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: Shanshan Pang, Dana A Lynn, Jacqueline Y Lo, Jennifer Paek, Sean P Curran
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 5048 (Oct 06 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 25284427 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Caenorhabditis elegans Proteins
• DNA-Binding Proteins
• Fatty Acids
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Transcription Factors
• skn-1 protein, C elegans
• Proline
• 1-Pyrroline-5-Carboxylate Dehydrogenase
• ALDH4A1 protein, human
• Oxygen

Topics

• 1-Pyrroline-5-Carboxylate Dehydrogenase (metabolism)
• Animals
• Caenorhabditis elegans
• Caenorhabditis elegans Proteins (metabolism)
• DNA-Binding Proteins (metabolism)
• Fatty Acids (chemistry)
• Food
• HEK293 Cells
• Humans
• Lipid Metabolism
• Metabolism
• NF-E2-Related Factor 2 (metabolism)
• Oxidative Stress
• Oxygen (chemistry)
• Proline (genetics, metabolism)
• RNA Interference
• Transcription Factors (metabolism)