scholarly journals Intracellular cholesterol transport proteins: roles in health and disease

2016 ◽  
Vol 130 (21) ◽  
pp. 1843-1859 ◽  
Author(s):  
Ugo Soffientini ◽  
Annette Graham
Keyword(s):  
Translational Regulation ◽  
Regulatory Protein ◽  
Current Evidence ◽  
Lipid Transfer ◽  
Oxysterol Binding Protein ◽  
Congenital Lipoid Adrenal Hyperplasia ◽  
Health And Disease ◽  
Steroidogenic Acute Regulatory ◽  
Related Proteins ◽  
Sterol Binding

Effective cholesterol homoeostasis is essential in maintaining cellular function, and this is achieved by a network of lipid-responsive nuclear transcription factors, and enzymes, receptors and transporters subject to post-transcriptional and post-translational regulation, whereas loss of these elegant, tightly regulated homoeostatic responses is integral to disease pathologies. Recent data suggest that sterol-binding sensors, exchangers and transporters contribute to regulation of cellular cholesterol homoeostasis and that genetic overexpression or deletion, or mutations, in a number of these proteins are linked with diseases, including atherosclerosis, dyslipidaemia, diabetes, congenital lipoid adrenal hyperplasia, cancer, autosomal dominant hearing loss and male infertility. This review focuses on current evidence exploring the function of members of the ‘START’ (steroidogenic acute regulatory protein-related lipid transfer) and ‘ORP’ (oxysterol-binding protein-related proteins) families of sterol-binding proteins in sterol homoeostasis in eukaryotic cells, and the evidence that they represent valid therapeutic targets to alleviate human disease.

scholarly journals The mammalian START domain protein family in lipid transport in health and disease

2011 ◽  
Vol 212 (3) ◽  
pp. 257-275 ◽  
Author(s):  
Barbara J Clark
Keyword(s):  
Regulatory Protein ◽  
Protein Family ◽  
Lipid Transport ◽  
Lipid Transfer ◽  
Lipid Trafficking ◽  
Disease States ◽  
Health And Disease ◽  
Start Domain ◽  
Domain Protein ◽  
Steroidogenic Acute Regulatory

Lipid transfer proteins of the steroidogenic acute regulatory protein-related lipid transfer (START) domain family are defined by the presence of a conserved ∼210 amino acid sequence that folds into an α/β helix-grip structure forming a hydrophobic pocket for ligand binding. The mammalian START proteins bind diverse ligands, such as cholesterol, oxysterols, phospholipids, sphingolipids, and possibly fatty acids, and have putative roles in non-vesicular lipid transport, thioesterase enzymatic activity, and tumor suppression. However, the biological functions of many members of the START domain protein family are not well established. Recent research has focused on characterizing the cell-type distribution and regulation of the START proteins, examining the specificity and directionality of lipid transport, and identifying disease states associated with dysregulation of START protein expression. This review summarizes the current concepts of the proposed physiological and pathological roles for the mammalian START domain proteins in cholesterol and lipid trafficking.

scholarly journals Functional analyses of phosphatidylserine/PI(4)P exchangers with diverse lipid species and membrane contexts set unanticipated rules on lipid transfer

2021 ◽  
Author(s):  
Souade Ikhlef ◽  
Nicolas-Frédéric Lipp ◽  
Vanessa Delfosse ◽  
Nicolas Fuggetta ◽  
William Bourguet ◽  
...  
Keyword(s):  
Lipid Transfer ◽  
Oxysterol Binding Protein ◽  
Lipid Exchange ◽  
Exchange Processes ◽  
Lipid Species ◽  
Acyl Chains ◽  
Phosphatidylinositol 4 ◽  
Functional Analyses ◽  
Related Proteins

Several members of the oxysterol-binding protein-related proteins (ORPs)/oxysterol-binding homology (Osh) family exchange phosphatidylserine (PS) and phosphatidylinositol 4-phosphate (PI(4)P) at the endoplasmic reticulum/plasma membrane (PM) interface. It is unclear whether they preferentially exchange PS and PI(4)P with specific acyl chains to tune the features of the PM, whether they use phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) instead of PI(4)P for exchange processes and whether their activity is influenced by the association of PS with sterol in the PM. Here, we measured in vitro how the yeast Osh6p and human ORP8 transported diverse PS and PI(4)P subspecies, including major cellular species, between membranes. We established how their activity is impacted by the length and unsaturation degree of these lipids. Surprisingly, the speed at which they individually transfer these ligands inversely depends on their affinity for them. To be fast, the transfer of high-affinity ligands requires an exchange with a counterligand of equivalent affinity. Besides, we determined that Osh6p and ORP8 cannot use PI(4,5)P2 for intracellular lipid exchange, as they have a low affinity for this lipid compared to PI(4)P, and do not transfer more PS into sterol-rich membranes. This study provides insights into PS/PI(4)P exchangers and sets unanticipated rules on how the activity of lipid transfer proteins relates to their affinity for ligands.

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