Abstract
The liver plays a central role in the regulation of cholesterol homeostasis. Hepatic cholesterol content is maintained by a complex interplay between input and output pathways; alterations in the balance among these processes may lead to accumulation of excess cholesterol in body compartments with potentially deleterious consequences at the level of blood vessels (atherosclerosis) and biliary tract (gallstone disease). Molecular biology has brought new insights into this field. Nuclear receptors have been shown to play a key role in the “sensing” of intracellular cholesterol levels and in the triggering of metabolic responses via the sterol regulatory element binding protein (SREBP) cascade. A nuclear receptor for bile acids, farnesoid X receptor (FXR), has been identified and the molecular pathways underlying feedback inhibition of bile acid synthesis, the main mechanism of irreversible degradation of cholesterol, have been clarified. Such regulation involves a number of additional coactivators/corepressors of the transcription of the limiting enzyme of bile acid synthesis, cholesterol 7α-hydroxylase. Finally, the main transporters of biliary lipids (bile acids, phospholipids and cholesterol) have been described; most of them undergo transcriptional control by nuclear receptors, allowing regulation of biliary lipid efflux in conditions of different intracellular availability. Despite a body of evidence coming from experimental models the intimate mechanisms of regulation have not been clearly defined and direct evidence in humans is rather limited. This review will focus on the role of nuclear receptors in the regulation of hepatic cholesterol degradation and biliary lipid secretion, and on the theoretical applications from a pharmacotherapeutic perspective.
Keywords: Nuclear Receptors, Hepatic Cholesterol, Gallstone Disease, cholesterol homeostasis, metabolic responses, farnesoid X receptor (FXR), biliary lipid secretion, pharmacotherapeutic perspective
Current Medicinal Chemistry
Title: Nuclear Receptors as Potential Molecular Targets in Cholesterol Accumulation Conditions: Insights from Evidence on Hepatic Cholesterol Degradation and Gallstone Disease in Humans
Volume: 15 Issue: 22
Author(s): M. Bertolotti, C. Gabbi, C. Anzivino, L. Carulli, P. Loria and N. Carulli
Affiliation:
Keywords: Nuclear Receptors, Hepatic Cholesterol, Gallstone Disease, cholesterol homeostasis, metabolic responses, farnesoid X receptor (FXR), biliary lipid secretion, pharmacotherapeutic perspective
Abstract: The liver plays a central role in the regulation of cholesterol homeostasis. Hepatic cholesterol content is maintained by a complex interplay between input and output pathways; alterations in the balance among these processes may lead to accumulation of excess cholesterol in body compartments with potentially deleterious consequences at the level of blood vessels (atherosclerosis) and biliary tract (gallstone disease). Molecular biology has brought new insights into this field. Nuclear receptors have been shown to play a key role in the “sensing” of intracellular cholesterol levels and in the triggering of metabolic responses via the sterol regulatory element binding protein (SREBP) cascade. A nuclear receptor for bile acids, farnesoid X receptor (FXR), has been identified and the molecular pathways underlying feedback inhibition of bile acid synthesis, the main mechanism of irreversible degradation of cholesterol, have been clarified. Such regulation involves a number of additional coactivators/corepressors of the transcription of the limiting enzyme of bile acid synthesis, cholesterol 7α-hydroxylase. Finally, the main transporters of biliary lipids (bile acids, phospholipids and cholesterol) have been described; most of them undergo transcriptional control by nuclear receptors, allowing regulation of biliary lipid efflux in conditions of different intracellular availability. Despite a body of evidence coming from experimental models the intimate mechanisms of regulation have not been clearly defined and direct evidence in humans is rather limited. This review will focus on the role of nuclear receptors in the regulation of hepatic cholesterol degradation and biliary lipid secretion, and on the theoretical applications from a pharmacotherapeutic perspective.
Export Options
About this article
Cite this article as:
Bertolotti M., Gabbi C., Anzivino C., Carulli L., Loria P. and Carulli N., Nuclear Receptors as Potential Molecular Targets in Cholesterol Accumulation Conditions: Insights from Evidence on Hepatic Cholesterol Degradation and Gallstone Disease in Humans, Current Medicinal Chemistry 2008; 15 (22) . https://dx.doi.org/10.2174/092986708785747544
DOI https://dx.doi.org/10.2174/092986708785747544 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Association of Newly Diagnosed Hypertension and Polypharmacy with
Frailty in a Tertiary Hospital Patients from Maracaibo City, Venezuela
Current Hypertension Reviews Late Life Depression: A Diagnostic and Pharmacological Review
Current Psychopharmacology Breathing Generation and Potential Pharmacotherapeutic Approaches to Central Respiratory Disorders
Current Medicinal Chemistry Central Nervous System Manifestations in Systemic Lupus Erythematosus
Current Rheumatology Reviews Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease
Current Alzheimer Research Nitric Oxide: Target for Therapeutic Strategies in Alzheimers Disease
Current Pharmaceutical Design Recent Developments in the Treatment of Alcoholic Chronic Pancreatitis
Current Drug Abuse Reviews Neuronal and Glial Cell Abnormality as Predictors of Progression of Diabetic Retinopathy
Current Pharmaceutical Design Screening for Rare Genetic Variants Associated with Atherosclerosis: Opportunity for Personalized Medicine
Current Vascular Pharmacology Dipeptidyl Peptidase IV Inhibitors: A New Paradigm in Type 2 Diabetes Treatment
Current Drug Targets Antiphospholipid Syndrome: Characteristics and Obstetrical Management
Current Drug Targets Mechanisms of Action of Anesthetics for the Modulation of Perioperative Thrombosis: Evidence for Immune Mechanisms from Basic and Clinical Studies
Current Pharmaceutical Design Brutons Tyrosine Kinase as a New Therapeutic Target
Anti-Cancer Agents in Medicinal Chemistry Reading and Writing the Blood-Brain Barrier: Relevance to Therapeutics
Recent Patents on CNS Drug Discovery (Discontinued) New Molecular Avenues in Parkinson ’ s Disease Therapy
Current Topics in Medicinal Chemistry Targeted Drug Delivery Across the Blood Brain Barrier in Alzheimer’s Disease
Current Pharmaceutical Design Soy Isoflavone Alleviates Aβ1-42-Induced Impairment of Learning and Memory Ability Through the Regulation of RAGE/LRP-1 in Neuronal and Vascular Tissue
Current Neurovascular Research Molecular Insights into Mechanisms of the Cell Death Program:Role in the Progression of Neurodegenerative Disorders
Current Alzheimer Research Nutraceuticals, Nutritional Therapy, Phytonutrients, and Phytotherapy for Improvement of Human Health: A Perspective on Plant Biotechnology Application
Recent Patents on Biotechnology Clearance of Amyloid-β Peptide by Neuronal and Non-Neuronal Cells: Proteolytic Degradation by Secreted and Membrane associated Proteases
Current Neurovascular Research