Toxic fatty aldehydes are generated during lipid metabolism and need to be neutralized by fatty aldehyde dehydrogenases to corresponding fatty acids. Loss of function of fatty aldehyde dehydrogenases is associated with neurologic disorders and cancers. Here, I characterized ALH-4, a fatty aldehyde dehydrogenase in C. elegans, and discovered that ALH-4 deficiency induces transcriptional upregulation of peroxisomal fatty acid oxidation genes and peroxisome proliferation through NHR-49 and NHR-79, and then reduces lipid storage. In addition, ALH-4 shows tissue-nonautonomous function. ALH-4 deficiency in the intestine induces peroxisome response in the hypodermis, implicating inter-tissue signaling. Interestingly, the responses mediated by NHR-49 are essential in ALH-4 deficient worms as ad...[ Read more ]

Toxic fatty aldehydes are generated during lipid metabolism and need to be neutralized by fatty aldehyde dehydrogenases to corresponding fatty acids. Loss of function of fatty aldehyde dehydrogenases is associated with neurologic disorders and cancers. Here, I characterized ALH-4, a fatty aldehyde dehydrogenase in C. elegans, and discovered that ALH-4 deficiency induces transcriptional upregulation of peroxisomal fatty acid oxidation genes and peroxisome proliferation through NHR-49 and NHR-79, and then reduces lipid storage. In addition, ALH-4 shows tissue-nonautonomous function. ALH-4 deficiency in the intestine induces peroxisome response in the hypodermis, implicating inter-tissue signaling. Interestingly, the responses mediated by NHR-49 are essential in ALH-4 deficient worms as additional loss of NHR-49 causes synthetic sterility. In human, loss of function of ALDH3A2, ALH-4 ortholog, causes Sjögren-Larsson Syndrome (SLS) with cutaneous and neuronal symptoms. The differential phenotypes and responses revealed in C. elegans could provide new point of views about the pathology and treatment of SLS.