiectomy on enzymes of glycolytic pathway, HMP pathway and TCA cycle in epididymis and vas deferens of rhesus monkey.

The importance of exocrine secretions of testis in the regulation of energy metabolism of the epididymis and vas deferens was examined in rhesus monkeys by performing efferentiectomy. At autopsy the epididymis was divided into initial segment, caput, corpus and cauda portions to make an account of regional differences, if any. Eleven enzymes of glycolysis, two key enzymes of HMP pathway and seven enzymes of TCA cycle were assayed in the epididymal segments and vas deferens of control (intact) and experimental (efferentiectomised for 90 days) monkeys. The results indicate that while anaerobic energy metabolism (glycolysis and HMP pathway) is sensitive to efferentiectomy chiefly in the proximal regions of epididymis, the oxidative pathway (TCA cycle) is dependent on testicular exocrine secretions throughout the length of epididymis, as well as in the vas deferens. Since all androgen-sensitive enzymes do not regress after efferentiectomy, it is suggested that unidentified exocrine factors of testis may have role in regulating energy metabolism in the epididymis and vas deferens.

Animals↗
PubMedDate not supplied

A 13C NMR study on fluxes into the TCA cycle of neuronal and glial tumor cell lines and primary cells.

Two tumor cell lines (C6 glioma and N1E-115 neuroblastoma), primary glia and primary neurons (from rat) were incubated with 2-13C-pyruvate and 3-13C-pyruvate in culture dishes. 13C NMR spectra of the cell extracts were used to determine the ratio of pyruvate carboxylase to pyruvate dehydrogenase activity. Pyruvate carboxylase activity was found higher in primary glia cells than in neurons. Glial cells synthesized more amino acids, ie, their TCA cycle was used to a larger extent for biosynthesis than is the case of neurons, where it is preferentially used for the energy metabolism.

Animals↗
PubMed1978

Role of carbon dioxide in germination of spores of Streptomyces viridochromogenes.

CO2 is required continuously during germination of Streptomyces viridochromogenes spores. Spores incubated in a defined germination medium in the absence of CO2 remain phase bright and do not release spore carbon. In the presence of CO2, the spores initiate germination accompanied by loss of refractility and spore carbon. The CO2 requirement is replaced by oxaloacetate or a mixture of tricarboxylic acid cycle (TCA) intermediates. Labeled CO2 is taken up by germinating spores, and is incorporated into protein and RNA. TCA cycle intermediates and related amino acids contain most of the acid-soluble label following short term exposures of germinating spores to 14CO2. TCA cycle inhibitors repress germination and 14CO2 uptake whereas folic acid antagonists do not. The results indicate that CO2 is incorporated into oxaloacetate which is converted to biosynthetic intermediates required for germination. Operation of the TCA cycle appears to be essential for spore germination. The conclusion is reached that CO2 is required during germination in order to maintain the cycle by an anaplerotic reaction.

Adenosine↗
PubMed1992

Glucose metabolism in proliferating epithelial cells from the rat colon.

1. The effects of fasting and fasting followed by refeeding on the activities of the oxidative pentose pathway (OPP) and the tricarboxylic acid cycle (TCA) in isolated rat colonocytes were estimated by the rate of production of 14CO2 from [1-14C]glucose and [6-14C]glucose, respectively. 2. Refeeding after a fast induced a 2-3-fold increase in glucose flux through the OPP and TCA cycle and the degree of change was similar in colonocytes from the proximal and distal colon. 3. Butyrate at a concentration of 40 mM inhibited the OPP by 20-30% (P less than 0.05) but had no effect on the activity of the TCA cycle. Glutamine at a concentration of 2 mM decreased the glucose flux through both the OPP and the TCA cycle by 30-50% (P less than 0.05). 4. Production of 14CO2 from the oxidation of butyrate or glucose indicated that the former was 5-7 times more active in colonocytes from fasted rats. After refeeding, however, butyrate utilization was similar to fasting values in the proximal colon but significantly lower (P less than 0.05) in the distal colon.

Animals↗
PubMed1977

Regulation of aflatoxin biosynthesis. 2 Comparative study of tricarboxylic acid cycle in aflatoxigenic and non-aflatoxigenic strains of Aspergillus flavus.

The presence of a functional TCA cycle and its intermediates has been shown in Aspergillus parasiticus and Aspergillus flavus. The role of the TCA cycle in aflatoxin biosynthesis has been studied. In A. parasiticus the TCA cycle was activated on the second day of growth (exponential growth phase) resulting in the onset of aflatoxin biosynthesis. Pyruvate accumulation to toxic levels in A. parasiticus is suggested to shift the growth phase from exponential to stationary with the onset of aflatoxin biosynthesis. In A. flavus, a non-aflatoxigenic strain, no pyruvate accumulation was observed. Moreover, the onset of aflatoxin production in A. parasiticus was followed by a decline in the levels of TCA cycle intermediates indicating their possible utilization in secondary metabolite synthesis. Accumulation of TCA cycle intermediates in A. flavus is suggested to be due to non-diversion to aflatoxin biosynthesis.

Aflatoxins↗
PubMed1975

Metabolism of short chain fatty acid in rat liver in biliary obstruction.

In an attempt to clarify the hepatic insufficiency in obstructive jaundice, hepatic metabolic rate of n-butyric acid, ketogenesis and CO2 formation from butyric acid were investigated using liver slices obtained from rats subjected to choledochal ligation or carbon tetrachloride (CCl4) injection. The hepatic metabolic rate of n-butyric acid was reduced with the prolongation of biliary obstruction, and the reduction was presumed to be caused for the most part by the reduced ketogenesis and in part by the impairment of the citric acid cycle (TCA-cycle). In 3approximately4 weeks after biliary obstruction, the metabolic rate reduced to a level comparable to liver necrosis produced by CCl4. This reduction of the metabolic rate of n-butyric acid is postulated as one of the pathogenic factors for fatal liver insufficiency in many cases of obstructive jaundice. While the reduction is mild and mobile in the early stage of jaundice, it may be of significance for preventing fatal liver insufficiency to relieve the obstruction as early as possible.

Animals↗
PubMed1992

Evolution of metabolic pathways by chance assembly of enzyme proteins generated from sense and antisense strands of pre-existing genes.

In order to get an insight into the evolutionary aspect of metabolic pathways, especially of the ubiquitous glycolytic pathway, we have carried out an extensive search of sense-sense and sense-antisense similarities for enzyme proteins in the glycolytic pathway, the pentose phosphate cycle, alcohol and lactate fermentation pathways and the TCA cycle. This investigation of amino acid sequences reveals a curious pattern of similarity relations; no similarity can be found between the enzyme proteins in a section of the glycolytic pathway where the glyceraldehyde-3-phosphate or even glycerol-3-phosphate is converted into the pyruvate while many examples of sense-sense and sense-antisense similarities are found even between enzyme proteins in distant blocks, e.g. between the proteins in the TCA cycle and those in the pentose phosphate cycle, as well as between the functionally associated proteins in each of these blocks. Complementary to this characteristic pattern of amino acid sequence similarity, the search for similarities of nucleotide sequences also finds that the similarities of glycolytic enzyme genes, some sense-sense and others sense-antisense similarities, are concentrated on the nucleotide sequences of prokaryotic 16S or eukaryotic 18S ribosomal RNA gene with its flanks, although some of the copy sequences are also found in transfer RNA genes as well as in 23S or 26S ribosomal RNA gene. These results strongly suggest that the metabolic pathways have been developed by the chance assembly of enzyme proteins generated from the sense and antisense strands of pre-existing genes, e.g. the fermentation pathways and pentose phosphate cycle by the proteins from the genes of enzymes in the glycolytic pathway and the TCA cycle from all these successively increased genes, ascribing the origin of metabolic enzyme genes to the close relation between the glycolytic enzyme protein genes and the RNA gene cluster.

Animals↗
PubMed1977

Effect of Zinc on tricarboxylic acid cycle intermediates and enzymes in relation to aflatoxin biosynthesis.

The stimulatory action of zinc on aflatoxin production by Aspergillus parasiticus NRRL3240 has been investigated by studying the levels of tricarboxylic acid (TCA) cycle intermediates and related enzymes in the fungal mycelium. During the stationary phase of growth, the levels of alpha-keto acids declined in zinc-sufficient cultures compared with those in zinc-dificient cultures. TCA cycle enzymes did not show any significant changes due to zinc availability. In zinc-deficient cultures, enzymes of the TCA cycle had maximum activity on the fourth day, after which their activity declined. In zinc-sufficient cultures, some enzymes showed maximum activity on the fourth day, others on the second day.

Aflatoxins↗
PubMed1992

Amino acid metabolism, muscular fatigue and muscle wasting. Speculations on adaptations at high altitude.

Recent investigations from our and other laboratories indicate that glycogen is a carbon-chain precursor in muscle for the synthesis of TCA cycle intermediates and glutamine. During intense exercise and in conditions of a relative lack of energy (hypoxia, trauma, sepsis) the metabolism of branched-chain amino acids (BCAA) is accelerated in muscle. In the primary BCAA aminotransferase reaction 2-oxoglutarate is used as amino-group acceptor (putting a carbon-drain on the TCA cycle) under formation of glutamate. Glutamate will subsequently react with ammonia, generated in the AMP deaminase reaction or by deamination of amino acids, under formation of glutamine in a reaction catalysed by glutamine synthetase (glutamate + ammonia + ATP--> glutamine + ADP). Muscle glycogen stores may be smaller or less available at high altitude. It is hypothesized that this will lead to premature fatigue (due to both a lack of fuel and of TCA cycle carbon-precursor) and to a reduction in the synthesis rate of glutamine. A chronic reduction in the synthesis rate of glutamine during a long term stay at high altitude on its turn may lead to gut atrophy, bacterial translocation, endotoxemia, muscle protein catabolism and a weakened immune status.

Adaptation, Physiological↗
PubMed2024

Salmonella Typhimurium screen identifies shifts in mixed-acid fermentation during gut colonization.

How enteric pathogens adapt their metabolism to a dynamic gut environment is not yet fully understood. To investigate how Salmonella enterica Typhimurium (S.Tm) colonizes the gut, we conducted an in vivo transposon mutagenesis screen in a gnotobiotic mouse model. Our data implicate mixed-acid fermentation in efficient gut-luminal growth and energy conservation throughout infection. During initial growth, the pathogen utilizes acetate fermentation and fumarate respiration. After the onset of gut inflammation, hexoses appear to become limiting, as indicated by carbohydrate analytics and the increased need for gluconeogenesis. In response, S.Tm adapts by ramping up ethanol fermentation for redox balancing and supplying the TCA cycle with α-ketoglutarate for additional energy. Our findings illustrate how S.Tm flexibly adapts mixed fermentation and its use of the TCA cycle to thrive in the changing gut environment. Similar metabolic wiring in other pathogenic Enterobacteriaceae may suggest a broadly conserved mechanism for gut colonization.

Animals↗
PubMed2026

IDH3-dependent mitochondrial function in stromal fibroblasts suppresses malignant tumor growth.

Malignant solid tumors comprise not only cancer cells but also diverse non-cancerous stromal cells that shape the tumor microenvironment. The tricarboxylic acid (TCA) cycle has an overarching presence in providing substrates needed to drive the electron transport chain and, ultimately, ATP synthesis. However, it remains unclear which stromal cell lineages influence tumor growth through TCA-dependent mitochondrial function, and whether such activities act in a tumor-promoting or tumor-suppressive manner. Isocitrate dehydrogenase 3 (IDH3), a rate-limiting TCA cycle enzyme that generates NADH to support mitochondrial respiration, provides a genetic entry point to interrogate mitochondrial TCA-dependent function in stromal cells. In this study, we established a mouse model in which tamoxifen administration induces CreERT2-dependent knockout of the α subunit of IDH3 (IDH3α) in all somatic cells. Using this model with transplantation of Idh3a-intact murine cancer cells, we found that host Idh3a deficiency accelerated growth of murine MC38 tumors in a cancer cell line-dependent manner. Bone marrow chimera experiments indicated that hematopoietic lineages were not responsible for this phenotype, suggesting a contribution from tissue-resident non-hematopoietic stromal cells that are not replaced by bone marrow transplantation. Single-cell RNA sequencing of human tumor specimens revealed broad IDH3A expression across multiple tumor microenvironment compartments, including fibroblasts. Consistently, in vitro co-culture assays demonstrated that Idh3a-intact, but not Idh3a-KO, fibroblasts suppressed cancer cell proliferation in a contact-dependent manner. Together, these findings identify IDH3α-dependent mitochondrial function in fibroblasts as a critical determinant of tumor progression and suggest that stromal mitochondrial metabolism represents an important axis for modulating tumor behavior.

Cancer↗