Separation of two active forms (holo-a and holo-b) of pigeon liver fatty acid synthetase and their interconversion by phosphorylation and dephosphorylation

Qureshi, Asaf A.; Jenik, Robert A.; Kim, Manok; Lornitzo, Frank A.; Porter, John W.

doi:10.1016/s0006-291x(75)80334-2

Cited by 52 publications

(12 citation statements)

References 14 publications

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“…birds. Using pigeon liver as a model and exclusively studying FAS in the cytoplasm, Qureshi and colleagues found that feeding induced 32 P incorporation into FAS, which was associated with a loss of enzyme activity ( 24 ). In vitro treatment with phosphatases dephosphorylated FAS and restored enzyme activity.…”

Section: Discussionmentioning

confidence: 99%

Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα

Jensen-Urstad

Song

Lodhi

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org targeted to treat lipid disorders, diabetes, and obesity, is highly expressed in the liver. Its induction by fasting promotes lipid uptake, fatty acid ␤ -oxidation, ketogenesis, and gluconeogenesis ( 1, 2 ). Ligand binding to PPAR ␣ causes it to heterodimerize with retinoid X receptor (RXR) ␣ , allowing activation of gene transcription at peroxisome proliferator response elements (PPRE) ( 3, 4 ). Synthetic PPAR ␣ ligands, such as fi brates, used for human lipid disorders ( 5 ) have been known for decades, but potential endogenous ligands were identifi ed only recently ( 6, 7 ). Mice with liver-specifi c deletion of the lipogenic enzyme fatty acid synthase (FAS) have impaired PPAR ␣ activity ( 8 ), and FAS activates PPAR ␣ by producing an endogenous phospholipid ligand ( 6 ). FAS also activates PPAR ␣ in brain and macrophages ( 9, 10 ).Mammalian FAS synthesizes long-chain fatty acids, primarily palmitate, through the activities of seven functional domains: acyl carrier, acyl transferase, ␤ -ketoacyl synthase, ␤ -ketoacyl reductase, ␤ -hydroxyacyl dehydratase, enoyl reductase, and thioesterase ( 11 ). Like PPAR ␣ , FAS is highly expressed in liver ( 12 ). In times of nutrient excess, hepatic FAS converts carbohydrate to lipid that is stored in lipid droplets or secreted in the form of VLDL ( 13 ). Nutrient excess is associated with elevated levels of insulin, known to induce FAS expression.These accepted physiological roles for PPAR ␣ and FAS appear to confl ict with the observation that inactivation of FAS impairs PPAR ␣ activation. How might FAS activate a process stimulated by feeding such as insulin-responsive lipogenesis and also activate a process stimulated by fasting such as the induction of PPAR ␣ -dependent gene expression?We hypothesized that distinct subcellular pools of FAS mediate these disparate effects. Compartmentalization would permit regulation of an FAS pool generating lipids for signaling that would be distinct from an FAS pool generating lipids for energy storage. In support of this hypothesis, Abstract Peroxisome proliferator-activated receptor (PPAR) ␣ is a nuclear receptor that coordinates liver metabolism during fasting. Fatty acid synthase (FAS) is an enzyme that stores excess calories as fat during feeding, but it also activates hepatic PPAR ␣ by promoting synthesis of an endogenous ligand. Here we show that the mechanism underlying this paradoxical relationship involves the differential regulation of FAS in at least two distinct subcellular pools: cytoplasmic and membrane-associated. In mouse liver and cultured hepatoma cells, the ratio of cytoplasmic to membrane FAS-specifi c activity was increased with fasting, indicating higher cytoplasmic FAS activity under conditions associated with PPAR ␣ activation. This effect was due to a nutrient-dependent and compartment-selective covalent modifi cation of FAS. Cytoplasmic FAS was preferentially phosphorylated during feeding or insulin treatment at Thr-1029 and Thr-1033, which fl ank a d...

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Section: Discussionmentioning

confidence: 99%

Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα

Jensen-Urstad

Song

Lodhi

et al. 2013

Journal of Lipid Research

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“…In livers from pigeons that were fasted and then re-fed, radiolabeled phosphate was incorporated into FAS only in the cytosolic fraction. The phosphorylation event was associated with low FAS activity, and dephosphorylation of FAS by incubation with phosphatases caused a 20-fold increase in FAS activity [81]. Another inhibitory phosphorylation was demonstrated in 3T3L1 adipocytes, where FAS threonine phosphorylation was associated with inhibition of FAS activity [77].…”

Section: Regulation Of Fas Activitymentioning

confidence: 99%

Fatty acid synthase and liver triglyceride metabolism: Housekeeper or messenger?

Jensen-Urstad

Semenkovich

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

321

201

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Fatty acid synthase (FAS) catalyzes the de novo synthesis of fatty acids. In the liver, FAS has long been categorized as a housekeeping protein, producing fat for storage of energy when nutrients are present in excess. Most previous studies of FAS regulation have focused on the control of gene expression. However, recent findings suggest that hepatic FAS may also be involved in signaling processes that include activation of peroxisome proliferator-activated receptor α (PPARα). Moreover, reports of rapid alterations in FAS activity and as well as findings of post-translational modifications of the FAS protein support the notion that dynamic events in addition to transcription impact FAS regulation. These results indicate that FAS enzyme activity can impact liver physiology through signaling as well as energy storage and that its regulation may be complex.

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“…89 It was also suggested that hepatic fatty acid synthetase may be regulated by phosphorylation-dephosphorylation. 123 However, any link with cyclic AMP remains to be established. In fact, Klain and Weiser 36 did not observe any change in the activity of the enzyme with animals injected with glucagon, and Witters et al were unable to demonstrate any change in the activity of this enzyme in isolated hepatocytes after incubation with insulin and glucagon 55 or in 32 P-labeling of the enzyme after incubation with glucagon.…”

Section: Hormonal Regulation Of Fatty Acid Synthesismentioning

confidence: 99%

Short-term Hormonal Control of Hepatic Lipogenesis

et al. 1980

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L ipids are essential components of all living cells, functioning as an energy store and playing an important role in all biologic membranes. Triacylglycerols, the storage form and most abundant of the glycerolipids, represent a highly concentrated form of energy, yielding twice as many calories per gram as carbohydrate or protein. The phospholipids are amphipathic compounds which, along with cholesterol, are found in membranes where they interact to provide a polar-faced, hydrophobic continuum of critical importance for proper cell structure and function.A major function of lipogenesis is to store (as triacylglycerols) the chemical energy or foodstuffs ingested above the immediate requirements of an organism. Contrary to protein, which is not stored, and to carbohydrate, which can only be stored in limited quantities, the capacity to store triacylglycerols is almost unlimited. The ability to keep large amounts of triacylglycerols on board would not be useful, however, if it were not possible to quickly and efficiently stop diverting foodstuffs into triacylglycerol formation and to quickly and efficiently start utilizing these compounds to provide the energy necessary to synthesize ATP. For this reason, mechanisms have evolved which finely tune the synthesis and degradation of triacylglycerol to the ever changing demand for ATP. In contrast, phospholipid and cholesterol synthesis must be, at least, partially maintained (or their degradation curtailed), even in the face of limited food intake or frank starvation, to provide sufficient quantities of these lipids to fulfill their crucial role in biologic membranes.In rodents the proportion of total body fatty acids synthesized by the liver ranges from 3% (fasted animals) to 50% (in animals force fed with glucose). 1 ' 2 Even greater percentages are synthesized in the human 3 and avian 4 liver. Dietary control of lipogenesis is more pronounced and more prompt in the liver than in any other tissue, further emphasizing the fact that the liver is of considerable importance as a lipogenic organ. 1 The rate of lipogenesis in mammalian liver is regulated by two types of mechanisms, distinguished by the time required for them to take effect. One involves long-term, adaptive changes in enzyme activity, due to fluctuations in the absolute amounts of the key lipogenic enzymes. 5 " 10 This type of regulation is subject to hormonal and nutritional factors and takes a few hours to come into effect. The other involves short-term mechanisms, which operate on a minute to minute basis. The latter, involving modulation of enzymatic activity by substrate supply, allosteric effectors, and interconversion of enzymes between active and inactive forms by a phosphorylation cycle, has not received as much attention as have the long-term adaptive changes of the lipogenic enzymes and is not as well understood as a means of regulating lipogenesis. In this review, we will focus attention on conditions and factors, e.g., hormones, that bring about rapid changes in the rate of hepatic lipogenesis;...

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Separation of two active forms (holo-a and holo-b) of pigeon liver fatty acid synthetase and their interconversion by phosphorylation and dephosphorylation

Cited by 52 publications

References 14 publications

Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα

Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα

Fatty acid synthase and liver triglyceride metabolism: Housekeeper or messenger?

Short-term Hormonal Control of Hepatic Lipogenesis

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