Document Type : Research Paper
Authors
1
Department of Exercise Physiology, Faculty of Sport Sciences, University of Isfahan, Isfahan, Iran
2
Department of Genetics, Royan Institute of Biotechnology, Isfahan, Iran
Abstract
Extended Abstract
Background and Purpose
This study investigates the intricate regulation of cholesterol biosynthesis, a vital metabolic process governed by a network of genes central to cholesterol synthesis, lipid metabolism, and cellular signaling. Focusing on four key genes—Idi1, Fdps, Sqle, and Hmgcs1—it examines their regulatory mechanisms under different physiological and environmental conditions, including high-fat dietary intake and physical exercise. Using computational modeling, the research deciphers complex interactions within these gene regulatory networks, aiming to provide a systems-level understanding of cholesterol biosynthesis regulation. In parallel, it explores innovative therapeutic targets, particularly microRNAs, as strategies for managing dyslipidemia. By integrating systems biology methodologies with bioinformatics tools, the study not only deepens understanding of cholesterol metabolism but also evaluates the potential impacts of exercise interventions and novel pharmaceutical approaches on lipid disorders. Ultimately, it seeks to identify critical pathways and molecular targets to inform the development of effective therapeutic strategies.
Materials and Methods
A computational systems biology design was employed to elucidate the regulatory mechanisms that coordinate cholesterol biosynthesis under different conditions, such as high-fat diet consumption and physical exercise. The analysis concentrated on the regulatory roles of Idi1, Fdps, Sqle, and Hmgcs1—genes known to play essential roles in lipid metabolism and cellular signaling.
Gene regulatory network construction and analysis were performed using advanced bioinformatics pipelines and computational modeling techniques. Transcriptional data provided the basis for mapping gene–gene interactions, permitting detailed characterization of their roles within the dynamic regulation of cholesterol biosynthetic pathways. Simulations of regulatory network behavior under diverse conditions, including high-fat diet exposure, were conducted to examine their impact on gene expression profiles and pathway dynamics.
To ensure biological relevance, network topology clustering analyses were validated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Further, the study evaluated how high-fat dietary intake and physical activity modulate these networks, with particular emphasis on mechanisms that restore lipid metabolic homeostasis.
As part of the therapeutic exploration, potential microRNA regulators targeting network nodes were identified. These computational predictions, integrated with available experimental findings, refined the regulatory models and allowed identification of key nodes, hubs, and interactions that represent promising intervention points for dyslipidemia management.
Results
Analysis of transcriptional activity confirmed that Idi1, Fdps, Sqle, and Hmgcs1 act as prominent hub genes in cholesterol biosynthesis, lipid metabolism, and broader cellular signaling. The regulatory network analysis revealed these genes as central mediators in controlling metabolic flux within cholesterol biosynthetic pathways.
Clustering analysis of the networks, supported by GO and KEGG enrichment, validated the biological coherence and functional significance of these pathways. These results highlighted essential interactions and core modules critical for maintaining cholesterol homeostasis, particularly in the face of environmental stressors such as high-fat diets.
Computational simulations demonstrated that exposure to a high-fat diet markedly alters the expression patterns of the key regulatory genes, disrupting network stability. In contrast, physical exercise interventions produced a counterbalancing effect, modulating the expression of hub genes toward restoring lipid metabolic balance. The model thus provided clear evidence for the potential of targeted exercise regimes to mitigate diet-induced dysregulation of cholesterol metabolism.
A further significant outcome was the identification of multiple microRNAs with regulatory influence over cholesterol biosynthesis networks. These microRNAs appear to modulate hub gene activity, presenting themselves as novel and potentially powerful therapeutic targets for dyslipidemia and associated metabolic disorders.
Integration of experimental datasets with computational models yielded an enriched systems-level perspective on gene–gene and gene–microRNA interactions. This integration enabled the pinpointing of pivotal regulatory nodes and feedback mechanisms that could be exploited for future diagnostic and therapeutic innovations.
Conclusion
This study offers comprehensive insights into the regulation of cholesterol biosynthesis, detailing the roles of the hub genes Idi1, Fdps, Sqle, and Hmgcs1. Through computational modeling supported by transcriptional profiles, it demonstrates dynamic regulation of these pathways under high-fat diet and exercise conditions, emphasizing the modulatory benefits of physical activity in maintaining lipid homeostasis.
Importantly, the research identifies regulatory microRNAs as promising therapeutic targets, heralding new approaches for managing dyslipidemia and related cardiovascular-metabolic disorders. By integrating bioinformatics and systems biology frameworks, it systematically maps the critical pathways and molecular interactions underlying cholesterol metabolism. The findings not only advance mechanistic understanding but also offer a robust foundation for designing targeted interventions—be they exercise prescriptions, microRNA-based therapeutics, or novel pharmacological agents—to optimize cholesterol regulation and improve metabolic health outcomes.
Keywords: Cholesterol Biosynthesis, Gene Regulatory Networks, Dyslipidemia, Exercise, Bioinformatics
Article Message
By identifying and characterizing key hub genes in cholesterol biosynthesis and elucidating their connections within gene regulatory networks, this study advances the understanding of cholesterol metabolism and the involvement of the cellular endoplasmic reticulum. GO and KEGG analyses confirm the inclusion of these genes in critical metabolic processes, suggesting their value as diagnostic biomarkers for metabolic diseases. The demonstrated interplay between physical activity and cholesterol biosynthesis underscores its potential as an effective strategy for metabolic regulation, with therapeutic implications spanning exercise-based interventions to targeted molecular therapies.
Ethical Considerations
This research was approved by the Ethics Committee of the University of Isfahan (Ethical Code: IR.UI.REC.1403.005).
Authors’ Contributions
Conceptualization, Data Collection, Manuscript Writing: Milad Abdollahi
Project Management, Review and Editing: Sayyed Mohammad Marandi
Data Analysis, Review and Editing: Zahra Safayinejad
Literature Review, Review and Editing: Mohammad Hossein Nasr Esfahani
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
The authors express deep appreciation to the Institute of Physical Education and Sport Sciences for their consistent and invaluable support throughout the course of this research.
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