scholarly journals Effect of nutritional state on the utilization of fatty acids for hepatitic triacylglycerol synthesis and secretion as very-low-density lipoprotein

1991 ◽  
Vol 275 (1) ◽  
pp. 87-92 ◽  
Author(s):  
G F Gibbons ◽  
F J Burnham
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Total Mass ◽  
De Novo ◽  
Acid Synthesis ◽  
Nutritional State ◽  
Low Density ◽  
Very Low Density Lipoproteins ◽  
Triacylglycerol Synthesis

The mass of very-low-density-lipoproteins (VLDL) triacylglycerol secreted from isolated hepatocytes was dependent on the nutritional state of the donor rats, and declined in the order sucrose-fed greater than chow-fed greater than polyunsaturated-fat-fed greater than starved. This was the case irrespective of the presence or absence of exogenous oleate. The contribution of newly synthesized fatty acids to the total mass of VLDL triacylglycerol also declined in the above order, and reflected the relative rates of fatty acid synthesis de novo in each of the groups. The contribution of exogenous oleate to VLDL triacylglycerol varied in a manner similar to that for newly synthesized fatty acid. However, the contribution either of exogenous oleate or of newly synthesized fatty acid never exceeded 17-20% of the total VLDL triacylglycerol fatty acid even in the sucrose-fed animals. The increased contribution of newly synthesized fatty acids in the sucrose-fed group was not sufficient to account for the increase in the total mass of VLDL triacylglycerol secreted. These results suggest that: (a) changes in the rate of triacylglycerol secretion are not a direct consequence of variations in the rate of fatty acid synthesis de novo; (b) in the short term, most of the triacylglycerol required for VLDL assembly and secretion is derived from an intracellular storage source: (c) the distribution of newly synthesized triacylglycerol between the cytosolic and secretory pools was similar irrespective of the source of fatty acids (i.e. synthesized de novo or exogenous).

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.

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.

scholarly journals Systematic mapping of genetic interactions for de novo fatty acid synthesis

2019 ◽  
Author(s):  
Michael Aregger ◽  
Keith A. Lawson ◽  
Maximillian Billmann ◽  
Michael Costanzo ◽  
Amy H. Y. Tong ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Strong Dependence ◽  
Acid Synthesis ◽  
Protein Glycosylation ◽  
Genetic Interactions ◽  
Lipid Uptake ◽  
Functional Relationships

ABSTRACTThe de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases including cancer. While several translational efforts have focused on direct perturbation of de novo fatty acid synthesis, only modest responses have been associated with mono-therapies. Since cancer cells are intrinsically buffered to combat metabolic stress, cells may adapt to loss of de novo fatty acid biosynthesis. To explore cellular response to defects in fatty acid synthesis, we used pooled genome-wide CRISPR screens to systematically map genetic interactions (GIs) in human HAP1 cells carrying a loss-of-function mutation in FASN, which catalyzes the formation of long-chain fatty acids. FASN mutant cells showed a strong dependence on lipid uptake that was reflected by negative GIs with genes involved in the LDL receptor pathway, vesicle trafficking, and protein glycosylation. Further support for these functional relationships was derived from additional GI screens in query cell lines deficient for other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2, ACACA. Our GI profiles identified a potential role for a previously uncharacterized gene LUR1 (C12orf49) in exogenous lipid uptake regulation. Overall, our data highlights the genetic determinants underlying the cellular adaptation associated with loss of de novo fatty acid synthesis and demonstrate the power of systematic GI mapping for uncovering metabolic buffering mechanisms in human cells.

scholarly journals Enterococcus faecalisEncodes an Atypical Auxiliary Acyl Carrier Protein Required for Efficient Regulation of Fatty Acid Synthesis by Exogenous Fatty Acids

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Lei Zhu ◽  
Qi Zou ◽  
Xinyun Cao ◽  
John E. Cronan
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Type Strain ◽  
Wild Type Strain ◽  
De Novo ◽  
Acid Synthesis ◽  
Wild Type ◽  
Content Type

ABSTRACTAcyl carrier proteins (ACPs) play essential roles in the synthesis of fatty acids and transfer of long fatty acyl chains into complex lipids. TheEnterococcus faecalisgenome contains two annotatedacpgenes, calledacpAandacpB. AcpA is encoded within the fatty acid synthesis (fab) operon and appears essential. In contrast, AcpB is an atypical ACP, having only 30% residue identity with AcpA, and is not essential. Deletion ofacpBhas no effect onE. faecalisgrowth orde novofatty acid synthesis in media lacking fatty acids. However, unlike the wild-type strain, where growth with oleic acid resulted in almost complete blockage ofde novofatty acid synthesis, theΔacpBstrain largely continuedde novofatty acid synthesis under these conditions. Blockage in the wild-type strain is due to repression offaboperon transcription, leading to levels of fatty acid synthetic proteins (including AcpA) that are insufficient to supportde novosynthesis. Transcription of thefaboperon is regulated by FabT, a repressor protein that binds DNA only when it is bound to an acyl-ACP ligand. Since AcpA is encoded in thefaboperon, its synthesis is blocked when the operon is repressed andacpAthus cannot provide a stable supply of ACP for synthesis of the acyl-ACP ligand required for DNA binding by FabT. In contrast to AcpA,acpBtranscription is unaffected by growth with exogenous fatty acids and thus provides a stable supply of ACP for conversion to the acyl-ACP ligand required for repression by FabT. Indeed,ΔacpBandΔfabTstrains have essentially the samede novofatty acid synthesis phenotype in oleic acid-grown cultures, which argues that neither strain can form the FabT-acyl-ACP repression complex. Finally, acylated derivatives of both AcpB and AcpA were substrates for theE. faecalisenoyl-ACP reductases and forE. faecalisPlsX (acyl-ACP; phosphate acyltransferase).IMPORTANCEAcpB homologs are encoded by many, but not all, lactic acid bacteria (Lactobacillales), including many members of the human microbiome. The mechanisms regulating fatty acid synthesis by exogenous fatty acids play a key role in resistance of these bacteria to those antimicrobials targeted at fatty acid synthesis enzymes. Defective regulation can increase resistance to such inhibitors and also reduce pathogenesis.

Effects of pregnancy and ovarian steroids on fatty acid synthesis and uptake in Syrian hamsters

1991 ◽  
Vol 260 (1) ◽  
pp. R153-R158 ◽  
Author(s):  
A. J. Bhatia ◽  
G. N. Wade
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
White Adipose Tissue ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Ovarian Steroids ◽  
Syrian Hamsters

The effects of pregnancy and ovarian steroids on the in vivo distribution of newly synthesized fatty acids (incorporation of tritium from 3H2O into fatty acid) in Syrian hamsters (Mesocricetus auratus) were examined. During late, but not early, gestation hamsters had reduced levels of newly synthesized fatty acids in heart, liver, uterus, and white adipose tissues (parametrial and inguinal fat pads). Treatment of ovariectomized hamsters with estradiol + progesterone significantly decreased fatty acid synthesis-uptake in heart, liver, and inguinal white adipose tissue. Treatment with either estradiol or progesterone alone was without significant effect in any tissue. Pretreatment of hamsters with Triton WR-1339 (tyloxapol), an inhibitor of lipoprotein lipase activity and tissue triglyceride uptake, abolished the effects of estradiol + progesterone in white adipose tissue and heart but not in liver. Thus hamsters lose body fat during pregnancy in part because of decreased de novo lipogenesis. The effect of pregnancy on lipogenesis is mimicked by treatment with estradiol + progesterone but not by either hormone alone. Furthermore, it appears that the liver is the principal site of estradiol + progesterone action on lipogenesis in Syrian hamsters.

scholarly journals Staphylococcus aureusUtilizes Host-Derived Lipoprotein Particles as Sources of Fatty Acids

2018 ◽  
Vol 200 (11) ◽  
Author(s):  
Phillip C. Delekta ◽  
John C. Shook ◽  
Todd A. Lydic ◽  
Martha H. Mulks ◽  
Neal D. Hammer
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Acid Synthesis ◽  
Low Density ◽  
Content Type ◽  
Lipoprotein Particles ◽  
Bacterial Fatty Acid

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) is a threat to global health. Consequently, much effort has focused on the development of new antimicrobials that target novel aspects ofS. aureusphysiology. Fatty acids are required to maintain cell viability, and bacteria synthesize fatty acids using the type II fatty acid synthesis (FASII) pathway. FASII is significantly different from human fatty acid synthesis, underscoring the therapeutic potential of inhibiting this pathway. However, many Gram-positive pathogens incorporate exogenous fatty acids, bypassing FASII inhibition and leaving the clinical potential of FASII inhibitors uncertain. Importantly, the source(s) of fatty acids available to pathogens within the host environment remains unclear. Fatty acids are transported throughout the body by lipoprotein particles in the form of triglycerides and esterified cholesterol. Thus, lipoproteins, such as low-density lipoprotein (LDL), represent a potentially rich source of exogenous fatty acids forS. aureusduring infection. We sought to test the ability of LDLs to serve as a fatty acid source forS. aureusand show that cells cultured in the presence of human LDLs demonstrate increased tolerance to the FASII inhibitor triclosan. Using mass spectrometry, we observed that host-derived fatty acids present in the LDLs are incorporated into the staphylococcal membrane and that tolerance to triclosan is facilitated by the fatty acid kinase A, FakA, and Geh, a triacylglycerol lipase. Finally, we demonstrate that human LDLs support the growth ofS. aureusfatty acid auxotrophs. Together, these results suggest that human lipoprotein particles are a viable source of exogenous fatty acids forS. aureusduring infection.IMPORTANCEInhibition of bacterial fatty acid synthesis is a promising approach to combating infections caused byS. aureusand other human pathogens. However,S. aureusincorporates exogenous fatty acids into its phospholipid bilayer. Therefore, the clinical utility of targeting bacterial fatty acid synthesis is debated. Moreover, the fatty acid reservoir(s) exploited byS. aureusis not well understood. Human low-density lipoprotein particles represent a particularly abundantin vivosource of fatty acids and are present in tissues thatS. aureuscolonizes. Herein, we establish thatS. aureusis capable of utilizing the fatty acids present in low-density lipoproteins to bypass both chemical and genetic inhibition of fatty acid synthesis. These findings imply thatS. aureustargets LDLs as a source of fatty acids during pathogenesis.

scholarly journals Alternative substrates for triacylglycerol synthesis in isolated adipocytes of different size from the rat

1981 ◽  
Vol 194 (2) ◽  
pp. 377-384 ◽  
Author(s):  
A A Francendese ◽  
M Digirolamo
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Glucose Utilization ◽  
De Novo ◽  
Acid Synthesis ◽  
The Other ◽  
Fat Cells ◽  
Triacylglycerol Synthesis ◽  
Isolated Adipocytes ◽  
Metabolic Deficiency

The metabolic utilization of 14C-labelled acetate, pyruvate, lactate and glucose by isolated epididymal fat-cells was compared in two groups of rats fed ad libitum, one group young and lean (150-200 g body wt.), the other older and spontaneously obese (500-650 g body wt.). The influence of unlabelled glucose (6 mM) and insulin on substrate utilization by adipocytes was also studied. (1) Pyruvate and lactate were found to be good precursors for fatty-acid synthesis in small fat-cells, but not in larger fat-cells. On the other hand, lactate conversion into CO2 and the glycerol moiety of acylglycerols proceeded activity in both types of cells, and in some cases, it even exceeded the rates of glucose utilization. (2) The addition of glucose or glucose plus insulin, but not insulin alone, enhanced the metabolism of acetate, pyruvate and lactate in both types of fat-cells. (3) Fatty-acid synthesis de novo in large fat-cells was markedly decreased regardless of the substrate utilized. These findings point to lactate as a significant precursor for triacylglycerol synthesis in adipocytes. Furthermore, decreased fatty-acid synthesis de novo appears to be an acquired metabolic deficiency of enlarging adipocytes, independent of precursor substrate availability.

scholarly journals Triacylglycerol synthesis in goat mammary gland. Factors influencing the esterification of fatty acids synthesized de novo

1984 ◽  
Vol 220 (2) ◽  
pp. 521-527 ◽  
Author(s):  
H O Hansen ◽  
I Grunnet ◽  
J Knudsen
Keyword(s):  
Fatty Acids ◽  
Mammary Gland ◽  
Fatty Acid ◽  
De Novo ◽  
Acid Synthesis ◽  
Diacylglycerol Acyltransferase ◽  
Exogenous Fatty Acid ◽  
Triacylglycerol Synthesis ◽  
Membrane Bound

ATP alone had no effect on incorporation of fatty acids synthesized de novo and membrane-bound diacylglycerol into triacylglycerol. Combined addition of ATP and Mg2+ totally inhibits incorporation of fatty acids synthesized de novo and stimulated incorporation of membrane-bound diacylglycerol. ATP, Mg2+ and glycerol 3-phosphate stimulate incorporation of fatty acids synthesized de novo into triacylglycerol, but inhibited the incorporation of membrane-bound diacylglycerol. Diacylglycerol generated in situ was shown to be superior to diacylglycerols preloaded on the membrane as substrate for the diacylglycerol acyltransferase. A model is proposed to explain the effect of absorbed exogenous fatty acid on fatty acid synthesis de novo in goat mammary gland.

scholarly journals Triacylglycerol synthesis in goat mammary gland. The effect of ATP, Mg2+ and glycerol 3-phosphate on the esterification of fatty acids synthesized de novo

1984 ◽  
Vol 220 (2) ◽  
pp. 513-519 ◽  
Author(s):  
H O Hansen ◽  
I Grunnet ◽  
J Knudsen
Keyword(s):  
Fatty Acids ◽  
Mammary Gland ◽  
Fatty Acid ◽  
De Novo ◽  
Fatty Acid Synthetase ◽  
Acid Synthesis ◽  
Medium Chain ◽  
Medium Chain Fatty Acids ◽  
Triacylglycerol Synthesis ◽  
Chain Fatty Acids

Goat mammary-gland microsomal fraction by itself induces synthesis of medium-chain-length fatty acids by goat mammary fatty acid synthetase and incorporates short- and medium-chain fatty acids into triacylglycerol. Addition of ATP in the absence or presence of Mg2+ totally inhibits triacylglycerol synthesis from short- and medium-chain fatty acids, and severely inhibits synthesis de novo of medium-chain fatty acids. The inhibition by ATP of fatty acid synthesis and triacylglycerol synthesis de novo can be relieved by glycerol 3-phosphate. The effect of ATP could not be mimicked by the non-hydrolysable ATP analogue, adenosine 5′-[beta, gamma-methylene]triphosphate and could not be shown to be caused by inhibition of the diacylglycerol acyltransferase by a phosphorylation reaction. Possible explanations for the mechanism of the inhibition by ATP are discussed, and a hypothetical model for its action is outlined.

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