Sterol regulators of cholesterol homeostasis and beyond: The oxysterol hypothesis revisited and revised

doi:10.1016/j.plipres.2008.04.002

Progress in Lipid Research

Volume 47, Issue 6, November 2008, Pages 391-404

https://doi.org/10.1016/j.plipres.2008.04.002 Get rights and content

Abstract

This review traces the evolution of the ‘Oxysterol Hypothesis’, which was first formulated by Kandutsch and colleagues in 1978. The original hypothesis asserted that the suppressive effect of cholesterol on its own synthesis is mediated not by cholesterol itself, but by oxygenated forms of cholesterol, so called oxysterols. Subsequently, it has become clear that cholesterol plays a pivotal role in its own feedback regulation. However, recent findings have rekindled interest in oxysterols as potential physiological regulators of cholesterol homeostasis, in addition to drawing attention to other sterol regulators. Thus, certain oxysterols can suppress the activation of the master transcriptional regulators of lipid homeostasis (SREBPs) by binding to an oxysterol sensing protein in the Endoplasmic Reticulum (Insig). Some (oxy)sterols can accelerate the degradation of the key cholesterol biosynthetic enzyme, HMG-CoA reductase, and/or serve as natural ligand activators of a nuclear receptor (LXR) involved in coordinating many aspects of reverse cholesterol transport. Recent studies on endogenously produced oxysterols indicate that they may play a more subtle and acute role than originally envisaged, smoothing cholesterol responses in the short term. We also review the metabolism of oxysterols and other recent findings about oxysterols beyond a purely cholesterol homeostatic context, such as their proposed role in the Hedgehog development pathway.

Introduction

Today, cholesterol is most widely known for its association with atherosclerotic heart disease. However, despite its negative reputation, cholesterol is a necessary constituent of all our cells, and fulfills important functions, as an essential component of mammalian cell membranes, a precursor for steroid hormones and bile acids, as well as being involved in various cell signaling pathways [1]. Cholesterol synthesis, uptake, and efflux are all tightly regulated processes that work together to ensure that there is sufficient cholesterol for the cell’s various needs, whilst preventing over-accumulation of cholesterol, which can cause cell death [2].

Thirty years ago, Kandutsch, Chen, and Heiniger proposed what has subsequently become known as the Oxysterol Hypothesis of Cholesterol Homeostasis [3]. In its original form, this hypothesis contended that it is oxygenated forms of cholesterol, so-called oxysterols, that mediate feedback regulation of cholesterol biosynthesis, rather than cholesterol itself [3]. This hypothesis was based on results which showed that pure cholesterol added to cells was unable to inhibit sterol synthesis, whereas impure cholesterol containing minute quantities of oxysterols had potent inhibitory effects. Since publication of this paper, the validity of the Oxysterol Hypothesis has repeatedly been questioned and the experimental techniques employed by Kandutsch and colleagues scrutinized. Table 1 presents a selection of key discoveries that have shaped the Oxysterol Hypothesis. In order to gain a better understanding of this hypothesis, we begin by briefly describing the major types and sources of oxysterols, and then reviewing some of the key studies that led to its formulation. We discuss the criticisms that have been leveled at the Oxysterol Hypothesis and suggest how this hypothesis may be revised in the light of recent findings. It is unlikely that endogenous oxysterols accumulate sufficiently to exert significant effects on membrane behaviour to contribute to cholesterol homeostasis. Therefore, the well-described effects of oxysterols on the ordering of membranes are beyond the scope of this review and interested readers are referred elsewhere [4]. Finally, we discuss other proposed biological activities of oxysterols, some of which are not directly related to cholesterol homeostasis.

Section snippets

Oxysterols: types and origins

More than two centuries have past since Poulletier de la Salle, studying bile and gallstones, first characterized cholesterol (or ‘cholesterine’ as it was originally named by Chevreul) [5], [6]. The existence of oxysterols was recognized a century later by Lifschütz who regarded “oxycholesterol” as a single chemical entity, a monohydroxylated derivative of cholesterol [7]. Currently, dozens of different oxysterols are known. Sometimes considered as a homogeneous class, it should be appreciated

Formulation of the hypothesis

The arrival of the Oxysterol Hypothesis came half a century after feedback control by cholesterol was first observed by Schoenheimer and Breusch [20]. In these landmark metabolic studies, it was found that mice synthesized less cholesterol when placed on a cholesterol containing diet. Two decades later, the concept of feedback regulation of cholesterol synthesis by cholesterol and related steroids was further developed by Gould and Taylor [21], and Tomkins and colleagues [22]. By the time the

Sterol sensors in the SREBP pathway

The year 1993 marked an important milestone towards our current understanding of cholesterol homeostasis, with the purification of the first member of the family of key transcription factors, the SREBPs, from nuclear extracts of cultured HeLa cells [42]. Since the discovery of SREBP, exogenous oxysterols have been routinely used to suppress the activation of these master regulators of cellular lipid homeostasis [43]. As discussed below, the mechanism by which certain oxysterols suppress SREBP

A revised Oxysterol Hypothesis

In light of the recent developments discussed in Section 4, we propose a revised Oxysterol Hypothesis which argues that while cholesterol is central to achieving its own balance, oxysterols play an important role in smoothing this regulation in the short term (Fig. 4A). In the absence of such a regulator, cellular cholesterol homeostatic responses become erratic and exaggerated (Fig. 4B). This auxiliary role of oxysterols probably explains in large part why genetic manipulation of a particular

Metabolism and elimination of oxysterols

Oxysterols are metabolized for deactivation and eventual elimination from the body. By virtue of their increased polarity relative to cholesterol, oxysterols tend to efflux more readily from cells, although there are exceptions to this rule as seen with the impaired efflux from macrophages of 7-ketocholesterol (also called 7-oxocholesterol) [84]. Indeed, production of certain oxysterols is believed to be important for sterol transport to the liver as an alternative mechanism to high-density

Future directions and recommendations

The challenge ahead is to quantify in physiological settings the levels of various oxysterols in appropriate systems, to further evaluate their biological roles [14], and to learn more about how they are inactivated/metabolized.

Conclusion

The Oxysterol Hypothesis has inevitably evolved since its formulation by Kandutsch and colleagues three decades ago as our understanding of cholesterol homeostasis has advanced. Encompassing but also moving beyond the initial focus of their action on inhibiting cholesterol synthesis, oxysterols are now recognized to potentially act at multiple points in cholesterol homeostasis (Fig. 6): increasing expression of cholesterol efflux genes by serving as a ligand for LXR, decreasing cholesterol

Acknowledgement

We thank James Krycer, Laura Sharpe and Julian Stevenson for critically reading this manuscript. Andrew Brown’s laboratory is supported by grants from the National Health and Medical Research Council (350828) and the Prostate Cancer Foundation of Australia (PR36).

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Citation Excerpt :
The majority of oxysterols formed in non–enzymatic way is ring–oxidized, mainly at the 7–position (e.g. 7β–hydroxycholesterol, 7β−OH; 7–ketocholesterol, 7–K), contrary to oxysterols produced during enzymatic reactions, which are chain–oxidized (e.g. 24S–hydroxycholesterol, 24−OH; 25–hydroxycholesterol, 25−OH or 27–hydroxycholesterol, 27−OH). However, there are exceptions to this rule; for example, 25−OH and 7α−OH can be produced by both enzymatic and non–enzymatic way [8]. Besides, some oxysterols (e.g. 7–K, 7α– and 7β−OH, as well as α– and β–5,6–epoxycholesterol) can also be delivered exogenously, particularly with cholesterol–enriched highly processed foods [9].
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ReviewSterol regulators of cholesterol homeostasis and beyond: The oxysterol hypothesis revisited and revised

Abstract

Introduction

Section snippets

Oxysterols: types and origins

Formulation of the hypothesis

Sterol sensors in the SREBP pathway

A revised Oxysterol Hypothesis

Metabolism and elimination of oxysterols

Future directions and recommendations

Conclusion

Acknowledgement

Cell

Atherosclerosis

Steroids

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Biochim Biophys Acta

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Cell

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Mol Cell

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Cell Metab

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Biochem Biophys Res Commun

Atherosclerosis

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Lipids Health Dis

Biochem Pharmacol

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J Biol Chem

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Cell Metab

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Cell

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FEBS Letters

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Review
Sterol regulators of cholesterol homeostasis and beyond: The oxysterol hypothesis revisited and revised