Retracted: Advances in the physiological and pathological implications of cholesterol

Abstract

Cholesterol has evolved to fulfill sophisticated biophysical, cell signalling, and endocrine functions in animal systems. At the cellular level, cholesterol is found in membranes where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid-protein membrane microdomains with critical topographical and signalling functions. At the organismal level, cholesterol is the precursor of all steroid hormones, including gluco- and mineralo-corticoids, sex hormones, and vitamin D, which regulate carbohydrate, sodium, reproductive, and bone homeostasis, respectively. This sterol is also the immediate precursor of bile acids, which are important for intestinal absorption of dietary lipids as well as energy homeostasis and glucose regulation. Complex mechanisms maintain cholesterol within physiological ranges and the dysregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these conditions has been demonstrated by genetic and pharmacological manipulations in animal models of human disease that are discussed herein. Importantly, the understanding of basic aspects of cholesterol biology has led to the development of high-impact pharmaceutical therapies during the past century. The continuing effort to offer successful treatments for prevalent cholesterol-related diseases, such as atherosclerosis and neurodegenerative disorders, warrants further interdisciplinary research in the coming decades.

Role of cholesterol in SNARE-mediated trafficking on intracellular membranes

“…Mutations in the genes encoding NPC1 or NPC2 inhibit the egress of cholesterol from late endosomes (Klein et al, 2006) and reduce its delivery to the Golgi, plasma membrane and recycling endosomes (Cubells et al, 2007;Kanerva et al, 2013;Reverter et al, 2014;Urano et al, 2008). Together, this triggers a dysfunction of membrane trafficking, which is associated with cardiovascular, neurological and lysosomal storage diseases (Cortes et al, 2013;De Matteis and Luini, 2011;Ikonen, 2006;Maxfield and Tabas, 2005). (Pre-)lysosomal cholesterol export most likely involves the transfer of cholesterol from luminal NPC2 to membrane-associated NPC1, followed by insertion of the aliphatic side chain of cholesterol into the (pre-)lysosomal membrane (Infante et al, 2008;Wang et al, 2010).…”

Sterol Composition in Infant Formulas and Estimated Intake

“…Apart from its role as a structural component, cholesterol is a precursor of bile acids and steroid hormones. 4 During the past decades, there have been a growing number of papers published in relevant scientific journals attempting to explain the relationship between cholesterol intake from HM and the possible prevention of cardiovascular diseases in adulthood. In this sense, Owen et al, 5 in a systematic review of 17 observational studies, concluded that breastfeeding (particularly exclusive breastfeeding) may be associated with lower blood cholesterol in later life.…”

Early Onset Intrauterine Growth Restriction in a Mouse Model of Gestational Hypercholesterolemia and Atherosclerosis

“…In addition, the requirement of cholesterol to sustain appropriate fetal development [10] has hindered the use of pharmacological treatments to reduce cholesterol in hypercholesterolemic pregnant women due to their possible teratogenic effects. As in many other areas of biomedical research, animals have nevertheless proven valuable experimental models of fetal programming due to their genetic homogeneity, more controlled environment, accessibility to obtain fetuses at different developmental stages, and feasibility for interventions during gestation.…”