Cellular cholesterol trafficking and compartmentalization

Abstract

Cholesterol is an essential structural component in the cell membranes of most vertebrates. The biophysical properties of cholesterol and the enzymology of cholesterol metabolism provide the basis for how cells handle cholesterol and exchange it with one another. A tightly controlled--but only partially characterized--network of cellular signalling and lipid transfer systems orchestrates the functional compartmentalization of this lipid within and between organellar membranes. This largely dictates the exchange of cholesterol between tissues at the whole body level. Increased understanding of these processes and their integration at the organ systems level provides fundamental insights into the physiology of cholesterol trafficking.

Cholesterol transport from late endosomes to the Golgi regulates t-SNARE trafficking, assembly, and function

“…Although increased t-SNARE endocytosis in AnxA6-overexpressing cells cannot be completely ruled out as contributing to the phenotype observed, the ability of AnxA6 to impact on SNARE localization and functioning is probably linked to its association with late endosomes, which plays a crucial role in cholesterol trafficking and homeostasis. Late endosomes are a sorting station and are capable of exporting cholesterol via vesicular (Maxfield and Tabas, 2005; Urano et al , 2008) and nonvesicular (protein-mediated) transport mechanisms involving NPC1 (Garver and Heidenreich, 2002) and cytoplasmic sterol-binding proteins (e.g., oxysterol-binding protein/OSBP-related proteins [OSBP/ORPs], ORP5; Ngo et al , 2010; Du et al , 2011) or through StAR-related lipid transfer domain (START)-domain proteins (Soccio and Breslow, 2003; Alpy and Tomasetto, 2005; Ikonen, 2008). In CHO-A6 cells, cholesterol accumulates in late endosomes, probably due to AnxA6 interference with NPC1 activity.…”

The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

“…These critical cellular functions are supported by regulatory mechanisms that maintain normal cholesterol levels and prevent hypercholesterolemia, which is a major risk factor for cardiovascular disease in humans. Cholesterol homeostasis in vertebrates is achieved primarily through de novo synthesis and dietary uptake (Ikonen 2008). Although extensive studies have defined a central role for the sterol regulatory elementbinding protein (SREBP) family of transcription factors in controlling cholesterol synthesis (Brown and Goldstein 1997), the mechanisms that regulate dietary cholesterol absorption remain more poorly understood.…”

Encystation commitment inGiardia duodenalis: a long and winding road

“…These include hydroxymethylglutaryl CoA synthase (HMGCoA-syn) and the rate-limiting enzyme HMGCoA reductase (HMGCoA-red) (Hernández & Wasserman, 2006), the de novo synthesis of farnesyl and geranylgeranyl isoprenoids and ubiquinone (Luján et al, 1997) and the presence of sequences with low homology to squalene oxidase, squalene synthetase and lanosterol 14-α-demethylase in the annotated GiardiaDB. However, the cyclization of squalene to lanosterol and further conversion to cholesterol, demanding at least 11 O 2 molecules (Ikonen, 2008) are unlikely to occur in Giardia since it is microaerophilic. Instead trophozoites take up cholesterol by calcium-independent endocytosis (Luján et al, 1996(Luján et al, , 1997) mediated by a 69-kDa cell surface glycoprotein receptor (CR) recognizing the cholesterol moiety of low density lipoproteins (LDL) (Kaul, 2003) which is antigenically similar in mammalian cells and Giardia (Kaul et al, 2001).…”

“…Protein kinase A (PKA) is activated by cAMP and phosphorylates the precursor form of the 125 kDa-sized sterol-responsive element binding protein (pSREBP; Fig. 2) which may be retained in the ER by the SREBP cleavage-activating protein (SCAP) and insulin-induced gene protein (INSIG) (Ikonen, 2008;Kaul, 2003;Yellaturu et al, 2005). In Giardia specific Ca 2+ -dependent, membrane-associated and alkaline-soluble PLA 2 activities have been demonstrated (Vargas-Villarreal et al, 2007); AA is generated as an intermediate product in the giardial Lands cycle that allows the remodeling of uptaken phospholipids and generation of new ones (Das et al, 2001) and noteworthy endogenous cAMP promotes vegetative growth and the activation phase of excystation (Abel et al, 2001).…”