Side-chain oxysterols: From cells to membranes to molecules

Abstract

This review discusses the application of cellular biology, molecular biophysics, and computational simulation to understand membrane-mediated mechanisms by which oxysterols regulate cholesterol homeostasis. Side-chain oxysterols, which are produced enzymatically in vivo, are physiological regulators of cholesterol homeostasis and primarily serve as cellular signals for excess cholesterol. These oxysterols regulate cholesterol homeostasis through both transcriptional and non-transcriptional pathways; however, many molecular details of their interactions in these pathways are still not well understood. Cholesterol trafficking provides one mechanism for regulation. The current model of cholesterol trafficking regulation is based on the existence of two distinct cholesterol pools in the membrane: a low and a high availability/activity pool. It is proposed that the low availability/activity pool of cholesterol is integrated into tightly packing phospholipids and relatively inaccessible to water or cellular proteins, while the high availability cholesterol pool is more mobile in the membrane and is present in membranes where the phospholipids are not as compressed. Recent results suggest that that oxysterols may promote cholesterol egress from membranes by shifting cholesterol from the low to the high activity pools. Furthermore, molecular simulations suggest a potential mechanism for oxysterol “activation” of cholesterol through its displacement in the membrane. This review discusses these results as well as several other important interactions between oxysterols and cholesterol in cellular and model lipid membranes.

Plasma Signature of Neurological Disease in the Monogenetic Disorder Niemann-Pick Type C

“…Plasma oxysterols (7-ketocholetserol and 3␤,5␣,6␤-triol) generated by non-enzymatic pathways are largely produced by the liver (43,44) and thus are likely to be more useful to understand liver pathology rather than brain pathology. However, 24(S)-HC is derived from cholesterol by an enzyme, 24-hydroxylase, which is primarily expressed in the neurons of the central nervous system (45,46).…”

Esterification of 24S-OHC induces formation of atypical lipid droplet-like structures, leading to neuronal cell death

“…We propose that DART-MS analysis may serve as a useful tool for investigation not just of 24S-OHC esters, as in our present study, but of a wide variety of esters of sterols and fatty acids. For example, there has been growing interest in oxysterol research because there are a number of bioactivities of oxysterols that have received much attention (40,41), and oxysterols also have potential for use as biomarkers of neurodegenerative diseases (10,42,43). Although it will be necessary to devise appropriate techniques before DART-MS can be used for precise quantitative analysis, it is thought that the DART-MS method will ultimately be valuable for evaluation not only of free oxysterol, but also of oxysterol esters in the tissue, plasma, and cerebrospinal fluid of patients suffering from neurodegenerative disease.…”

Sample preparation: A critical step in the analysis of cholesterol oxidation products

“…These compounds have been well documented for being potentially cytotoxic, mutagenic, carcinogenic, and they have been associated with the promotion of atherosclerosis (Brown & Jessup, 1999;Leonarduzzi, Sottero, & Poli, 2002;Lordan, Mackrill, & O'Brien, 2009;Olkkonen, Béaslas, & Nissilä, 2012; Otaegui-Arrazola, Menendez-Carreño, Ansorena, & Astiasarán, 2010;Poli, Sottero, Gargiulo, & Leonarduzzi, 2009). It is thought that COPs modulate the structure and function of the cellular membrane and inhibit the activity of enzymes involved in cholesterol biosynthesis (Bielska, Schlesinger, Covey, & Ory1, 2012;Brown & Jessup, 2009;Gill, Chow, & Brown, 2008;Jusakul, Yongvanit, Loilome, Namwat, & Kuver, 2011;Olsen, Schlesinger, & Baker, 2009;Olsen, Schlesinger, Ory, & Baker, 2012).…”