Cholesterol

The liver is the principal organ responsible for cholesterol biosynthesis and regulation. The liver continuously monitors cholesterol concentrations within its own cells and throughout the body. In response, it activates or suppresses genes that control the expression of key proteins involved in cholesterol homeostasis. These include enzymes responsible for cholesterol synthesis, the number of hepatic receptors that mediate cholesterol uptake, and the rate of excretion either as free cholesterol or in the form of bile acids. This complex feedback system allows the liver to maintain cholesterol balance, but it also complicates our understanding of how dietary cholesterol impacts circulating levels.

Although nearly all cells in the human body have the capacity to synthesize cholesterol, approximately 50% of the total endogenous production occurs in the liver. As such, the liver plays a dominant role in determining the concentration of cholesterol circulating in the bloodstream. Cholesterol originating from both dietary sources (exogenous) and internal synthesis (endogenous) is packaged by the liver into very-low-density lipoproteins (VLDL), which are then secreted into the bloodstream. As VLDLs travel through the circulatory system, they are progressively metabolized by lipoprotein lipases, eventually giving rise to low-density lipoproteins (LDL). LDL particles can be taken up by peripheral tissues via LDL receptors to fulfill local cholesterol demands. When cellular cholesterol requirements are met, the excess cholesterol is transferred to high-density lipoproteins (HDL), which serve as the body’s primary mechanism for reverse cholesterol transport. HDL particles collect excess cholesterol from peripheral tissues and return it to the liver and intestines, where it is either recycled or excreted via the biliary system. This is why, in clinical medicine, LDL is referred to as “bad cholesterol,” while HDL is known as “good cholesterol.” Elevated LDL cholesterol levels are considered a significant risk factor for cardiovascular disease, while higher HDL cholesterol levels are generally associated with a reduced risk.

What makes cholesterol so functionally versatile is its unique three-part structure, combining hydrophilic, hydrophobic, and rigid domains. This enables it to serve diverse biological roles. In mammalian cells, cholesterol is a fundamental component of the plasma membrane. One of its key roles is to provide structural integrity and rigidity, which compensates for the lack of a cell wall, as found in bacteria and plant cells. By inserting between phospholipids, cholesterol reduces membrane permeability to ions and small molecules such as gases. The concentration of cholesterol in cellular membranes varies according to function, with internal organelle membranes generally containing less cholesterol than the outer plasma membrane. This distribution is closely linked to the specific biophysical and functional requirements of each membrane type. Cholesterol can also play a role in cellular membranes as a component of signaling pathways.

If cholesterol had no other functions except to stabilize cellular membranes, it would still be an essential molecule. However, its importance extends further as a precursor for the synthesis of crucial hormones. Cholesterol serves as the precursor for hormones secreted by the adrenal gland, including cortisol and aldosterone, as well as the sex hormones as estrogen, progesterone, and testosterone. These hormones regulate numerous physiological processes, from metabolism and stress response to reproductive function and fluid balance. Cholesterol serves also as a precursor for steroid hormones necessary for fetal development, including placental estrogens. Approximately half of the cholesterol required during fetal development is derived from LDL particles, while the other half is synthesized by the fetus itself. This dual-source system ensures adequate supply during critical stages of growth and organ formation.

Cholesterol is also the major structural component used in the synthesis of vitamin D and its metabolites, which are essential for bone health. Additionally, it plays a role in the absorption of fat-soluble vitamins (A, D, E, and K) and in the transport of these vitamins, particularly vitamins K and E, which rely on cholesterol in the form of LDL and HDL particles for distribution throughout the body. Oral forms of vitamin D also depend on this transport system.

While cholesterol plays essential roles in our bodies, its excess, whether due to lifestyle or genetic predisposition, can lead to serious health issues. The most well-known of these is atherosclerosis, a disease in which cholesterol-rich particles accumulate within artery walls and silently progress until a major cardiovascular event occurs (see Figure 1.). Humans have a limited ability to catabolize cholesterol. When levels of circulating cholesterol-rich lipoproteins, particularly LDL, exceed the liver’s capacity to clear them, these particles begin to penetrate arterial walls, becoming embedded in the tissue. Once inside the arterial wall, LDL particles can undergo oxidation, triggering an inflammatory response. This initiates the formation of atherosclerotic plaques, composed of lipid-laden macrophages (foam cells), cellular debris, and cholesterol. These plaques are largely asymptomatic for years, and often only visible through CT scans or imaging tests. But when the build-up grows severe enough to reduce blood flow to vital organs, it can cause damage ranging from chronic ischemia to sudden infarction. The body doesn’t ignore this build-up. In response, macrophages, T cells, and other immune cells infiltrate the affected artery, releasing inflammatory cytokines. Over time, this immune activity can destabilize the plaque. The most dangerous scenario is plaque rupture: when the fibrous cap covering a plaque splits open, the inner contents spill into the bloodstream, triggering the formation of a blood clot (thrombus). This clot can immediately block the artery, causing a heart attack or stroke. Some forms of cholesterol, particularly free cholesterol and oxidized cholesterol (oxysterols), are toxic to vascular cells. These compounds kill lesional macrophages, promoting necrotic core formation within the plaque. This necrosis resembles an inflammatory abscess and can severely compromise arterial integrity, leading to acute vascular occlusion and infarction. While genetics play a role, atherosclerosis can be slowed or even halted by addressing its major risk factors. Proven preventive steps include stopping smoking, adopting a healthy diet low in saturated fats, staying physically active, and managing cholesterol levels through lifestyle or medication. Chronically elevated body cholesterol (hypercholesterolemia) doesn’t only threaten the heart and brain. It can also lead to cholesterol gallstones, liver dysfunction, cholesterol crystal metabolism, dermatological changes such as xanthelasma or other lipid deposits.