Abstract
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.
Highlights
Glycerophospholipids and sphingolipids are major components of biological membranes [1]
Fatty aldehydes are generated during the turnover of membrane lipids and when cells are under oxidative stress
Because excess fatty aldehydes form toxic adducts with proteins and lipids, their levels are tightly controlled by a family of aldehyde dehydrogenases whose dysfunction has been implicated in genetic disease and cancer in humans
Summary
Glycerophospholipids and sphingolipids are major components of biological membranes [1]. The regulated turnover of their head groups and acyl chains alters membrane structural properties such as fluidity, thickness and curvature. Membrane derived polyunsaturated fatty acids are essential precursors of eicosanoids and endocannabinoids that modulate inflammatory response [2]. Polyunsaturated acyl chains are prone to attack by reactive oxygen species (ROS), which are generated by metabolic activities and environmental factors [3]. Such peroxidation of PUFAs generates short chain and medium chain fatty aldehydes [4]. Long chain fatty aldehydes can be derived from the metabolism of sphingolipids, etherlipids and fatty alcohols [5]. The level of cellular fatty aldehydes is under tight regulation via the conserved aldehyde dehydrogenase (ALDH) superfamily [8]
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