Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency in C. elegans

AbstractThe intracellular level of fatty aldehydes is tightly regulated to minimize the formation of toxic aldehyde adducts of cellular components. Accordingly, deficiency of a fatty aldehyde dehydrogenase FALDH causes the neurologic disorder Sjögren-Larsson syndrome (SLS) in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Based on lipidomic and imaging analysis, we report that the loss of endoplasmic reticulum-, mitochondria- and peroxisomes-associated ALH-4, the C. elegans FALDH ortholog, increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency since alh-4; nhr-49 double mutant animals are not viable. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels, and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy for SLS.

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Nuclear receptors NHR-49 and NHR-79 promote peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency in C. elegans

PLoS Genetics ◽

10.1371/journal.pgen.1009635 ◽

2021 ◽

Vol 17 (7) ◽

pp. e1009635

Author(s):

Lidan Zeng ◽

Xuesong Li ◽

Christopher B. Preusch ◽

Gary J. He ◽

Ningyi Xu ◽

...

Keyword(s):

Aldehyde Dehydrogenase ◽

Therapeutic Strategy ◽

Fatty Aldehyde ◽

Peroxisome Proliferation ◽

Imaging Analysis ◽

Neurologic Disorder ◽

Aldehyde Dehydrogenases ◽

C Elegans ◽

Catabolic Enzymes ◽

Fatty Aldehydes

The intracellular level of fatty aldehydes is tightly regulated by aldehyde dehydrogenases to minimize the formation of toxic lipid and protein adducts. Importantly, the dysregulation of aldehyde dehydrogenases has been implicated in neurologic disorder and cancer in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Here, we report that ALH-4 is a C. elegans aldehyde dehydrogenase that specifically associates with the endoplasmic reticulum, mitochondria and peroxisomes. Based on lipidomic and imaging analysis, we show that the loss of ALH-4 increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency since alh-4; nhr-49 double mutant animals are sterile. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy to tackle pathology related to excess fatty aldehydes.

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Fatty aldehyde dehydrogenase, the enzyme downstream of tetrahydrobiopterin-dependent alkylglycerol monooxygenase

Pteridines ◽

10.1515/pterid-2013-0004 ◽

2013 ◽

Vol 24 (1) ◽

pp. 105-109 ◽

Cited By ~ 2

Author(s):

Markus A. Keller ◽

Katrin Watschinger ◽

Georg Golderer ◽

Gabriele Werner-Felmayer ◽

Ernst R. Werner

Keyword(s):

Aldehyde Dehydrogenase ◽

Treatment Options ◽

Ether Lipid ◽

Signalling Pathways ◽

Fatty Aldehyde ◽

Ether Lipids ◽

Lipid Degradation ◽

Physiological Importance ◽

Fatty Aldehydes ◽

Larsson Syndrome

AbstractThe tetrahydrobiopterin-dependent degradation of ether lipids by alkylglycerol monooxygenase (AGMO) produces fatty aldehydes, which are toxic to cells. Therefore, it is of great physiological importance that these harmful compounds are converted into their corresponding, less toxic fatty acids by fatty aldehyde dehydrogenase (FALDH). Dysfunction of this enzyme causes Sjögren-Larsson syndrome. This severe inherited disorder is accompanied by symptoms such as ichthyosis, mental retardation and spasticity. Surprisingly, fatty alcohols and not fatty aldehydes were found to accumulate in fibroblasts of Sjögren-Larsson syndrome patients, suggesting that there can be wide-ranging alterations in the lipid composition of patient cells. In particular, this has to be considered when searching for possible treatment options for patients suffering from Sjögren-Larsson syndrome. For example, inhibition of fatty aldehyde producing ether lipid degradation would have multiple implications on ether lipid- and fatty alcohol-mediated signalling pathways.

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A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase

Nature Communications ◽

10.1038/ncomms5439 ◽

2014 ◽

Vol 5 (1) ◽

Cited By ~ 35

Author(s):

Markus A. Keller ◽

Ulrich Zander ◽

Julian E. Fuchs ◽

Christoph Kreutz ◽

Katrin Watschinger ◽

...

Keyword(s):

Substrate Specificity ◽

Aldehyde Dehydrogenase ◽

Fatty Aldehyde ◽

Larsson Syndrome

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Five Fatty Aldehyde Dehydrogenase Enzymes from Marinobacter and Acinetobacter spp. and Structural Insights into the Aldehyde Binding Pocket

Applied and Environmental Microbiology ◽

10.1128/aem.00018-17 ◽

2017 ◽

Vol 83 (12) ◽

Cited By ~ 3

Author(s):

Jonathan H. Bertram ◽

Kalene M. Mulliner ◽

Ke Shi ◽

Mary H. Plunkett ◽

Peter Nixon ◽

...

Keyword(s):

Aldehyde Dehydrogenase ◽

Binding Pocket ◽

Fatty Aldehyde ◽

Acinetobacter Baylyi ◽

Central Function ◽

Content Type ◽

Energy Conversion And Storage ◽

Acinetobacter Spp ◽

Fatty Aldehydes ◽

And Storage

ABSTRACT Enzymes involved in lipid biosynthesis and metabolism play an important role in energy conversion and storage and in the function of structural components such as cell membranes. The fatty aldehyde dehydrogenase (FAldDH) plays a central function in the metabolism of lipid intermediates, oxidizing fatty aldehydes to the corresponding fatty acid and competing with pathways that would further reduce the fatty aldehydes to fatty alcohols or require the fatty aldehydes to produce alkanes. In this report, the genes for four putative FAldDH enzymes from Marinobacter aquaeolei VT8 and an additional enzyme from Acinetobacter baylyi were heterologously expressed in Escherichia coli and shown to display FAldDH activity. Five enzymes (Maqu_0438, Maqu_3316, Maqu_3410, Maqu_3572, and the enzyme reported under RefSeq accession no. WP_004927398 ) were found to act on aldehydes ranging from acetaldehyde to hexadecanal and also acted on the unsaturated long-chain palmitoleyl and oleyl aldehydes. A comparison of the specificities of these enzymes with various aldehydes is presented. Crystallization trials yielded diffraction-quality crystals of one particular FAldDH (Maqu_3316) from M. aquaeolei VT8. Crystals were independently treated with both the NAD+ cofactor and the aldehyde substrate decanal, revealing specific details of the likely substrate binding pocket for this class of enzymes. A likely model for how catalysis by the enzyme is accomplished is also provided. IMPORTANCE This study provides a comparison of multiple enzymes with the ability to oxidize fatty aldehydes to fatty acids and provides a likely picture of how the fatty aldehyde and NAD+ are bound to the enzyme to facilitate catalysis. Based on the information obtained from this structural analysis and comparisons of specificities for the five enzymes that were characterized, correlations to the potential roles played by specific residues within the structure may be drawn.

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