Dysfunction of an energy sensor NFE2L1 triggers uncontrollable AMPK signal and glucose metabolism reprogramming

Abstract

NFE2L1/Nrf1, the core regulator involved in redox homeostasis, is essential for embryonic development and material metabolism homeostasis. Dysfunction of NFE2L1 could induce multiple systemic metabolic diseases. However, the underlying molecular mechanism of NFE2L1 in regulating glycose and lipid metabolism is still unclear. Herein, the glucose starvation experiments verified that the loss of NFE2L1 in human hepatocarcinoma HepG2 cells would lead to a lethal phenotype when glucose deprivation. And the glucose uptake experiments showed that NFE2L1 could affect the absorption of glucose by cells. Then, selective inhibition of glucose metabolism and protein deglycosylation experiments showed that the glycation of NFE2L1 was regulated by glycolysis. These results suggested that NFE2L1 functioned as both the sensor and the regulator of glucose homeostasis. Transcriptome, metabolome and seahorse results revealed that damage of NFE2L1 reprogrammed glucose metabolism and aggravated the Warburg effect. And the electron microscopy results revealed that NFE2L1 knockdown damaged the mitochondrial. Proteins Co-immunoprecipitation experiments demonstrated that NFE2L1 could sense the energy state and directly regulate AMPK signal. The novel AMP/NFE2L1/AMPK signaling pathway that discovered in this study is not only a further improvement of AMPK signal, but also a key node that mediates the crosstalk between redox homeostasis and metabolism homeostasis.

Breakdown and repair of the aging brain metabolic system

“…It is one of the key regulators of redox signaling and homeostasis. Dysfunction of this TF is associated with glucose metabolism reprogramming via AMPK signaling (Yang et al, 2021). NFE2L1 also upregulates expression of proteasomal genes in an ERK-signaling dependent manner (Zhang et al, 2021b), which is suggested to contribute to the development of neurodegenerative diseases (Lee et al, 2011).…”