Alternative lipid mobilization: The insect shuttle system

Horst, Dick J. Van der; Hoof, Dennis Van; Marrewijk, W.J.A. Van; Rodenburg, Kees W.

doi:10.1007/978-1-4419-9270-3_15

Cited by 40 publications

(63 citation statements)

References 33 publications

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“…Similar to mammals, Drosophila store energy from surplus calories in the form of triglycerides in specialized lipid dropletcontaining cells (17). In flies that were exposed to diet-restriction, inhibition of the TSP significantly reduced levels of triglyceride and significantly increased levels of protein (Fig.…”

Section: Resultsmentioning

confidence: 96%

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Kabil

Banerjee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

129

154

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The mechanisms through which dietary restriction enhances health and longevity in diverse species are unclear. The transsulfuration pathway (TSP) is a highly conserved mechanism for metabolizing the sulfur-containing amino acids, methionine and cysteine. Here we show that Drosophila cystathionine β-synthase (dCBS), which catalyzes the rate-determining step in the TSP, is a positive regulator of lifespan in Drosophila and that the pathway is required for the effects of diet restriction on animal physiology and lifespan. dCBS activity was up-regulated in flies exposed to reduced nutrient conditions, and ubiquitous or neuron-specific transgenic overexpression of dCBS enhanced longevity in fully fed animals. Inhibition of the TSP abrogated the changes in lifespan, adiposity, and protein content that normally accompany diet restriction. RNAi-mediated knockdown of dCBS also limited lifespan extension by diet. Diet restriction reduced levels of protein translation in Drosophila, and we show that this is largely caused by increased metabolic commitment of methionine cycle intermediates to transsulfuration. However, dietary supplementation of methionine restored normal levels of protein synthesis to restricted animals without affecting lifespan, indicating that global reductions in translation alone are not required for diet-restriction longevity. Our results indicate a mechanism by which dietary restriction influences physiology and aging.hydrogen sulfide | essential amino acids | metabolism | healthspan F or a broad range of taxonomically diverse organisms, the quality of their diet acts as a powerful modulator of health and longevity through molecular mechanisms that are largely unknown. Lifespan is extended, for example, when food is restricted to an extent that falls short of inducing starvation. In mammals, this manipulation, which is often called dietary restriction (DR), not only increases lifespan but also imparts a broad-spectrum improvement in health during aging. In humans, for example, DR reduces risk factors for diabetes, cardiovascular disease, and cancer (1).Transsulfuration is an evolutionarily ancient metabolic process that involves a network of enzymes responsible for the metabolism of sulfur-containing amino acids. The transsulfuration pathway (TSP) has been studied extensively in mammals, in which it has been shown to direct the conversion of homocysteine to cysteine following the breakdown of methionine, an essential amino acid. Flux through the TSP is known to affect overall cellular metabolism by directly influencing cysteine and methionine levels. Methionine availability affects protein synthesis and methylation, and it has been implicated in murine aging (2). Cysteine availability controls the synthesis of glutathione (GSH), which is the chief regulator of cellular redox homeostasis and an important agent in xenobiotic detoxification (Fig. 1A). Patients with genetic defects in the TSP are characterized by high levels of homocysteine, low levels of GSH, and increased incidence of age-related path...

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Section: Resultsmentioning

confidence: 96%

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Kabil

Banerjee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

129

154

View full text Add to dashboard Cite

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“…Their lipoproteins and lipoprotein receptors resemble those of vertebrates (van der Horst et al, 2002;Van der Horst et al, 2009;Khaliullina et al, 2010) and the functionally conserved BBB is formed by septate junctions composed of molecules almost identical to those in vertebrate tight junctions (Awasaki et al, 2008;Stork et al, 2008;Mayer et al, 2009). Here, we investigate whether the Drosophila lipoprotein lipophorin (Lpp) crosses the larval BBB, and whether it influences larval brain development.…”

Section: Introductionmentioning

confidence: 99%

Lipoprotein Particles Cross the Blood–Brain Barrier inDrosophila

Brankatschk

Eaton

2010

J. Neurosci.

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The blood-brain barrier (BBB) regulates passage of nutrients and signaling molecules from the circulation into the brain. Whether lipoproteins cross the BBB in vivo has been controversial, and no clear requirement for circulating lipoproteins in brain development has been shown. We address these issues in Drosophila, which has an functionally conserved BBB, and lipoproteins that resemble those of vertebrates. We show that the Drosophila lipoprotein lipophorin exists in two isoforms. Both isoforms cross the BBB, but accumulate on distinct subsets of cells within the brain. In addition to acting as a lipid carrier, lipophorin carries both sterol-linked and GPI-linked proteins into the circulation and transports them across the BBB. Finally, lipophorin promotes neuroblast proliferation by a mechanism that does not depend on delivery of dietary lipids. Transport of lipophorin and its cargo across the BBB represents a novel mechanism by which peripherally synthesized proteins might enter the brain and influence its development. Furthermore, lipid-linkage may be an efficient method to transport therapeutic molecules across the BBB.

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“…Vertebrate lipoprotein particles are scaffolded by apolipoproteins and consist of a phospholipid monolayer surrounding a core of esterified cholesterol and triglycerides. Insects form similar particles that are called Lipophorins (Lp) and contain Apolipophorins I and II (ApoLI and ApoLII) (30,31). These proteins are produced in the fat body (32) by cleavage of the precursor pro-Apolipophorin (32,33), and are not synthesized by imaginal disk cells (34) but receive them through the hemolymph.…”

mentioning

confidence: 99%

Patched, the receptor of Hedgehog, is a lipoprotein receptor

Callejo

Culí

Guerrero

2008

Proc. Natl. Acad. Sci. U.S.A.

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The Hedgehog (Hh) family of secreted signaling proteins has a broad variety of functions during metazoan development and implications in human disease. Despite Hh being modified by two lipophilic adducts, Hh migrates far from its site of synthesis and programs cellular outcomes depending on its local concentrations. Recently, lipoproteins were suggested to act as carriers to mediate Hh transport in Drosophila. Here, we examine the role of lipophorins (Lp), the Drosophila lipoproteins, in Hh signaling in the wing imaginal disk, a tissue that does not express Lp but obtains it through the hemolymph. We use the up-regulation of the Lp receptor 2 (LpR2), the main Lp receptor expressed in the imaginal disk cells, to increase Lp endocytosis and locally reduce the amount of available free extracellular Lp in the wing disk epithelium. Under this condition, secreted Hh is not stabilized in the extracellular matrix. We obtain similar results after a generalized knock-down of hemolymph Lp levels. These data suggest that Hh must be packaged with Lp in the producing cells for proper spreading. Interestingly, we also show that Patched (Ptc), the Hh receptor, is a lipoprotein receptor; Ptc actively internalizes Lp into the endocytic compartment in a Hh-independent manner and physically interacts with Lp. Ptc, as a lipoprotein receptor, can affect intracellular lipid homeostasis in imaginal disk cells. However, by using different Ptc mutants, we show that Lp internalization does not play a major role in Hh signal transduction but does in Hh gradient formation.Drosophila ͉ LDLR ͉ morphogen

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Alternative lipid mobilization: The insect shuttle system

Cited by 40 publications

References 33 publications

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Lipoprotein Particles Cross the Blood–Brain Barrier inDrosophila

Patched, the receptor of Hedgehog, is a lipoprotein receptor

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