Nuclear Receptors as Potential Molecular Targets in Cholesterol Accumulation Conditions: Insights from Evidence on Hepatic Cholesterol Degradation and Gallstone Disease in Humans

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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: Gallstone Disease; Hepatic Cholesterol; Nuclear Receptors; biliary lipid secretion; cholesterol homeostasis; farnesoid X receptor (FXR); metabolic responses; pharmacotherapeutic perspective

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986708785747544

Affiliations: Dipartimento di Medicina, Endocrinologia, Metabolismo e Geriatria, Universita degli Studi di Modena e Reggio Emilia, Nuovo Ospedale Civile, Via Giardini, 1355, 41100 Modena, Italy.

Publication date: September 1, 2008

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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