scholarly journals Defective carbohydrate metabolism in mice homozygous for the tubby mutation

2006 ◽  
Vol 27 (2) ◽  
pp. 131-140 ◽  
Author(s):  
Yun Wang ◽  
Kevin Seburn ◽  
Lawrence Bechtel ◽  
Bruce Y. Lee ◽  
Jin P. Szatkiewicz ◽  
...  
Keyword(s):  
Carbohydrate Metabolism ◽  
De Novo ◽  
Ketone Bodies ◽  
Late Onset ◽  
Acid Synthesis ◽  
Pentose Phosphate ◽  
Mrna Levels ◽  
Protein Levels ◽  
Energy Needs ◽  
Glucose 6 Phosphate Dehydrogenase

Tub is a member of a small gene family, the tubby-like proteins (TULPs), with predominant expression in neurons. Mice carrying a mutation in Tub develop retinal and cochlear degeneration as well as late-onset obesity with insulin resistance. During behavioral and metabolic testing, we found that homozygous C57BL/6J- Tub tub mice have a lower respiratory quotient than C57BL/6J controls before the onset of obesity, indicating that tubby homozygotes fail to activate carbohydrate metabolism and instead rely on fat metabolism for energy needs. In concordance with this, tubby mice show higher excretion of ketone bodies and accumulation of glycogen in the liver. Quantitation of liver mRNA levels shows that, during the transition from light to dark period, tubby mice fail to induce glucose-6-phosphate dehydrogenase ( G6pdh), the rate-limiting enzyme in the pentose phosphate pathway that normally supplies NADPH for de novo fatty acid synthesis and glutathione reduction. Reduced G6PDH protein levels and enzymatic activity in tubby mice lead accordingly to lower levels of NADPH and reduced glutathione (GSH), respectively. mRNA levels for the lipolytic enzymes acetyl-CoA synthetase and carnitine palmitoyltransferase are increased during the dark cycle and decreased during the light period, and several citric acid cycle genes are dysregulated in tubby mice. Examination of hypothalamic gene expression showed high levels of preproorexin mRNA leading to accumulation of orexin peptide in the lateral hypothalamus. We hypothesize that abnormal hypothalamic orexin expression leads to changes in liver carbohydrate metabolism and may contribute to the moderate obesity observed in tubby mice.

scholarly journals Hepatic GH Receptor Signaling Directly Suppresses Hepatic Steatosis and De Novo Lipogenesis, Independent of Changes in Plasma IGF1 and Insulin

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A48-A48
Author(s):  
Maria del Carmen Vazquez Borrego ◽  
Mercedes del Rio Moreno ◽  
Andre Sarmento-Cabral ◽  
Mariyah Mahmood ◽  
Papasani V Subbaiah ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Target Genes ◽  
De Novo ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Mrna Levels ◽  
Male Mice ◽  
Alcoholic Fatty Liver ◽  
Insulin Levels ◽  
Triglyceride Accumulation

Abstract A reduction in GH, as well as IGF1, is associated with non-alcoholic fatty liver disease (NAFLD). However, the relative contribution of changes in circulating GH and IGF1, to hepatic triglyceride accumulation (steatosis), remains to be clearly defined. To study the direct actions of GH on hepatocyte metabolism, we have utilized a mouse model of adult-onset, hepatocyte-specific, GHR knockdown (aHepGHRkd; 10–12 week-old, GHRfl/fl male mice, treated with AAV8-TBGp-Cre). In this and previous reports, we have observed that aHepGHRkd male mice rapidly develop steatosis (after 7 days) associated with enhanced de novo lipogenesis (DNL; measured by deuterated H2O labeling, 10h after 0800h food removal), and low ketone levels, suggestive of reduced hepatic β-oxidation. Of note, aHepGHRkd also reduces plasma IGF1 levels to >80% of GHR-intact controls (GHRfl/fl mice treated with AAV8-TBGp-Null), leading to a rise in GH, due to loss of IGF1 negative feedback to the pituitary/hypothalamus. This reciprocal shift in IGF1/GH is associated with an increase in insulin levels. Therefore, it is possible that the steatosis that develops in aHepGHRkd mice is the consequence of systemic insulin resistance supplying excess substrates (glucose and NEFA) for hepatic lipogenesis. However, inconsistent with this theory is the fact that glucose and NEFA levels are not altered after aHepGHRkd. To tease out the indirect (perhaps driven by high insulin levels) vs. direct effects of GH on hepatocyte lipid accumulation, male aHepGHRkd mice were injected with a vector expressing rat IGF1 (AAV8-TBGp-rIGF1). Reconstitution of hepatocyte IGF1 in aHepGHRkd mice, raised plasma IGF1 and normalized GH, insulin and ketone levels, but hepatic steatosis and DNL remained greater than that of GHR-intact controls, indicating GH directly suppresses hepatic fat accumulation. RNAseq analysis of livers from aHepGHRkd mice showed expression of genes related to carbohydrate metabolism (Gck, Khk) and fatty acid synthesis (Fasn, Srebf1, Usf1), processing (Scd1) and uptake (Cd36) were increased, while genes related to gluconeogenesis (Pck1, Fbp1, G6pc) were reduced. Remarkably, IGF1 reconstitution had no major impact on the hepatic transcriptome of aHepGHRkd mice, with the exception of reducing the expression of Srebf1, consistent with the reduction in circulating insulin levels. Interestingly, carbohydrate-responsive element-binding protein (CHREBP) levels, but not mRNA levels, were greater in aHepGHRkd mice with or without IGF1 reconstitution, consistent with upregulation of CHREBP target genes (Khk and Fasn among others). Taken together, these results suggest GH directly regulates steatosis, at least in part, by suppressing carbohydrate-driven DNL, where additional studies are underway to test this hypothesis.

scholarly journals Sterol regulatory element binding protein and dietary lipid regulation of fatty acid synthesis in the mammary epithelium

2010 ◽  
Vol 299 (6) ◽  
pp. E918-E927 ◽  
Author(s):  
Michael C. Rudolph ◽  
Jenifer Monks ◽  
Valerie Burns ◽  
Meridee Phistry ◽  
Russell Marians ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mammary Gland ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Regulatory Element ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Mrna Levels ◽  
Sterol Regulatory Element

The lactating mammary gland synthesizes large amounts of triglyceride from fatty acids derived from the blood and from de novo lipogenesis. The latter is significantly increased at parturition and decreased when additional dietary fatty acids become available. To begin to understand the molecular regulation of de novo lipogenesis, we tested the hypothesis that the transcription factor sterol regulatory element binding factor (SREBF)-1c is a primary regulator of this system. Expression of Srebf1c mRNA and six of its known target genes increased ≥2.5-fold at parturition. However, Srebf1c-null mice showed only minor deficiencies in lipid synthesis during lactation, possibly due to compensation by Srebf1a expression. To abrogate the function of both isoforms of Srebf1, we bred mice to obtain a mammary epithelial cell-specific deletion of SREBF cleavage-activating protein (SCAP), the SREBF escort protein. These dams showed a significant lactation deficiency, and expression of mRNA for fatty acid synthase ( Fasn), insulin-induced gene 1 ( Insig1), mitochondrial citrate transporter ( Slc25a1), and stearoyl-CoA desaturase 2 ( Scd2) was reduced threefold or more; however, the mRNA levels of acetyl-CoA carboxylase-1α ( Acaca) and ATP citrate lyase ( Acly) were unchanged. Furthermore, a 46% fat diet significantly decreased de novo fatty acid synthesis and reduced the protein levels of ACACA, ACLY, and FASN significantly, with no change in their mRNA levels. These data lead us to conclude that two modes of regulation exist to control fatty acid synthesis in the mammary gland of the lactating mouse: the well-known SREBF1 system and a novel mechanism that acts at the posttranscriptional level in the presence of SCAP deletion and high-fat feeding to alter enzyme protein.

Respiratory pathways and fat synthesis in the developing castor oil seed

1979 ◽  
Vol 57 (9) ◽  
pp. 1008-1014 ◽  
Author(s):  
P. D. Simcox ◽  
W. Garland ◽  
V. DeLuca ◽  
D. T. Canvin ◽  
D. T. Dennis
Keyword(s):  
Fatty Acid ◽  
Castor Oil ◽  
Fatty Acid Biosynthesis ◽  
Acid Synthesis ◽  
Pentose Phosphate ◽  
Carboxylase Activity ◽  
Bisphosphate Carboxylase ◽  
Oil Seed ◽  
Pentose Phosphate Pathways ◽  
Glucose 6 Phosphate Dehydrogenase

During castor oil seed development, changes occur in the activities of enzymes involved in fatty acid biosynthesis, glycolysis, and the pentose phosphate pathways. The activities of acetyl-CoA carboxylase, phosphofructokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase per seed increase during the phase of rapid oil synthesis in the endosperm. As the seed matures and the rate of fatty acid synthesis decreases, there is a corresponding diminution in the activities of these enzymes. An indication of the metabolic capacity of the plastids was determined by monitoring the ribulose-1,5-bisphosphate carboxylase activity in the endosperm.

scholarly journals Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

2021 ◽  
Author(s):  
Magali Humbert ◽  
Kristina Seiler ◽  
Severin Mosimann ◽  
Vreni Rentsch ◽  
Katyayani Sharma ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Fatty Acid ◽  
Myeloid Leukemia ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Acid Synthesis ◽  
Mrna Levels ◽  
Differentiation Therapy ◽  
Granulocytic Differentiation ◽  
Acute Myeloid

AbstractFatty acid synthase (FASN) is the only human lipogenic enzyme available for de novo fatty acid synthesis and is often highly expressed in cancer cells. We found that FASN mRNA levels were significantly higher in acute myeloid leukemia (AML) patients than in healthy granulocytes or CD34+ hematopoietic progenitors. Accordingly, FASN levels decreased during all-trans retinoic acid (ATRA)-mediated granulocytic differentiation of acute promyelocytic leukemia (APL) cells, partially via autophagic degradation. Furthermore, our data suggest that inhibition of FASN expression levels using RNAi or (-)-epigallocatechin-3-gallate (EGCG) accelerated the differentiation of APL cell lines and significantly re-sensitized ATRA refractory non-APL AML cells. FASN reduction promoted translocation of transcription factor EB (TFEB) to the nucleus, paralleled by activation of CLEAR network genes and lysosomal biogenesis. Together, our data demonstrate that inhibition of FASN expression in combination with ATRA treatment facilitates granulocytic differentiation of APL cells and may extend differentiation therapy to non-APL AML cells.

Maternal dietary iron restriction modulates hepatic lipid metabolism in the fetuses

2005 ◽  
Vol 288 (1) ◽  
pp. R104-R111 ◽  
Author(s):  
Junlong Zhang ◽  
Rohan M. Lewis ◽  
Chunli Wang ◽  
Nicholas Hales ◽  
Christopher D. Byrne
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Synthase ◽  
Plasma Cholesterol ◽  
Liver Lipid ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Liver Cholesterol ◽  
Mrna Levels ◽  
Protein Levels

Maternal dietary Fe restriction reduced fasting plasma cholesterol and triglyceride (TG) concentrations in the fetuses, as well as decreased plasma TG levels in the adult offspring. To investigate how maternal Fe restriction was affecting fetal lipid metabolism, we investigated whether there were changes in liver lipid metabolism in the full-term fetuses. There was a ∼27% ( P < 0.05) increase in cholesterol but ∼29% reduction ( P = 0.01) in TG concentrations in the liver of the Fe-restricted fetuses. Hepatic mRNA levels of cholesterol 7α hydroxylase and liver X receptor-α (LXRα) were reduced by ∼50% ( P < 0.01) and ∼34% ( P < 0.01), respectively. As LXRα regulates expression of sterol response element binding protein-1c (SREBP-1c) expression, we measured SREBP-1c expression. There was an ∼43% ( P < 0.001) reduction in mRNA levels of SREBP-1c and its response genes, including acetyl-CoA carboxylase by ∼35% ( P = 0.01), fatty acid synthase by ∼18% ( P = 0.05), and diacylglycerol acyltransferase by ∼19% ( P = 0.03). Furthermore, protein levels of CD36 were reduced by ∼27% ( P = 0.02) in Fe-restricted fetuses. In conclusion, changes in liver cholesterol and TG concentrations in Fe-restricted fetuses may be coordinated through reduced expression of heme-containing cholesterol 7α hydroxylase and its regulator LXRα, mainly via downregulation of expression of genes in bile acid synthesis and fatty acid synthesis pathways.

De novo Synthesis of Glucose-6-Phosphate- (E.C. 1.1.1.49) and 6-Phosphogluconate Dehydrogenase (E.C. 1.1.1.44) in Plant Storage Tissue Slices

1974 ◽  
Vol 29 (11-12) ◽  
pp. 700-704 ◽  
Author(s):  
Günter Kahl
Keyword(s):  
De Novo ◽  
Pentose Phosphate ◽  
De Novo Synthesis ◽  
Tissue Slices ◽  
Storage Tissue ◽  
Tuber Tissue ◽  
Phosphogluconate Dehydrogenase ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Equilibrium Centrifugation ◽  
Plant Storage

Resting potato tuber tissue possesses only faint activity of the two dehydrogenases of the oxidative pentose phosphate cycle, glucose-6-phosphate- and 6-phosphogluconate dehydrogenase. Slicing of the tissue, however, greatly enhances the action of both enzymes. The slicing-induced increase in activity is a consequence of intensified action of at least 5 glucose-6-phosphate dehydrogenase isozymes and a more differentiated activation/inactivation of seven 6-phosphogluconate dehydrogenase isozymes. Using density labelling and isopycnic equilibrium centrifugation it could be demonstrated, that the bulk of both enzymes appearing after slicing the tissue is the result of de novo synthesis rather than activation of pre-existing proenzymes.

NADPH Producing Enzymes as Promising Drug Targets for Chagas Disease

2019 ◽  
Vol 26 (36) ◽  
pp. 6564-6571
Author(s):  
Artur T. Cordeiro
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Acid Synthesis ◽  
Pentose Phosphate ◽  
New Drugs ◽  
Trypanosomatid Parasites ◽  
Drug Target Validation ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Glucose 6 Phosphate Dehydrogenase

Reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH) is a cofactor used in different anabolic reactions, such as lipid and nucleic acid synthesis, and for oxidative stress defense. NADPH is essential for parasite growth and viability. In trypanosomatid parasites, NADPH is supplied by the oxidative branch of the pentose phosphate pathway and by enzymes associated with the citric acid cycle. The present article will review recent achievements that suggest glucose-6-phosphate dehydrogenase and the cytosolic isoform of the malic enzyme as promising drug targets for the discovery of new drugs against Trypanosoma cruzi and T. brucei. Topics involving an alternative strategy in accelerating T. cruzi drug-target validation and the concept of drug-target classification will also be revisited.

scholarly journals Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in Bloodstream Trypanosoma brucei

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 358
Author(s):  
Cecilia Ortíz ◽  
Francesca Moraca ◽  
Marc Laverriere ◽  
Allan Jordan ◽  
Niall Hamilton ◽  
...  
Keyword(s):  
De Novo ◽  
Pentose Phosphate ◽  
Small Subset ◽  
Cell Physiology ◽  
Single Digit ◽  
In Vitro Proliferation ◽  
African Trypanosomes ◽  
Thiol Redox ◽  
Glucose 6 Phosphate Dehydrogenase

Glucose 6-phosphate dehydrogenase (G6PDH) fulfills an essential role in cell physiology by catalyzing the production of NADPH+ and of a precursor for the de novo synthesis of ribose 5-phosphate. In trypanosomatids, G6PDH is essential for in vitro proliferation, antioxidant defense and, thereby, drug resistance mechanisms. So far, 16α-brominated epiandrosterone represents the most potent hit targeting trypanosomal G6PDH. Here, we extended the investigations on this important drug target and its inhibition by using a small subset of androstane derivatives. In Trypanosoma cruzi, immunofluorescence revealed a cytoplasmic distribution of G6PDH and the absence of signal in major organelles. Cytochemical assays confirmed parasitic G6PDH as the molecular target of epiandrosterone. Structure-activity analysis for a set of new (dehydro)epiandrosterone derivatives revealed that bromination at position 16α of the cyclopentane moiety yielded more potent T. cruzi G6PDH inhibitors than the corresponding β-substituted analogues. For the 16α brominated compounds, the inclusion of an acetoxy group at position 3 either proved detrimental or enhanced the activity of the epiandrosterone or the dehydroepiandrosterone derivatives, respectively. Most derivatives presented single digit μM EC50 against infective T. brucei and the killing mechanism involved an early thiol-redox unbalance. This data suggests that infective African trypanosomes lack efficient NADPH+-synthesizing pathways, beyond the Pentose Phosphate, to maintain thiol-redox homeostasis.

scholarly journals Keap1/Nrf2 pathway in the frontiers of cancer and non-cancer cell metabolism

2015 ◽  
Vol 43 (4) ◽  
pp. 639-644 ◽  
Author(s):  
Dionysios V. Chartoumpekis ◽  
Nobunao Wakabayashi ◽  
Thomas W. Kensler
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Metabolic Pathways ◽  
De Novo ◽  
Cell Metabolism ◽  
Acid Synthesis ◽  
Pentose Phosphate ◽  
De Novo Lipogenesis ◽  
Nrf2 Pathway ◽  
Cancer Cell Survival

Cancer cells adapt their metabolism to their increased needs for energy and substrates for protein, lipid and nucleic acid synthesis. Nuclear erythroid factor 2-like 2 (Nrf2) pathway is usually activated in cancers and has been suggested to promote cancer cell survival mainly by inducing a large battery of cytoprotective genes. This mini review focuses on metabolic pathways, beyond cytoprotection, which can be directly or indirectly regulated by Nrf2 in cancer cells to affect their survival. The pentose phosphate pathway (PPP) is enhanced by Nrf2 in cancers and aids their growth. PPP has also been found to be up-regulated in non-cancer tissues and other pathways, such as de novo lipogenesis, have been found to be repressed after activation of the Nrf2 pathway. The importance of these Nrf2-regulated metabolic pathways in cancer compared with non-cancer state remains to be determined. Last but not least, the importance of context about Nrf2 and cancer is highlighted as the Nrf2 pathway may be activated in cancers but its pharmacological activators are useful in chemoprevention.

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