scholarly journals Analysis of lines of mice selected for fat content: 3. Flux through the de novo lipid synthesis pathway

1991 ◽  
Vol 58 (2) ◽  
pp. 123-127 ◽  
Author(s):  
Emmanuel A. Asante ◽  
William G. Hill ◽  
Grahame Bulfield
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Lipid Synthesis ◽  
Fold Increase ◽  
Acid Synthesis ◽  
Fat Content ◽  
Direct Selection ◽  
Lean Line

SummaryThe flux through the de novo fatty acid synthesis pathway was estimated in lines of mice which differed substantially in fat content following 26 generations of selection at 10 weeks of age. Previous estimates of lipogenic enzyme activities had indicated an increase in the capacity for lipogenesis in the Fat compared to the Lean line. Therefore the in vivo flux in lipogenesis was measured in both liver and gonadal fat pad (GFP) tissues of males at 5 and 10 weeks of age, using the rat of incorporation of 3H from 3H2O and 14C from acetate and citra te into total lipids. AT both ages and in both tissues the Fat line had a higher flux, about 20% increase in the liver and up to three-fold increase (range 1·2- to 3·4-fold) in the GFP. We conclude that direct selection for fatness in mice has resulted in metabolic changes in the ratio of de novo fatty acid synthesis, and that the changes are largely detectable before 10 weeks, the age of selection.

scholarly journals USP22-dependent accumulation of lipidomes drives hepatocellular carcinoma progression by stabilizing PPARγ

2020 ◽  
Author(s):  
Zhen Ning ◽  
Xin Guo ◽  
Xiaolong Liu ◽  
Chang Lu ◽  
Aman Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Fatty Acid ◽  
Molecular Mechanism ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Acid Synthesis ◽  
Specific Protease ◽  
Pparγ Expression

Abstract Elevated de novo lipogenesis (DNL) is considered to be a crucial factor in hepatocellular carcinoma (HCC) development. However, the molecular mechanism for its occurrence in HCC is still unclear. Herein, we identified ubiquitin-specific protease 22 (USP22) as a key regulator for de novo fatty acid synthesis, which directly interacts with, deubiquitinates and stabilizes PPARγ through K48-linked deubiquitination, and in turn, this stabilization increases ACC and ACLY transcription. In addition, we found that USP22 promoted the de novo synthesis of fatty acid labeling from glucose tracers. USP22-dysregulated de novo fatty acid synthesis contributes to HCC progression, but USP22 was functionality suppressed by inhibiting the expression of PPARγ, ACLY, or ACC in in vitro cell proliferation and in vivo tumorigenesis experiments. In HCC, USP22 expression positively correlates with PPARγ expression, and simultaneously, high expression of USP22 and PPARγ or USP22, ACC and ACLY is associated with a poor prognosis. Taken together, we identified a previously undescribed USP22-regulated lipogenesis molecular mechanism that involves the PPARγ-ACLY/ACC axis in HCC tumorigenesis and provide a rationale for therapeutic targeting of lipogenesis via USP22 inhibition.

Fatty Acid Synthesis by Rat Liver after Chronic Ethanol Feeding with a Low-Fat Diet

1994 ◽  
Vol 87 (4) ◽  
pp. 441-446 ◽  
Author(s):  
K. J. Simpson ◽  
S. Venkatesan ◽  
T. J. Peters
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Fatty Acid Synthase ◽  
Plasma Lipids ◽  
Fold Increase ◽  
Acid Synthesis ◽  
Low Fat ◽  
Hepatic Fatty Acid ◽  
Low Fat Diet

1. Chronic alcohol feeding with a low-fat diet (4.4% total calories) produced a two- to three-fold increase in hepatic triacylglycerol and esterified cholesterol compared with pair-fed low-fat diet controls. Plasma lipids were similar in both groups. 2. Hepatic fatty acid synthesis rates measured in vivo with 3H2O were significantly lower in the alcohol-fed animals than in controls. Activities of hepatic fatty acid synthase (EC 2.3.1.85) and acetyl-CoA carboxylase (EC 6.4.1.2) were reduced in the alcohol-fed rats. 3. These results indicate that enhanced hepatic fatty acid synthesis does not occur in rats fed alcohol and a low-fat diet for 4 weeks, and is thus not implicated in the pathogenesis of alcohol-induced fatty liver.

scholarly journals Fatty acid synthesis in the perfused liver of adrenalectomized rats

1976 ◽  
Vol 156 (3) ◽  
pp. 593-602 ◽  
Author(s):  
C J Kirk ◽  
T R Verrinder ◽  
D A Hems
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Direct Action ◽  
Acid Synthesis ◽  
Diabetic Rats ◽  
Perfused Liver ◽  
Control Sham ◽  
Adrenalectomized Rats

1. Fatty acid synthesis, measured in the perfused liver of fed adrenalectomized rats with 3H2O and 14C-labelled precursors, was less than in control sham-operated rats. 2. This defect was more extensive for synthesis of fatty acids incorporated into triacylglycerols than into phospholipids. 3. There was impairment in desaturation and export of newly synthesized fatty acid. 4. Fatty acid synthesis and desaturation were restored to normal rates 5h after treatment with cortisol in vivo. 5. Fatty acid synthesis was seasonally variable, being highest in the winter; the impairment after adrenalectomy was observed in all seasons. 6. In perfusions with oleate (0.7 mM), no further impairment in fatty acid synthesis was discerned in livers from adrenalectomized rats, in which the rate resembled that in control livers. 7. No defect in the incorporation of oleate into glycerides was discerned in livers from adrenalectomized rats. 8. Cortisol exerted no stimulatory effect on fatty acid synthesis when added to perfusion media. 9. The impairment in hepatic lipogenesis, demonstrable after adrenalectomy, shows that adrenal glucocorticoids promote hepatic capacity for fatty acid synthesis de novo, at least in intact non-diabetic rats. It is suggested that this effect is mediated by insulin, perhaps through direct action on the liver.

scholarly journals The Role of Mitochondrial Fat Oxidation in Cancer Cell Proliferation and Survival

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2600
Author(s):  
Matheus Pinto De Oliveira ◽  
Marc Liesa
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Cancer Proliferation

Tumors remodel their metabolism to support anabolic processes needed for replication, as well as to survive nutrient scarcity and oxidative stress imposed by their changing environment. In most healthy tissues, the shift from anabolism to catabolism results in decreased glycolysis and elevated fatty acid oxidation (FAO). This change in the nutrient selected for oxidation is regulated by the glucose-fatty acid cycle, also known as the Randle cycle. Briefly, this cycle consists of a decrease in glycolysis caused by increased mitochondrial FAO in muscle as a result of elevated extracellular fatty acid availability. Closing the cycle, increased glycolysis in response to elevated extracellular glucose availability causes a decrease in mitochondrial FAO. This competition between glycolysis and FAO and its relationship with anabolism and catabolism is conserved in some cancers. Accordingly, decreasing glycolysis to lactate, even by diverting pyruvate to mitochondria, can stop proliferation. Moreover, colorectal cancer cells can effectively shift to FAO to survive both glucose restriction and increases in oxidative stress at the expense of decreasing anabolism. However, a subset of B-cell lymphomas and other cancers require a concurrent increase in mitochondrial FAO and glycolysis to support anabolism and proliferation, thus escaping the competing nature of the Randle cycle. How mitochondria are remodeled in these FAO-dependent lymphomas to preferably oxidize fat, while concurrently sustaining high glycolysis and increasing de novo fatty acid synthesis is unclear. Here, we review studies focusing on the role of mitochondrial FAO and mitochondrial-driven lipid synthesis in cancer proliferation and survival, specifically in colorectal cancer and lymphomas. We conclude that a specific metabolic liability of these FAO-dependent cancers could be a unique remodeling of mitochondrial function that licenses elevated FAO concurrent to high glycolysis and fatty acid synthesis. In addition, blocking this mitochondrial remodeling could selectively stop growth of tumors that shifted to mitochondrial FAO to survive oxidative stress and nutrient scarcity.

scholarly journals Fatty Acid Cosubstrates Provide β-Oxidation Precursors for Rhamnolipid Biosynthesis in Pseudomonas aeruginosa, as Evidenced by Isotope Tracing and Gene Expression Assays

2012 ◽  
Vol 78 (24) ◽  
pp. 8611-8622 ◽  
Author(s):  
Lin Zhang ◽  
Tracey A. Veres-Schalnat ◽  
Arpad Somogyi ◽  
Jeanne E. Pemberton ◽  
Raina M. Maier
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Fold Increase ◽  
Acid Synthesis ◽  
Octadecanoic Acid ◽  
Isotope Tracing ◽  
Pathway Gene ◽  
Potential Applications

ABSTRACTRhamnolipids have multiple potential applications as “green” surfactants for industry, remediation, and medicine. As a result, they have been intensively investigated to add to our understanding of their biosynthesis and improve yields. Several studies have noted that the addition of a fatty acid cosubstrate increases rhamnolipid yields, but a metabolic explanation has not been offered, partly because biosynthesis studies to date have used sugar or sugar derivatives as the carbon source. The objective of this study was to investigate the role of fatty acid cosubstrates in improving rhamnolipid biosynthesis. A combination of stable isotope tracing and gene expression assays was used to identify lipid precursors and potential lipid metabolic pathways used in rhamnolipid synthesis when fatty acid cosubstrates are present. To this end, we compared the rhamnolipids produced and their yields using either glucose alone or glucose and octadecanoic acid-d35as cosubstrates. Using a combination of sugar and fatty acids, the rhamnolipid yield was significantly higher (i.e., doubled) than when glucose was used alone. Two patterns of deuterium incorporation (either 1 or 15 deuterium atoms) in a single Rha-C10lipid chain were observed for octadecanoic acid-d35treatment, indicating that in the presence of a fatty acid cosubstrate, bothde novofatty acid synthesis and β-oxidation are used to provide lipid precursors for rhamnolipids. Gene expression assays showed a 200- to 600-fold increase in the expression ofrhlAandrhlBrhamnolipid biosynthesis genes and a more modest increase of 3- to 4-fold of thefadAβ-oxidation pathway gene when octadecanoic acid was present. Taken together, these results suggest that the simultaneous use ofde novofatty acid synthesis and β-oxidation pathways allows for higher production of lipid precursors, resulting in increased rhamnolipid yields.

Development of lipogenesis and insulin sensitivity in tissues of the ob/ob mouse

1981 ◽  
Vol 240 (2) ◽  
pp. E101-E107 ◽  
Author(s):  
M. L. Kaplan ◽  
G. A. Leveille
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Glycogen Synthesis ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Glycerophosphate Dehydrogenase

Lipogenesis and insulin sensitivity are evaluated in adipose tissue, liver, and diaphragm of ob/ob and non-ob/ob mice. In ob/ob mice, hepatic fatty acid synthesis from [U-14C]glucose is elevated by 4 wk of age, and adipose tissue fatty acid synthesis increases at approximately 7 wk. Hepatic activities in ob/ob mice of glucose-6-phosphate dehydrogenase (EC 1.1.1.49), 6-phosphogluconate dehydrogenase (EC 1.1.1.44), malate dehydrogenase (EC 1.1.1.40), and alpha-glycerophosphate dehydrogenase (EC 1.1.1.8) are dramatically increased by 7 wk of age. Diminished insulin-stimulated glycogen synthesis is first noted in the diaphragm of ob/ob mice at 7 wk of age. Insulin-stimulated glycogen synthesis in adipose tissue of ob/ob mice is impaired at 3 wk. At 7 wk, insulin-stimulated fatty acid synthesis in adipose tissue of ob/ob mice is markedly increased. Adipose tissue glyceride-glycerol synthesis continues to increase throughout development, whereas fatty acid synthesis decreases after 7 wk. The data suggest that alterations in lipid synthesis occur very early in the development of ob/ob mouse, prior to expression to overt obesity, at which time a major contribution to lipogenesis is made by the liver. The altered de novo lipogenesis does not precede the reported diminution in energy metabolism.

scholarly journals Ethanol administration and the relationship of malonyl-coenzyme A concentrations to the rate of fatty acid synthesis in rat liver

1973 ◽  
Vol 136 (3) ◽  
pp. 639-647 ◽  
Author(s):  
Robert W. Guynn ◽  
Dulce Veloso ◽  
Raymond L. Harris ◽  
J. W. Randolph Lawson ◽  
Richard L. Veech
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Fatty Acid Synthetase ◽  
Acid Synthesis ◽  
Ethanol Administration ◽  
Liver Fatty Acid ◽  
Malonyl Coa ◽  
Significant Difference

1. The effect of ethanol on liver fatty acid synthesis was studied in vivo in 24h-starved and ‘meal-fed’ rats (i.e. fed for 3h per day and not ad libitum). 2. In the fed animal3H2O was incorporated into fat at a rate of 0.46μmol of C2 units/min per g wet wt. of liver. Administration of either ethanol (3.2g/kg) or equicaloric amounts of glucose had no effect on the rate of3H2O incorporation into lipid. 3. In the 24h-starved animal, administration of the same dose of ethanol produced an increase in the rate of3H2O incorporation from 0.06 to 0.12μmol of C2 units/min per g fresh wt. after 3h whereas [malonyl-CoA] increased from 0.006 to 0.009μmol/g. Glucose given in amounts equicaloric to ethanol was significantly more lipogenic, increasing both the3H2O incorporation from 0.06 to 0.20μmol of C2 units/min per g and the malonyl-CoA content from 0.006 to 0.013 μmol/g wet wt. at 3h. 4. The decrease in the redox state of free cytoplasm NAD or NADP couples or the changes in content of citrate, glucose 6-phosphate and pyruvate of liver after ethanol administration had no measurable effect on the rate of fatty acid synthesis in vivo. 5. Under the conditions of the experiments there was no significant difference, among any of the groups, in the activity of liver fatty acid synthetase measured in vitro. A double-reciprocal plot of the rate of3H2O incorporation and the total tissue malonyl-CoA concentrations showed a striking relationship. It has been concluded that the rate of fatty acid synthesis in vivo is determined principally by the Vmax. of fatty acid synthetase and the concentration of free malonyl-CoA. 6. It has also been concluded that under the conditions of the present study, the synthesis of fatty acids de novo is unlikely to be an important factor in the increased liver lipid content associated with ethanol administration.

scholarly journals Modulation of lipid-synthesizing enzymes by insulin in differentiated ob17 adipose-like cells

1983 ◽  
Vol 214 (2) ◽  
pp. 443-449 ◽  
Author(s):  
P Grimaldi ◽  
C Forest ◽  
P Poli ◽  
R Negrel ◽  
G Ailhaud
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Specific Activity ◽  
Fatty Acid Synthetase ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
Acetate Incorporation ◽  
Long Term Effects ◽  
Response Curves ◽  
Glycerol 3 Phosphate Dehydrogenase

ob17 cells convert into adipose-like cells when maintained in the presence of physiological concentrations of insulin and tri-iodothyronine. After this conversion, insulin removal from differentiated ob17 cells gives within 24-48 h a large decrease in fatty acid synthetase, glycerol 3-phosphate dehydrogenase and acid:CoA ligase activities, as well as in the rate of fatty acid synthesis determined by [14C]acetate incorporation into lipids. All parameters are restored by insulin addition to initial values within 24-48 h. Dose-response curves of insulin on the restoration of glycerol 3-phosphate dehydrogenase activity and of fatty acid synthesis give half-maximally effective concentrations close to 1 nM, in agreement with the affinity for insulin of the insulin receptors previously characterized in these cells. Immunotitration experiments indicate that the changes in the specific activity of fatty acid synthetase are due to parallel changes in the cellular enzyme content. Therefore the ob17 cell line should be a useful model to study the long-term effects of insulin on the modulation of lipid synthesis in adipose cells.

scholarly journals Synthesis of fatty acids in the perfused mouse liver

1974 ◽  
Vol 142 (3) ◽  
pp. 611-618 ◽  
Author(s):  
D. Michael W. Salmon ◽  
Neil L. Bowen ◽  
Douglas A. Hems
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Saturated Fatty Acids ◽  
Carbon Sources ◽  
Acid Synthesis ◽  
Hepatic Glycogen ◽  
Total Rate ◽  
Glucose Carbon

1. Fatty acid synthesis de novo was measured in the perfused liver of fed mice. 2. The total rate, measured by the incorporation into fatty acid of3H from3H2O (1–7μmol of fatty acid/h per g of fresh liver), resembled the rate found in the liver of intact mice. 3. Perfusions with l-[U-14C]lactic acid and [U-14C]glucose showed that circulating glucose at concentrations less than about 17mm was not a major carbon source for newly synthesized fatty acid, whereas lactate (10mm) markedly stimulated fatty acid synthesis, and contributed extensive carbon to lipogenesis. 4. The identification of 50% of the carbon converted into newly synthesized fatty acid lends further credibility to the use of3H2O to measure hepatic fatty acid synthesis. 5. The total rate of fatty acid synthesis, and the contribution of glucose carbon to lipogenesis, were directly proportional to the initial hepatic glycogen concentration. 6. The proportion of total newly synthesized lipid that was released into the perfusion medium was 12–16%. 7. The major products of lipogenesis were saturated fatty acids in triglyceride and phospholipid. 8. The rate of cholesterol synthesis, also measured with3H2O, expressed as acetyl residues consumed, was about one-fourth of the basal rate of fatty acid synthesis. 9. These results are discussed in terms of the carbon sources of hepatic newly synthesized fatty acids, and the effect of glucose, glycogen and lactate in stimulating lipogenesis, independently of their role as precursors.

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