title: SKN-1 and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation.
abstract: Mechanisms that coordinate different metabolic pathways, such as glucose and lipid, have been recognized. However, a potential interaction between amino acid and lipid metabolism remains largely elusive. Here we show that during starvation of Caenorhabditis elegans, proline catabolism is coupled with lipid metabolism by SKN-1. Mutation of alh-6, a conserved proline catabolic enzyme, accelerates fat mobilization, enhances the expression of genes involved in fatty acid oxidation and reduces survival in response to fasting. This metabolic coordination is mediated by the activation of the transcription factor SKN-1/Nrf2, possibly due to the accumulation of the alh-6 substrate P5C, and also requires the transcriptional co-regulator MDT-15. Constitutive activation of SKN-1 induces a similar transcriptional response, which protects animals from fat accumulation when fed a high carbohydrate diet. In human cells, an orthologous alh-6 enzyme, ALDH4A1, is also linked to the activity of Nrf2, the human orthologue of SKN-1, and regulates the expression of lipid metabolic genes. Our findings identify a link between proline catabolism and lipid metabolism, and uncover a physiological role for SKN-1 in metabolism.
authors.affiliation: Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Pang
authors.affiliation: 1] Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089, USA [2] Department of Molecular and Computational Biology, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Dana A
authors.initials: DA
authors.lastname: Lynn
authors.affiliation: 1] Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089, USA [2] Department of Molecular and Computational Biology, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Jacqueline Y
authors.initials: JY
authors.lastname: Lo
authors.affiliation: Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Paek
authors.affiliation: 1] Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089, USA [2] Department of Molecular and Computational Biology, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California 90089, USA [3] Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Curran
mesh_terms: D050842:1-Pyrroline-5-Carboxylate Dehydrogenase / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005227:Fatty Acids / Q000737:chemistry; D005502:Food; D057809:HEK293 Cells; D006801:Humans; D050356:Lipid Metabolism; D008660:Metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D011392:Proline / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D014157:Transcription Factors; C073702:skn-1 protein, C elegans; D011392:Proline; D050842:1-Pyrroline-5-Carboxylate Dehydrogenase; C494240:ALDH4A1 protein, human; D010100:Oxygen