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Updated: Sep 30, 2026

Lipid Supplementation for Longevity and Gene Transcriptional Analysis in Caenorhabditis elegans
Published on: December 9, 2022
Krüppel-like factors regulate lipid homeostasis to modulate SKN-1/Nrf activity, oxidative stress resistance and
Jorge Iván Castillo-Quan1, Aiden McCarty2, Ugne Kurdeikaite1,2
1Joslin Diabetes Center, Harvard Medical School, Harvard University, Boston, MA 02215, USA.
Abstract:
Maintenance of lipid and redox homeostasis is essential for stress resistance and longevity, but the transcriptional networks coordinating these processes remain incompletely understood. In Caenorhabditis elegans, the transcription factors SKN-1A/Nrf1 and SKN-1C/Nrf2 mediate distinct stress responses that promote proteostasis, lipid homeostasis, and oxidative stress resistance. Here, we identify the Krüppel-like factor KLF-1 as a regulator of lipid accumulation that modulates SKN-1 activity. KLF-1 was required for SKN-1A and SKN-1C activation and for the oxidative stress resistance and longevity of germline-deficient animals, without changing skn-1 transcript abundance. KLF-1 selectively modulated the lipid homeostatic response of SKN-1A but was dispensable for its proteasome recovery response. Genetic and supplementation experiments further indicated that KLF-1 influences SKN-1A activation through lipid accumulation, while its regulation of SKN-1C involves both lipid-dependent and lipid-independent mechanisms. KLF-1 and the related KLF-2 exerted opposing effects on lipid accumulation while acting independently of the lipogenic regulator Sterol regulatory element-Binding Protein 1 (SBP-1/SREBP1). Consistent with these opposing effects, KLF-1 and KLF-2 regulated the expression of unc-51/ULK1, atg-9/ATG9A, and lipl-1/LIPJ/K in opposite directions, implicating lipophagy-associated pathways in their regulation of lipid homeostasis. Together, these findings establish KLF-dependent regulation of lipid homeostasis as an upstream physiological determinant of SKN-1 activity, linking lipid metabolism with oxidative stress resistance and longevity.
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