תובנה - Computational Biology - # Regulation of lipolysis by the SIR-2.1/HSF-1/ATGL-1 pathway in C. elegans

An Intestinal Pathway Involving the Sirtuin SIR-2.1, Heat Shock Factor HSF-1, and Adipose Triglyceride Lipase ATGL-1 Regulates Lipolysis in C. elegans

Q: How do the post-translational modifications of ATGL-1 by SIR-2.1 and PKA pathways precisely coordinate to regulate lipolysis?

The post-translational modifications of ATGL-1 by SIR-2.1 and PKA pathways play a crucial role in coordinating the regulation of lipolysis. SIR-2.1, a deacetylase, and PKA, a protein kinase, converge on ATGL-1 to modulate its activity and stability. SIR-2.1 is involved in deacetylating ATGL-1, which can impact its enzymatic activity and function in lipid mobilization. On the other hand, PKA phosphorylates ATGL-1, leading to its stabilization and activation, thereby promoting the breakdown of stored triglycerides into free fatty acids for energy utilization. The coordination between SIR-2.1 and PKA pathways ensures a balanced and efficient regulation of lipolysis. SIR-2.1's deacetylation of ATGL-1 may fine-tune its activity, while PKA's phosphorylation can enhance its function, ultimately contributing to the overall process of lipid mobilization. This intricate interplay between post-translational modifications by SIR-2.1 and PKA pathways allows for precise control over ATGL-1 function, ensuring optimal energy metabolism and homeostasis in the organism.

Q: How do the specific mechanisms by which HSF-1 differentially regulates the expression of hsp-70 and miR-53 in response to starvation versus heat shock?

HSF-1, the heat shock transcription factor, exhibits differential regulation of gene expression in response to starvation versus heat shock. In the context of heat shock, HSF-1 activates the expression of heat shock proteins like hsp-70 to protect cells from proteotoxic stress. This activation involves the binding of HSF-1 to heat shock gene promoters, leading to the transcription of stress-responsive genes that aid in cellular protection and survival during heat stress. On the other hand, in response to starvation, HSF-1 shows a distinct regulatory pattern involving the microRNA miR-53. During starvation, SIR-2.1 activates lipolysis by suspending the HSF-1-mediated suppression of miR-53, which in turn inhibits the expression of certain target genes, such as ATGL-1. This differential regulation of miR-53 by HSF-1 in response to starvation allows for the modulation of lipid mobilization and energy metabolism in the organism. The specific mechanisms underlying the differential regulation of hsp-70 and miR-53 by HSF-1 in response to different stress conditions involve the interaction of HSF-1 with specific regulatory elements and co-factors that modulate its transcriptional activity. The context-specific responses of HSF-1 to heat shock and starvation highlight the versatility and adaptability of this transcription factor in orchestrating cellular stress responses and metabolic pathways.

Q: Could the insights from this study on the crosstalk between proteostasis and lipid metabolism be leveraged to develop interventions that promote healthy aging and stress resilience in higher organisms?

The insights gained from the study on the crosstalk between proteostasis and lipid metabolism offer valuable implications for developing interventions that promote healthy aging and stress resilience in higher organisms. By understanding the intricate interplay between pathways involved in maintaining protein homeostasis and regulating lipid metabolism, researchers can identify potential targets for therapeutic interventions aimed at enhancing overall health and longevity. One potential application of these insights is the development of targeted therapies that modulate the activity of key regulators such as HSF-1, SIR-2.1, and ATGL-1 to optimize energy metabolism, proteostasis, and stress responses in aging organisms. By manipulating these pathways, it may be possible to enhance cellular resilience to stress, improve metabolic health, and mitigate age-related decline in physiological functions. Furthermore, the identification of specific molecular mechanisms underlying the coordination between proteostasis and lipid metabolism opens up avenues for the development of novel pharmacological agents or lifestyle interventions that can promote healthy aging and combat age-related diseases. By targeting key nodes in these interconnected pathways, it may be possible to enhance stress resilience, improve metabolic flexibility, and ultimately support healthy aging in higher organisms.

מושגי ליבה

The sirtuin SIR-2.1 activates lipolysis during starvation by suspending the HSF-1-mediated repression of the adipose triglyceride lipase ATGL-1 in the C. elegans intestine.

תקציר

The study investigates the regulation of lipolysis in the roundworm C. elegans, a model organism for understanding lipid metabolism and its connection to longevity pathways.

Key highlights:

The sirtuin SIR-2.1 activates lipolysis during starvation by upregulating the expression of the adipose triglyceride lipase ATGL-1.
SIR-2.1 achieves this by suspending an HSF-1-mediated repression of ATGL-1 expression, which occurs at the post-transcriptional level through microRNAs, particularly miR-53.
The PKA pathway, through its catalytic subunit KIN-1, also regulates lipolysis by post-translationally modifying and stabilizing ATGL-1 protein.
HSF-1 inhibits lipolysis not only during feeding, but also under proteostasis disturbances, which promotes fat deposition during aging as HSF-1 function declines.
The study reveals a crosstalk between proteostasis maintenance and lipid/energy metabolism, which may modulate stress resilience and aging.

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biorxiv.org

סטטיסטיקה

Starvation increases free fatty acid levels in a SIR-2.1-dependent manner.
Silencing of atgl-1 prevents starvation-induced lipid mobilization.
Starvation upregulates atgl-1 mRNA and ATGL-1::GFP reporter expression in a SIR-2.1-dependent manner.
Blocking microRNA maturation restores lipolysis in sir-2.1 mutants.
Activation of HSF-1 by overexpression or hsp-90 RNAi inhibits lipolysis.
Intestinal expression of the misfolded protein Q82::YFP inhibits lipolysis in an HSF-1-dependent manner.
HSF-1 overexpression increases lipid stores in an age-dependent manner, which is mediated through ATGL-1.

ציטוטים

"SIR-2.1 activation mediates starvation-induced lipolysis through atgl-1 mRNA upregulation."
"Loss of HSF-1 function is required for SIR-2.1-dependent lipolysis in the intestine."
"HSF-1 inhibits lipid mobilization and ATGL-1 expression through the microRNA system."
"The protein kinase A KIN-1 affects lipolysis and ATGL-1 function downstream from SIR-2.1 and HSF-1."
"HSF-1 modulates age-related fat deposition through ATGL-1."

תובנות מפתח מזוקקות מ:

An intestinal Sir2-HSF1-ATGL1 pathway regulates lipolysis in C. elegans

by Somogyvari,M... ב- www.biorxiv.org 04-13-2024

https://www.biorxiv.org/content/10.1101/2024.04.11.588856v1

שאלות מעמיקות

How do the post-translational modifications of ATGL-1 by SIR-2.1 and PKA pathways precisely coordinate to regulate lipolysis?

The post-translational modifications of ATGL-1 by SIR-2.1 and PKA pathways play a crucial role in coordinating the regulation of lipolysis. SIR-2.1, a deacetylase, and PKA, a protein kinase, converge on ATGL-1 to modulate its activity and stability. SIR-2.1 is involved in deacetylating ATGL-1, which can impact its enzymatic activity and function in lipid mobilization. On the other hand, PKA phosphorylates ATGL-1, leading to its stabilization and activation, thereby promoting the breakdown of stored triglycerides into free fatty acids for energy utilization.
The coordination between SIR-2.1 and PKA pathways ensures a balanced and efficient regulation of lipolysis. SIR-2.1's deacetylation of ATGL-1 may fine-tune its activity, while PKA's phosphorylation can enhance its function, ultimately contributing to the overall process of lipid mobilization. This intricate interplay between post-translational modifications by SIR-2.1 and PKA pathways allows for precise control over ATGL-1 function, ensuring optimal energy metabolism and homeostasis in the organism.

How do the specific mechanisms by which HSF-1 differentially regulates the expression of hsp-70 and miR-53 in response to starvation versus heat shock?

HSF-1, the heat shock transcription factor, exhibits differential regulation of gene expression in response to starvation versus heat shock. In the context of heat shock, HSF-1 activates the expression of heat shock proteins like hsp-70 to protect cells from proteotoxic stress. This activation involves the binding of HSF-1 to heat shock gene promoters, leading to the transcription of stress-responsive genes that aid in cellular protection and survival during heat stress.
On the other hand, in response to starvation, HSF-1 shows a distinct regulatory pattern involving the microRNA miR-53. During starvation, SIR-2.1 activates lipolysis by suspending the HSF-1-mediated suppression of miR-53, which in turn inhibits the expression of certain target genes, such as ATGL-1. This differential regulation of miR-53 by HSF-1 in response to starvation allows for the modulation of lipid mobilization and energy metabolism in the organism.
The specific mechanisms underlying the differential regulation of hsp-70 and miR-53 by HSF-1 in response to different stress conditions involve the interaction of HSF-1 with specific regulatory elements and co-factors that modulate its transcriptional activity. The context-specific responses of HSF-1 to heat shock and starvation highlight the versatility and adaptability of this transcription factor in orchestrating cellular stress responses and metabolic pathways.

Could the insights from this study on the crosstalk between proteostasis and lipid metabolism be leveraged to develop interventions that promote healthy aging and stress resilience in higher organisms?

The insights gained from the study on the crosstalk between proteostasis and lipid metabolism offer valuable implications for developing interventions that promote healthy aging and stress resilience in higher organisms. By understanding the intricate interplay between pathways involved in maintaining protein homeostasis and regulating lipid metabolism, researchers can identify potential targets for therapeutic interventions aimed at enhancing overall health and longevity.
One potential application of these insights is the development of targeted therapies that modulate the activity of key regulators such as HSF-1, SIR-2.1, and ATGL-1 to optimize energy metabolism, proteostasis, and stress responses in aging organisms. By manipulating these pathways, it may be possible to enhance cellular resilience to stress, improve metabolic health, and mitigate age-related decline in physiological functions.
Furthermore, the identification of specific molecular mechanisms underlying the coordination between proteostasis and lipid metabolism opens up avenues for the development of novel pharmacological agents or lifestyle interventions that can promote healthy aging and combat age-related diseases. By targeting key nodes in these interconnected pathways, it may be possible to enhance stress resilience, improve metabolic flexibility, and ultimately support healthy aging in higher organisms.