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Fasting-induced hormonal regulation of lysosomal function
Liqun Chen1, Ke Wang1, Aijun Long1
1MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
This study explores how fasting hormones regulate lysosomes, which are cell structures that break down and recycle nutrients. Researchers found that the hormone FGF21, produced during fasting, plays a key role in maintaining lysosome function in mice. FGF21 activates a calcium signaling pathway that inhibits Mid1, a protein that normally targets PP2A for degradation. Increased PP2A levels then dephosphorylate TFEB, a master regulator of lysosome biogenesis. This process supports lysosome activity and lipid metabolism during fasting. The findings suggest that FGF21 acts as a hormonal signal linking extracellular cues to lysosomal homeostasis.
Area of Science:
- Hormonal regulation of metabolism
- Lysosomal biology in metabolic medicine
- Endocrine signaling pathways in liver function
Background:
Lysosomes regulate nutrient recycling and adaptation to starvation. Internal nutrient signaling influences lysosome dynamics, but external cues remain poorly understood. Prior research has shown lysosomes respond to nutrient availability through transcriptional control. However, the role of circulating hormones in lysosomal function is unclear. This gap motivated investigations into hormonal regulation of lysosomes. No prior work had resolved how fasting hormones affect lysosome homeostasis. The study aimed to identify extracellular signals that modulate lysosomal activity. This paper's contribution is a novel FGF21-dependent pathway in lysosomal regulation.
Purpose Of The Study:
The study aimed to uncover how fasting hormones regulate lysosomal function. Researchers focused on FGF21, a hormone induced during fasting. They sought to determine whether FGF21 affects lysosomal homeostasis in mice. The specific problem was to identify hormonal signals that modulate lysosomal activity. The motivation was to link lysosome function with extracellular signals. The goal was to understand how FGF21 influences lysosomal biogenesis. The study also aimed to explore the role of TFEB in this process. This approach could clarify how fasting hormones coordinate metabolic responses.
Main Methods:
The research used genetic models of Fgf21 deficiency in mice. Lysosomal function was assessed through hepatic gene expression analysis. Calcium mobilization from the endoplasmic reticulum was measured. Transcriptional activity of TFEB was evaluated using reporter assays. Mid1 expression levels were quantified via qPCR and Western blot. Protein phosphatase PP2A activity was analyzed in liver lysates. Autophagy and lipid metabolism markers were monitored in knockout models. These tools allowed the team to trace the FGF21 signaling cascade.
Main Results:
Fgf21 deficiency reduced lysosomal gene expression in the liver. TFEB activity was diminished in mice lacking FGF21. Endoplasmic reticulum calcium levels increased with FGF21 treatment. DREAM activation was observed following FGF21-induced calcium release. Mid1 expression decreased in response to FGF21 signaling. PP2A levels rose in FGF21-treated models, correlating with TFEB dephosphorylation. Lysosome biogenesis genes were upregulated in wild-type but not Fgf21-deficient mice. These findings suggest a direct link between FGF21 and lysosomal homeostasis.
Conclusions:
The authors propose that FGF21 regulates lysosomal function via calcium signaling. They suggest that DREAM activation mediates FGF21 effects on Mid1. TFEB dephosphorylation by PP2A is essential for lysosome biogenesis. The FGF21-TFEB axis links extracellular signals to lysosomal homeostasis. This pathway supports lipid metabolism during fasting in mice. The study highlights FGF21 as a key modulator of lysosomal activity. These findings may inform future research on metabolic adaptation. The authors emphasize the importance of hormonal regulation in lysosomal function.
Frequently Asked Questions
FGF21 induces calcium release from the endoplasmic reticulum, activating DREAM and inhibiting Mid1 expression.
FGF21 promotes PP2A accumulation, which dephosphorylates TFEB, upregulating lysosome biogenesis genes.
Calcium mobilization from the endoplasmic reticulum is necessary for DREAM activation, a key step in FGF21 signaling.
Mid1 is an E3 ligase that targets PP2A for degradation; its inhibition by FGF21 increases PP2A levels.
TFEB activity was assessed using reporter assays and analysis of dephosphorylation in liver lysates.
The authors suggest FGF21 links extracellular hormonal signals to lysosomal homeostasis during fasting.