Cholesterol is an important lipid constituent of all cellular membranes and myelin. The brain contains about one quarter of the total unesterified cholesterol in human subjects, while this organ constitutes only 2% of the total body mass. Brain cholesterol is mainly synthesized locally and only negligible amounts of circulatory cholesterol takes part in brain cholesterol metabolism as its transfer is restricted by the blood–brain barrier (BBB). The lipid components of biological membranes are important for normal cell function, and their improper distribution or metabolism can have serious consequences for cells and organisms. Changes in the organization of lipids can have profound effects on cellular functions such as signal transduction and membrane trafficking. These membrane effects can cause disease in humans as a result of genetic alterations or environmental effects (such as diet), or both. Cholesterol is one of the most important regulators of lipid organization, and mammals have developed sophisticated and complex mechanisms to maintain cellular cholesterol levels in membranes within a narrow range. Cholesterol is synthesized in the ER and delivered to other organelles by a combination of vesicular and non-vesicular transport processes.
Organisms must maintain the proper functioning of their membranes in response to various changes. In humans, one of the most significant factors affecting the membrane is dietary intake of cholesterol and fats, which are delivered to cells throughout the body through lipoproteins. A rapid response to increasing cholesterol levels is the esterification of excess cholesterol by an ER enzyme, acyl CoA:cholesterol acyltransferase (ACAT). The esterified cholesterol is stored in cytoplasmic lipid droplets. The cholesterol esters in the droplets are hydrolyzed by neutral cholesterol ester hydrolases, which in some cells include a hormone-sensitive lipase that also hydrolyses triglycerides in fat cells. The cholesterol released from the droplets can be used for cell membranes and, in steroidogenic cells, for steroid hormone synthesis. Many genes involved in cholesterol metabolism are regulated by SREBP. When cholesterol levels are high, SREBP and SCAP are retained in the ER by binding to INSIG, a resident ER protein. When cholesterol is low, the SREBP–SCAP complex exits from the ER, and SREBP undergoes two proteolytic cleavages. This releases the cytosolic domain of SREBP, which is then translocated into the nucleus and regulates the transcription of many genes, including the LDL receptor and HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. The key extracellular acceptors for cholesterol are high-density lipoproteins (HDLs) and one of their associated apolipoproteins, ApoA-I. The family of ABC transporters has a key role in delivering cholesterol and phospholipids to apolipoproteins, and defects in these transporters lead to several human diseases. In most peripheral tissues, metabolism of cholesterol (other than esterification/de-esterification) is a minor biochemical pathway. However, most cells convert a small fraction of cholesterol into oxysterols, and these molecules are important for intracellular signalling.
Atherosclerosis is the major human disease associated with cholesterol and lipid metabolism. The earliest detectable event in atherogenesis (the process of forming atheromas) is the accumulation of plasma lipoproteins in the subendothelium, or intima, of focal areas of the arterial tree. The lipoproteins are retained owing to a combination of proteoglycan binding and lipoprotein aggregation, which impedes egress from the arterial wall because of their increased particle size. These retained lipoproteins, particularly those that are modified by oxidation, aggregation and other means, elicit a series of biological responses that lead to atherogenesis. Receptor-mediated uptake by means of the LDL receptor is usually limited because of its homeostatic downregulation by cholesterol. However, aggregated LDL, a major form of LDL in atherosclerotic lesions, can deliver enormous amounts of cholesterol to macrophages and cause foam-cell formation. The cholesterol and lipids play role in Alzheimer’s disease formation. The basis is the observation that there is a genetic linkage between age of onset of Alzheimer’s disease and the presence of the ε4 allele of apolipoprotein E (ApoE). Polymorphisms in other proteins involved in cholesterol metabolism may also have a genetic linkage with this disease. ApoE is one of the main carriers of cholesterol in the brain, and it seems possible that alterations in cholesterol distribution or levels might have a role in formation of amyloid deposits.