Causes of high cholesterol
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Causes of High Cholesterol
High cholesterol, particularly elevated levels of low-density lipoprotein (LDL) cholesterol, is a significant risk factor for cardiovascular diseases (CVD). Understanding the causes of high cholesterol is crucial for effective prevention and management. This article synthesizes findings from multiple research studies to elucidate the primary causes of high cholesterol.
Genetic Factors and Familial Hypercholesterolemia
Familial Hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically elevated LDL cholesterol. This condition arises from mutations affecting the LDL receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 (PCSK9). Individuals with FH have a significantly higher risk of developing coronary heart disease (CHD) due to the severely elevated serum cholesterol concentrations.
Lipoprotein(a) and Genetic Risk: High levels of lipoprotein(a) and corresponding LPA risk genotypes are also identified as novel risk factors for clinical familial hypercholesterolemia. Individuals with both high lipoprotein(a) concentrations and FH mutations have the highest risk of myocardial infarction.
Cholesteryl Ester Transfer Protein (CETP) Deficiency
CETP Deficiency: CETP catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins. A mutation in the CETP gene can lead to CETP deficiency, resulting in increased HDL cholesterol levels and decreased LDL cholesterol levels. This condition is particularly prevalent in certain populations, such as in Japan, due to a founder effect. While CETP deficiency is associated with a favorable lipoprotein profile, it does not necessarily correlate with a reduced risk of CHD.
Inflammation and Immune Response
Cholesterol and Inflammation: High cholesterol levels can lead to cholesterol accumulation in macrophages and other immune cells, promoting inflammatory responses. This includes the activation of Toll-like receptor (TLR) signaling and inflammasome activation, which further amplifies cholesterol accumulation and inflammation. This inflammatory response is beneficial in fighting infections but exacerbates chronic metabolic diseases like atherosclerosis and obesity.
Remnant Cholesterol and Inflammation: Elevated remnant cholesterol is causally associated with low-grade inflammation and ischemic heart disease (IHD). In contrast, elevated LDL cholesterol is associated with IHD without causing inflammation.
Dietary Factors
Dietary Cholesterol: Historically, dietary cholesterol was believed to increase blood cholesterol levels and the risk of CVD. However, recent research indicates that dietary cholesterol does not significantly impact blood cholesterol levels or CVD risk. Consequently, dietary guidelines have removed previous restrictions on dietary cholesterol intake. It is important to note that foods high in cholesterol often contain saturated fatty acids, which can increase CVD risk.
Conclusion
High cholesterol can result from a combination of genetic factors, such as familial hypercholesterolemia and CETP deficiency, as well as inflammatory responses linked to cholesterol accumulation in immune cells. While dietary cholesterol has a minimal impact on blood cholesterol levels, the consumption of saturated fats remains a concern. Understanding these causes is essential for developing targeted interventions to manage and prevent high cholesterol and its associated health risks.
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