sterols) cause a change in this domain's oligomerization state, which makes it more susceptible to destruction by the proteasome. this enzyme's activity can also be reduced by phosphorylation by an amp-activated protein kinase. because this kinase is activated by amp, which is produced when atp is hydrolyzed, it follows that cholesterol synthesis is halted when atp levels are low. plasma transport and regulation of absorption lipid logistics: transport of triglycerides and cholesterol in organisms in form of lipoproteins as chylomicrons, vldl, ldl, idl, hdl. as an isolated molecule, cholesterol is only minimally soluble in water, or hydrophilic. because of this, it dissolves in blood at exceedingly small concentrations. to be transported effectively, cholesterol is instead packaged within lipoproteins, complex discoidal particles with exterior amphiphilic proteins and lipids, whose outward-facing surfaces are water-soluble and inward-facing surfaces are lipid-soluble. this allows it to travel through the blood via emulsification. unbound cholesterol, being amphipathic, is transported in the monolayer surface of the lipoprotein particle along with phospholipids and proteins. cholesterol esters bound to fatty acid, on the other hand, are transported within the fatty hydrophobic core of the lipoprotein, along with triglyceride. there are several types of lipoproteins in the blood. in order of increasing density, they are chylomicrons, very-low-density lipoprotein (vldl), intermediate-density lipoprotein (idl), low-density lipoprotein (ldl), and high-density lipoprotein (hdl). lower protein/lipid ratios make for less dense lipoproteins. cholesterol within different lipoproteins is identical, although some is carried as its native "free" alcohol form (the cholesterol-oh group facing the water surrounding the particles), while others as fatty acyl esters, known also as cholesterol esters, within the particles. lipoprotein particles are organized by complex apolipoproteins, typically 80–100 different proteins per particle, which can be recognized and bound by specific receptors on cell membranes, directing their lipid payload into specific cells and tissues currently ingesting these fat transport particles. these surface receptors serve as unique molecular signatures, which then help determine fat distribution delivery throughout the body. chylomicrons, the least dense cholesterol transport molecules, contain apolipoprotein b-48, apolipoprotein c, and apolipoprotein e (the principal cholesterol carrier in the brain) in their shells. chylomicrons carry fats from the intestine to muscle and other tissues in need of fatty acids for energy or fat production. unused cholesterol remains in more cholesterol-rich chylomicron remnants, and taken up from here to the bloodstream by the liver. vldl molecules are produced by the liver from triacylglycerol and cholesterol which was not used in the synthesis of bile acids. these molecules contain apolipoprotein b100 and apolipoprotein e in their shells, and can be degraded by lipoprotein lipase on the artery wall to idl. this arterial wall cleavage allows absorption of triacylglycerol and increases the concentration of circulating cholesterol. idl molecules are then consumed in two processes: half is metabolized by htgl and taken up by the ldl receptor on the liver cell surfaces, while the other half continues to lose triacylglycerols in the bloodstream until they become cholesterol-laden ldl particles. ldl particles are the major blood cholesterol carriers. each one contains approximately 1,500 molecules of cholesterol ester. ldl molecule shells contain just one molecule of apolipoprotein b100, recognized by ldl receptors in peripheral tissues. upon binding of apolipoprotein b100, many ldl receptors concentrate in clathrin-coated pits. both ldl and its receptor form vesicles within a cell via endocytosis. these vesicles then fuse with a lysosome, where the lysosomal acid lipase enzyme hydrolyzes the cholesterol esters. the cholesterol can then be used for membrane biosynthesis or esterified and stored within the cell, so as to not interfere with the cell membranes. ldl receptors are used up during cholesterol absorption, and its synthesis is regulated by srebp, the same protein that controls the synthesis of cholesterol de novo, according to its presence inside the cell. a cell with abundant cholesterol will have its ldl receptor synthesis blocked, to prevent new cholesterol in ldl molecules from being taken up. conversely, ldl receptor synthesis proceeds when a cell is deficient in cholesterol. when this process becomes unregulated, ldl molecules without receptors begin to appear in the blood. these ldl molecules are oxidized and taken up by macrophages, which become engorged and form foam cells. these foam cells often become trapped in the walls of blood vessels and contribute to atherosclerotic plaque formation. differences in cholesterol homeostasis affect the development of early atherosclerosis (carotid intima-media thickness). these plaques are the main causes of heart attacks, strokes, and other serious medical problems, leading to the association of so-called ldl cholesterol (actually a lipoprotein) with "bad" cholesterol. hdl particles are thought to transport cholesterol back to the liver, either for excretion or for other tissues that synthesize hormones, in a process known as reverse cholesterol transport (rct). large numbers of hdl particles correlates with better health outcomes, whereas low numbers of hdl particles is associated with atheromatous disease progression in the arteries. metabolism, recycling and excretion cholesterol is susceptible to oxidation and easily forms oxygenated derivatives called oxysterols. three different mechanisms can form these: autoxidation, secondary oxidation to lipid peroxidation, and cholesterol-metabolizing enzyme oxidation. a great interest in oxysterols arose when they were shown to exert inhibitory actions on cholesterol biosynthesis. this finding became known as the "oxysterol hypothesis". additional roles for oxysterols in human physiology include their participation in bile acid biosynthesis, function as transport forms of cholesterol, and regulation of gene transcription. in biochemical experiments radiolabelled forms of cholesterol, such as tritiated-cholesterol are used. these derivatives undergo degradation upon storage and it is essential to purify cholesterol prior to use. cholesterol can be purified using small sephadex lh-20 columns. cholesterol is oxidized by the liver into a variety of bile acids. these, in turn, are conjugated with glycine, taurine, glucuronic acid, or sulfate. a mixture of conjugated and nonconjugated bile acids, along with cholesterol itself, is excreted from the liver into the bile. approximately 95% of the bile acids are reabsorbed from the intestines, and the remainder are lost in the feces. the excretion and reabsorption of bile acids forms the basis of the enterohepatic circulation, which is essential for the digestion and absorption of dietary fats. under certain circumstances, when more concentrated, as in the gallbladder, cholesterol crystallises and is the major constituent of most gallstones (lecithin and bilirubin gallstones also occur, but less frequently). every day, up to 1 g of cholesterol enters the colon. this cholesterol originates from the diet, bile, and desquamated intestinal cells, and can be metabolized by the colonic bacteria. cholesterol is converted mainly into coprostanol, a nonabsorbable sterol that is excreted in the feces. although cholesterol is a steroid generally associated with mammals, the human pathogen mycobacterium tuberculosis is able to completely degrade this molecule and contains a large number of genes that are regulated by its presence. many of these cholesterol-regulated genes are homologues of fatty acid β-oxidation genes, but have evolved in such a way as to bind large steroid substrates like cholesterol. dietary sources animal fats are complex mixtures of triglycerides, with lesser amounts of both the phospholipids and cholesterol molecules from which all animal (and human) cell membranes are constructed. since all animal cells manufacture cholesterol, all animal-based foods contain cholesterol in varying amounts. major dietary sources of cholesterol include red meat, egg yolks and whole eggs, liver, kidney, giblets, fish oil, and butter. human breast milk also contains significant quantities of cholesterol. plant cells synthesize cholesterol as a precursor for other compounds, such as phytosterols and steroidal glycoalkaloids, with cholesterol remaining in plant foods only in minor amounts or absent. some plant foods, such as avocado, flax seeds and peanuts, contain phytosterols, which compete with cholesterol for absorption in the intestines, and reduce the absorption of both dietary and bile cholesterol. a typical diet contributes on the order of 0.2 gram of phytosterols, which is not enough to have a significant impact on blocking cholesterol absorption. phytosterols intake can be supplemented through the use of phytosterol-containing functional foods or dietary supplements that are recognized as having potential to reduce levels of ldl-cholesterol. medical guidelines and recommendations in 2015, the united states department of agriculture dietary guidelines advisory committee (dgac) recommended that americans eat as little dietary cholesterol as possible, because most foods that are rich in cholesterol are also high in saturated fat and thereby may increase the risk of cardiovascular disease. a 2013 report by the american heart association and the american college of cardiology recommended focusing on healthy dietary patterns rather than specific cholesterol limits, as they are hard for clinicians and consumers to implement. they recommend the dash and mediterranean diet, which are low in cholesterol. a 2017 review by the american heart association recommends switching saturated fats for polyunsaturated fats to reduce cardiovascular disease risk. some supplemental guidelines have recommended doses of phytosterols in the 1.6–3.0 grams per day range (health canada, efsa, atp iii, fda). a recent meta-analysis demonstrating a 12% reduction in ldl-cholesterol at a mean dose of 2.1 grams per day. however, the benefits of a diet supplemented with phytosterols have also been questioned. clinical significance hypercholesterolemia main articles: hypercholesterolemia and lipid hypothesis cholesterolemia and mortality for men and women <50 years and >60 years according to the lipid hypothesis, elevated levels of cholesterol in the blood lead to atherosclerosis which may increase the risk of heart attack, stroke, and peripheral artery disease. since higher blood ldl – especially higher ldl concentrations and smaller ldl particle size – contributes to this process more than the cholesterol content of the hdl particles, ldl particles are often termed "bad cholesterol". high concentrations of functional hdl, which can remove cholesterol from cells and atheromas, offer protection and are commonly referred to as "good cholesterol". these balances are mostly genetically determined, but can be changed by body composition, medications, diet, and other factors. a 2007 study demonstrated that blood total cholesterol levels have an exponential effect on cardiovascular and total mortality, with the association more pronounced in younger subjects. because cardiovascular disease is relatively rare in the younger population, the impact of high cholesterol on health is larger in older people. elevated levels of the lipoprotein fractions, ldl, idl and vldl, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis. conversely, the total cholesterol can be within normal limits, yet be made up primarily of small ldl and small hdl particles, under which conditions atheroma growth rates are high. a post hoc analysis of the ideal and the epic prospective studies found an association between high levels of hdl cholesterol (adjusted for apolipoprotein a-i and apolipoprotein b) and increased risk of cardiovascular disease, casting doubt on the cardioprotective role of "good cholesterol". about one in 250 individuals can have a genetic mutation for the ldl cholesterol receptor that causes them to have familial hypercholesterolemia. inherited high cholesterol can also include genetic mutations in the pcsk9 gene and the gene for apolipoprotein b. elevated cholesterol levels are treated with a strict diet consisting of low saturated fat, trans fat-free, low cholesterol foods, often followed by one of various hypolipidemic agents, such as statins, fibrates, cholesterol absorption inhibitors, monoclonal antibody therapy (pcsk9 inhibitors), nicotinic acid derivatives or bile acid sequestrants. there are several international guidelines on the treatment of hypercholesterolaemia. human trials using hmg-coa reductase inhibitors, known as statins, have repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly lowers cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults. studies have shown that reducing ldl cholesterol levels by about 38.7 mg/dl with the use of statins can reduce cardiovascular disease and stroke risk by about 21%. studies have also found that statins reduce atheroma progression. as a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of their cholesterol levels (total cholesterol below 5.0 mmol/l ), and in men without cardiovascular disease, there is benefit from lowering abnormally high cholesterol levels ("primary prevention"). primary prevention in women was originally practiced only by extension of the findings in studies on men, since, in women, none of the large statin trials conducted prior to 2007 demonstrated a significant reduction in overall mortality or in cardiovascular endpoints. meta-analyses have demonstrated significant reductions in all-cause and cardiovascular mortality, without significant heterogeneity by sex. risk for heart disease level interpretation mg/dl mmol/l < 200