Drosophila NPC1b Promotes an Early Step in Sterol Absorption from the Midgut Epithelium

Voght, Stephen P.; Fluegel, Megan L.; Andrews, Laurie A.; Pallanck, Leo J.

doi:10.1016/j.cmet.2007.01.011

Cited by 84 publications

(98 citation statements)

References 34 publications

(47 reference statements)

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“…Consistent with this, we found that DHR96 is expressed in the region of the larval midgut, where npc1b exerts its functions ( Fig. 4A; King-Jones et al 2006;Voght et al 2007). This overlap in DHR96 and npc1b expression also appears to be functionally significant because specific expression of wild-type DHR96 in the midgut of DHR96 mutants is sufficient to restore appropriate npc1b transcriptional repression in response to cholesterol (Fig.…”

Section: Dhr96 Mutants Accumulate Cholesterolsupporting

confidence: 71%

“…(*) P < 0.05; (**) P < 0.01; (***) P < 1 3 10 À4 . cholesterol levels seen in npc1b mutants at this stage of development, which likely derive from maternal loading of cholesterol during oogenesis (Voght et al 2007). …”

Section: Dhr96 Mutants Accumulate Cholesterolmentioning

confidence: 99%

“…Control larvae, DHR96 1 mutants, npc1b 1 mutants, and npc1b 1 ;DHR96 1 double mutants were grown on the lowcholesterol medium in the presence of 3 H-cholesterol. Radioactive glucose was also added to the food in order to normalize the levels of cholesterol absorption and to control for different feeding rates (Voght et al 2007). Under these conditions, DHR96 mutants display a similar level of cholesterol uptake as wild-type larvae (Fig.…”

Section: Dhr96 Mutants Accumulate Cholesterolmentioning

confidence: 99%

“…(A) DHR96 and npc1b are both expressed in the midgut. Midguts were dissected from NPC1b-GAL4;UASnGFP third instar larvae (NCP1b > nGFP) (Voght et al 2007) and stained with affinity-purified antibodies to detect DHR96 protein. DHR96 protein is shown in red, and NPC1b expression is shown in green.…”

Section: Dhr96 Mutants Accumulate Cholesterolmentioning

confidence: 99%

“…Little is known, however, about the mechanisms that regulate the uptake of dietary cholesterol in Drosophila. A recent study showed that the fly ortholog of NPC1L1, npc1b, is expressed specifically in the midgut and is essential for dietary cholesterol absorption (Voght et al 2007). Other NPC disease gene homologs in Drosophila also contribute to cholesterol homeostasis.…”

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The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

Horner¹,

Pardee²,

et al. 2009

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Cholesterol homeostasis is required to maintain normal cellular function and avoid the deleterious effects of hypercholesterolemia. Here we show that the Drosophila DHR96 nuclear receptor binds cholesterol and is required for the coordinate transcriptional response of genes that are regulated by cholesterol and involved in cholesterol uptake, trafficking, and storage. DHR96 mutants die when grown on low levels of cholesterol and accumulate excess cholesterol when maintained on a high-cholesterol diet. The cholesterol accumulation phenotype can be attributed to misregulation of npc1b, an ortholog of the mammalian Niemann-Pick C1-like 1 gene NPC1L1, which is essential for dietary cholesterol uptake. These studies define DHR96 as a central regulator of cholesterol homeostasis. Cholesterol is an essential component of cell membranes that influences the permeability and fluidity of the lipid bilayer. Cholesterol also acts as a precursor for steroid hormone biosynthesis and contributes to cell-cell signaling pathways. These critical cellular functions are supported by regulatory mechanisms that maintain normal cholesterol levels and prevent hypercholesterolemia, which is a major risk factor for cardiovascular disease in humans. Cholesterol homeostasis in vertebrates is achieved primarily through de novo synthesis and dietary uptake (Ikonen 2008). Although extensive studies have defined a central role for the sterol regulatory elementbinding protein (SREBP) family of transcription factors in controlling cholesterol synthesis (Brown and Goldstein 1997), the mechanisms that regulate dietary cholesterol absorption remain more poorly understood. One central component of this pathway is the Niemann-Pick C1-like 1 gene NPC1L1, which encodes a plasma membrane protein that mediates the uptake of dietary cholesterol by the intestine (Wang 2007;Ge et al. 2008). Mouse mutants for NPC1L1 display significantly reduced levels of cholesterol absorption and are insensitive to treatment with the anti-hypercholesterolemia drug ezetimibe, which acts as a specific NPC1L1 inhibitor (Davis et al. 2008). Another major regulator of cholesterol homeostasis is the liver X receptor a (LXRa) nuclear receptor, which binds cholesterol metabolites and regulates the transcription of genes that control cholesterol transport and metabolism, including NPC1L1 (Duval et al. 2006;Kalaany and Mangelsdorf 2006;Valasek et al. 2007).We used the fruit fly, Drosophila, as a model system to study the regulation of cholesterol homeostasis. Unlike vertebrates, insects are cholesterol auxotrophs that are unable to synthesize this essential compound (Va'nt Hoog 1936). Little is known, however, about the mechanisms that regulate the uptake of dietary cholesterol in Drosophila. A recent study showed that the fly ortholog of NPC1L1, npc1b, is expressed specifically in the midgut and is essential for dietary cholesterol absorption (Voght et al. 2007). Other NPC disease gene homologs in Drosophila also contribute to cholesterol homeostasis. The Drosophila ortholog of vert...

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Section: Dhr96 Mutants Accumulate Cholesterolsupporting

confidence: 71%

Section: Dhr96 Mutants Accumulate Cholesterolmentioning

confidence: 99%

Section: Dhr96 Mutants Accumulate Cholesterolmentioning

confidence: 99%

Section: Dhr96 Mutants Accumulate Cholesterolmentioning

confidence: 99%

mentioning

confidence: 99%

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The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

Horner¹,

Pardee²,

et al. 2009

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A journey into the world of insect lipid metabolism

Toprak¹,

Hegedus

Doğan³

et al. 2020

Arch Insect Biochem Physiol

116

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Lipid metabolism is fundamental to life. In insects, it is critical, during reproduction, flight, starvation, and diapause. The coordination center for insect lipid metabolism is the fat body, which is analogous to the vertebrate adipose tissue and liver. Fat body contains various different cell types; however, adipocytes and oenocytes are the primary cells related to lipid metabolism. Lipid metabolism starts with the hydrolysis of dietary lipids, absorption of lipid monomers, followed by lipid transport from midgut to the fat body, lipogenesis or lipolysis in the fat body, and lipid transport from fat body to other sites demanding energy. Lipid metabolism is under the control of hormones, transcription factors, secondary messengers and posttranscriptional modifications. Primarily, lipogenesis is under the control of insulin‐like peptides that activate lipogenic transcription factors, such as sterol regulatory element‐binding proteins, whereas lipolysis is coordinated by the adipokinetic hormone that activates lipolytic transcription factors, such as forkhead box class O and cAMP‐response element‐binding protein. Calcium is the primary–secondary messenger affecting lipid metabolism and has different outcomes depending on the site of lipogenesis or lipolysis. Phosphorylation is central to lipid metabolism and multiple phosphorylases are involved in lipid accumulation or hydrolysis. Although most of the knowledge of insect lipid metabolism comes from the studies on the model Drosophila; other insects, in particular those with obligatory or facultative diapause, also have great potential to study lipid metabolism. The use of these models would significantly improve our knowledge of insect lipid metabolism.

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Functional analysis of a NPC1 gene from the whitefly, Bemisia tabaci (Hemiptera: Aleyrodidae)

Yu,

Wang,

Liu

et al. 2023

Arch Insect Biochem Physiol

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Niemann‐Pick C (NPC) disease is a neurodegenerative disorder related to cellular sterol trafficking and mutation of NPC1 gene is the main cause for this disease. The function of NPC1 have been reported in a few insects but rarely studied in hemipterans. In the present study, we investigate the function of NPC1 in a hemipteran pest, the whitefly Bemisia tabaci. It was found that B. tabaci had only one NPC1 homolog (BtNPC1), in contrast to two homologs in many other insects. BtNPC1 was ubiquitously expressed at all developmental stages and body parts of whiteflies, with the highest level in adult abdomen, and the expression of BtNPC1 was induced by cholesterol feeding. To further investigate the function of BtNPC1, leaf‐mediated RNA interference experiments were carried out. Results showed that knockdown of BtNPC1 led to reduced survival of whiteflies, as well as reduced fecundity. Moreover, knockdown of BtNPC1 affected the development and metamorphosis of whitefly nymphs. Taken these together, we conclude that BtNPC1 played a crucial role in sterol‐related biological processes of B. tabaci and might be used as an insecticide target for development of novel pest management approaches.

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Drosophila NPC1b Promotes an Early Step in Sterol Absorption from the Midgut Epithelium

Cited by 84 publications

References 34 publications

The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

A journey into the world of insect lipid metabolism

Functional analysis of a NPC1 gene from the whitefly, Bemisia tabaci (Hemiptera: Aleyrodidae)

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