inzicht - Computational Biology - # Dietary regulation of lipid metabolism in C. elegans

Dietary Bacteria Modulate Lipid Metabolism in C. elegans through Phosphatidylcholine Synthesis Pathways

Q: How do the altered fatty acid profiles observed in DA-fed worms, such as the increased monounsaturated fatty acids and decreased cyclopropane fatty acids, contribute to the overall regulation of lipid homeostasis?

The altered fatty acid profiles in DA-fed worms play a crucial role in regulating lipid homeostasis through various mechanisms. The increased levels of monounsaturated fatty acids, such as 16:1n7 and 18:1n7, are likely to impact lipid metabolism by influencing the composition of membrane lipids, signaling molecules, and energy storage. Monounsaturated fatty acids are important components of phospholipids, which are essential for cell membrane structure and function. Changes in the levels of these fatty acids can affect membrane fluidity, permeability, and signaling pathways, thereby influencing cellular processes related to lipid metabolism. On the other hand, the decreased levels of cyclopropane fatty acids in DA-fed worms can also have significant implications for lipid homeostasis. Cyclopropane fatty acids are known to play a role in modulating membrane properties and stability. Their reduction in DA-fed worms may impact membrane integrity, lipid transport, and signaling processes, leading to alterations in lipid metabolism and storage. Overall, the altered fatty acid profiles in DA-fed worms, characterized by increased monounsaturated fatty acids and decreased cyclopropane fatty acids, contribute to the regulation of lipid homeostasis by influencing membrane composition, signaling pathways, and metabolic processes related to lipid metabolism.

Q: How might the potential physiological consequences of the diet-induced changes in lipid composition and lipid droplet dynamics in C. elegans translate to understanding metabolic disorders in higher organisms?

The diet-induced changes in lipid composition and lipid droplet dynamics observed in C. elegans can provide valuable insights into understanding metabolic disorders in higher organisms. These changes can have significant physiological consequences that may be relevant to metabolic disorders such as obesity, diabetes, and cardiovascular diseases in humans. Obesity: Alterations in lipid composition, including changes in fatty acid profiles and phospholipid levels, can impact energy storage, adipose tissue function, and lipid metabolism. Dysregulation of lipid droplet dynamics, characterized by changes in size, number, and distribution of lipid droplets, can contribute to the development of obesity by affecting lipid storage and utilization in adipocytes. Diabetes: Changes in lipid composition and metabolism can influence insulin sensitivity, glucose homeostasis, and lipid accumulation in tissues. Dysfunctional lipid droplet dynamics may lead to ectopic lipid deposition, insulin resistance, and impaired glucose metabolism, contributing to the pathogenesis of type 2 diabetes. Cardiovascular Diseases: Altered lipid profiles and lipid droplet dynamics can impact cardiovascular health by affecting lipid transport, cholesterol metabolism, and atherosclerosis development. Changes in phospholipid composition, particularly phosphatidylcholine levels, may influence vascular function, inflammation, and plaque formation in blood vessels. By studying the molecular mechanisms underlying diet-induced changes in lipid metabolism and lipid droplet dynamics in C. elegans, researchers can gain insights into the pathophysiology of metabolic disorders in higher organisms. These findings may inform the development of novel therapeutic strategies and dietary interventions for managing and preventing metabolic diseases in humans.

Q: Given the central role of phosphatidylcholine in mediating the dietary effects on lipid metabolism, are there other nutrients or dietary components that could modulate PC synthesis pathways to similarly impact lipid homeostasis?

While phosphatidylcholine (PC) plays a central role in mediating the dietary effects on lipid metabolism, there are other nutrients and dietary components that can modulate PC synthesis pathways and impact lipid homeostasis in a similar manner. Some of these nutrients and components include: Choline: Choline is a precursor for PC synthesis and is essential for maintaining adequate levels of PC in cells. Dietary choline intake can influence PC synthesis pathways and impact lipid metabolism by regulating the availability of phosphocholine for PC biosynthesis. Methionine: Methionine is involved in the one-carbon metabolism pathway, which contributes to the synthesis of S-adenosyl methionine (SAM), a key methyl donor for PC synthesis. Dietary methionine levels can affect the SAM-PC axis and modulate lipid metabolism through the regulation of PC levels. Vitamin B6: Vitamin B6 is a cofactor for enzymes involved in amino acid metabolism and transsulfuration pathways, which are interconnected with PC synthesis pathways. Adequate levels of vitamin B6 are essential for maintaining optimal PC synthesis and lipid homeostasis. Omega-3 Fatty Acids: Omega-3 fatty acids, such as EPA and DHA, have been shown to influence PC synthesis and lipid metabolism. These fatty acids can impact the composition of membrane phospholipids, including PC, and modulate lipid droplet dynamics and lipid storage in cells. By considering the interplay between these nutrients and dietary components with PC synthesis pathways, researchers can uncover additional mechanisms by which diet influences lipid metabolism and homeostasis. Understanding the role of these factors in modulating lipid pathways can provide insights into novel dietary interventions and therapeutic strategies for managing lipid-related disorders.

Belangrijkste concepten

Dietary vitamin B12 activates the S-adenosyl methionine (SAM) and phosphatidylcholine (PC) biosynthetic pathways, leading to elevated PC levels that suppress lipogenic gene expression and modulate lipid droplet dynamics in C. elegans.

Samenvatting

The study investigates the mechanisms by which distinct bacterial diets influence lipid metabolism in the nematode C. elegans. The key findings are:

The non-canonical bacterial diet DA1877 (DA) significantly reduces lipid content and alters the fatty acid composition in C. elegans compared to the standard Escherichia coli OP50 (OP) diet.
A forward genetic screen identified key genes in the B12-SAM-PC axis that mediate the diet-induced downregulation of the lipogenic gene fat-7. Specifically, dietary B12 stimulates SAM production and PC synthesis, which in turn suppresses fat-7 expression in a SBP-1-dependent manner.
The elevated PC levels in DA-fed worms impact intestinal lipid droplet dynamics by hindering the recruitment of the SEIP-1 protein to peri-lipid droplet cages.
The acid sphingomyelinase ASM-3 acts as a signaling mediator between the intestine and coelomocytes to further enhance PC synthesis and lipid reduction in response to the DA diet.
The study reveals a complex interplay between dietary factors, particularly vitamin B12, and metabolic regulation, with phosphatidylcholine serving as a central convergence point.

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Statistieken

Worms fed the DA diet have significantly decreased levels of triacylglycerol (TAG) compared to OP-fed worms.
The expression of the lipogenic gene fat-7 is reduced by 86.7% in DA-fed worms compared to OP-fed worms.
Worms fed the DA diet have higher levels of monounsaturated fatty acids (51.8% of total fatty acids) compared to OP-fed worms (22.7%).
The DA bacteria contain undetectable levels of cyclopropane fatty acids, which are present in OP bacteria.
Supplementation of B12 to OP-fed worms is sufficient to suppress the expression of the FAT-7::GFP reporter.

Citaten

"Dietary vitamin B12 activates the S-adenosyl methionine (SAM) and phosphatidylcholine (PC) biosynthetic pathways. This activation leads to elevated levels of PC, which in turn suppresses the expression of the gene fat-7 and modulates lipid droplet dynamics through the regulatory proteins SBP-1/SREBP1 and SEIP-1/SEIPIN, respectively."
"Additionally, we identified a feedback loop involving SBP-1-mediated regulation of acid sphingomyelinase ASM-3, which enhances the production of phospho-choline and further stimulates PC synthesis."

Belangrijkste Inzichten Gedestilleerd Uit

Dietary bacteria control C. elegans fat content through pathways converging at phosphatidylcholine

by Han,H., Nien... om www.biorxiv.org 02-28-2024

https://www.biorxiv.org/content/10.1101/2024.02.24.581900v2

Diepere vragen

How do the altered fatty acid profiles observed in DA-fed worms, such as the increased monounsaturated fatty acids and decreased cyclopropane fatty acids, contribute to the overall regulation of lipid homeostasis?

The altered fatty acid profiles in DA-fed worms play a crucial role in regulating lipid homeostasis through various mechanisms. The increased levels of monounsaturated fatty acids, such as 16:1n7 and 18:1n7, are likely to impact lipid metabolism by influencing the composition of membrane lipids, signaling molecules, and energy storage. Monounsaturated fatty acids are important components of phospholipids, which are essential for cell membrane structure and function. Changes in the levels of these fatty acids can affect membrane fluidity, permeability, and signaling pathways, thereby influencing cellular processes related to lipid metabolism.
On the other hand, the decreased levels of cyclopropane fatty acids in DA-fed worms can also have significant implications for lipid homeostasis. Cyclopropane fatty acids are known to play a role in modulating membrane properties and stability. Their reduction in DA-fed worms may impact membrane integrity, lipid transport, and signaling processes, leading to alterations in lipid metabolism and storage.
Overall, the altered fatty acid profiles in DA-fed worms, characterized by increased monounsaturated fatty acids and decreased cyclopropane fatty acids, contribute to the regulation of lipid homeostasis by influencing membrane composition, signaling pathways, and metabolic processes related to lipid metabolism.

How might the potential physiological consequences of the diet-induced changes in lipid composition and lipid droplet dynamics in C. elegans translate to understanding metabolic disorders in higher organisms?

The diet-induced changes in lipid composition and lipid droplet dynamics observed in C. elegans can provide valuable insights into understanding metabolic disorders in higher organisms. These changes can have significant physiological consequences that may be relevant to metabolic disorders such as obesity, diabetes, and cardiovascular diseases in humans.

Obesity: Alterations in lipid composition, including changes in fatty acid profiles and phospholipid levels, can impact energy storage, adipose tissue function, and lipid metabolism. Dysregulation of lipid droplet dynamics, characterized by changes in size, number, and distribution of lipid droplets, can contribute to the development of obesity by affecting lipid storage and utilization in adipocytes.

Diabetes: Changes in lipid composition and metabolism can influence insulin sensitivity, glucose homeostasis, and lipid accumulation in tissues. Dysfunctional lipid droplet dynamics may lead to ectopic lipid deposition, insulin resistance, and impaired glucose metabolism, contributing to the pathogenesis of type 2 diabetes.

Cardiovascular Diseases: Altered lipid profiles and lipid droplet dynamics can impact cardiovascular health by affecting lipid transport, cholesterol metabolism, and atherosclerosis development. Changes in phospholipid composition, particularly phosphatidylcholine levels, may influence vascular function, inflammation, and plaque formation in blood vessels.

By studying the molecular mechanisms underlying diet-induced changes in lipid metabolism and lipid droplet dynamics in C. elegans, researchers can gain insights into the pathophysiology of metabolic disorders in higher organisms. These findings may inform the development of novel therapeutic strategies and dietary interventions for managing and preventing metabolic diseases in humans.

Given the central role of phosphatidylcholine in mediating the dietary effects on lipid metabolism, are there other nutrients or dietary components that could modulate PC synthesis pathways to similarly impact lipid homeostasis?

While phosphatidylcholine (PC) plays a central role in mediating the dietary effects on lipid metabolism, there are other nutrients and dietary components that can modulate PC synthesis pathways and impact lipid homeostasis in a similar manner. Some of these nutrients and components include:

Choline: Choline is a precursor for PC synthesis and is essential for maintaining adequate levels of PC in cells. Dietary choline intake can influence PC synthesis pathways and impact lipid metabolism by regulating the availability of phosphocholine for PC biosynthesis.

Methionine: Methionine is involved in the one-carbon metabolism pathway, which contributes to the synthesis of S-adenosyl methionine (SAM), a key methyl donor for PC synthesis. Dietary methionine levels can affect the SAM-PC axis and modulate lipid metabolism through the regulation of PC levels.

Vitamin B6: Vitamin B6 is a cofactor for enzymes involved in amino acid metabolism and transsulfuration pathways, which are interconnected with PC synthesis pathways. Adequate levels of vitamin B6 are essential for maintaining optimal PC synthesis and lipid homeostasis.

Omega-3 Fatty Acids: Omega-3 fatty acids, such as EPA and DHA, have been shown to influence PC synthesis and lipid metabolism. These fatty acids can impact the composition of membrane phospholipids, including PC, and modulate lipid droplet dynamics and lipid storage in cells.

By considering the interplay between these nutrients and dietary components with PC synthesis pathways, researchers can uncover additional mechanisms by which diet influences lipid metabolism and homeostasis. Understanding the role of these factors in modulating lipid pathways can provide insights into novel dietary interventions and therapeutic strategies for managing lipid-related disorders.