Research Area

Lipid/Cholesterol Metabolism and Cardiovascular


The relationship of lipid/cholesterol metabolism and cardiovascular

The pathological basis of cardiovascular and cerebrovascular diseases is atherosclerosis (ASCVD). While dyslipidemia is an important risk factor for ASCVD, studies have found a clear causal relationship between hypercholesterolemia and atherosclerotic disease. To control ASCVD, blood lipids must be controlled. Clinical studies have found that blood lipids are very complex, mainly including total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), lipoprotein (a), ApoA1, ApoB and so on. Clinically, too high plasma total cholesterol (TC) and/or triglyceride (TG) or high density lipoprotein cholesterol (HDL-C) is called lipid abnormality. Abnormal dyslipidemia usually means abnormalities in lipid or sterol metabolism in the body. In addition to dyslipidemia caused by poor lifestyle, it is more due to mutations in lipid or sterol metabolism-related genes. Studies have shown that single-gene mutations cause cardiovascular disease more frequent.

Lipid/Cholesterol Metabolism and Cardiovascular

Type of abnormal lipid or sterol metabolism

1. Dyslipidemia with elevated cholesterol

The plasma lipoprotein metabolism in the body is divided into endogenous, exogenous metabolic pathways and reverse transport of cholesterol. Endogenous metabolic pathway refers to the synthesis of very low-density lipoprotein cholesterol (VLDL-C) from the liver and conversion to medium-density lipoprotein cholesterol and low-density fatty acid (LDL-C), and LDL-C is metabolized by the liver or other organs. The balance of this process is influenced by a number of factors, such as the enzymes, proteins or receptors involved in the process. These genetic mutations cause dyslipidemia, which is mainly caused by elevated LDL-C or total cholesterol (TC), such as, low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (ApoB-100) and Proprotein convertase subtilisin 9. It is located on chromosome 19p13. 2. After mutation of the gene, it will result in insufficient clearance of LDL particles. Apolipoprotein B-100 (ApoB-100) is the main apolipoprotein of LDL particles. The protein is encoded by ApoB, and ApoB is located on chromosome 2p24. 1. It is essential for the formation of LDL-LDLR complex. Proprotein convertase subtilisin 9 (PCSK9) is expressed in the liver and binds to LDL- LDLR complex, and increases the affinity of LDL and LDLR. Therefore, LDL cannot be released in the endosome, and LDLR and LDL are simultaneously degraded. PCSK9 is located on chromosome 1p32. 3, functional gain mutation increases intracellular LDLR degradation, resulting in decreased cell surface LDLR expression, and LDL-C has a reduced clearance rate from the cells. Abnormal expression of these genes often leads to familial hypercholesterolemia (FH) and has a higher risk of premature coronary heart disease. In addition, apolipoprotein E (ApoE) gene mutation, low-density lipoprotein receptor adaptor 1 gene (LDLRAP1) biallelic mutation can also cause genetic hypercholesterolemia. In addition to LDL-C transport and uptake-related proteins, mutations in LDL-C metabolism-related enzymes also trigger FH, for instance, cholesterol 7-hydroxylase. Cholesterol 7-hydroxylase is expressed only in the liver, which initiates the synthesis of bile acids in the classical pathway of bile acid formation. It is encoded by the cholesterol 7-hydroxylase (CYP7A1) gene, which is located on chromosome 8q12. Mutations in the CYP7A1 gene cause a decrease in CYP7A1 activity, cholesterol catabolism and bile acid synthesis. And then the intrahepatic cholesterol levels is increased. The increase cause the down-regulates LDLR of liver, leading to an increase in plasma LDL-C levels. The loss of function has an increased risk of early onset atherosclerosis. In addition, the lack of lysosomal acid lipase A leads to the accumulation of cholesteryl esters and TG in lysosomes, and the decrease in intracellular free cholesterol leads to an increase in endogenous cholesterol synthesis. At the same time, the reduction of intracellular free cholesterol reduced the efflux of high-density fatty acid(HDL-C), which ultimately resulted in elevated plasma LDL-C levels and decreased HDL-C levels.

2. Dyslipidemia characterized by elevated triglyceride (TG)

The chylomicrons are synthesized in the small intestine by dietary intake of cholesterol and TG, and receive ApoE and apolipoprotein C (ApoC) from HDL. After maturation, lipoprotein lipase (LPL) is activated, and the core TG is hydrolyzed to release free fatty acids and generate energy. The process by which chylomicrons are catabolized in the liver is an exogenous metabolic pathway. If this pathway is disturbed, it will be manifest as elevated TG and other dyslipidemia. The most common cause is LPL mutation leading to LPL deficiency. In addition, ApoC2, an important cofactor for LPL activation, is involved, and its mutations affect the activation of LPL, resulting in TG accumulation. The ApoA5 gene cluster has a high effect on high-density lipoprotein cholesterol (HDL-C), and it has been reported in the literature that this gene affects TG levels. Its mutations also affect dyslipidemia. Almost all of these mutations have been shown to reduce or eliminate LPL activity, leading to the accumulation of chylomicrons, which in turn cause atherosclerosis.

In addition, dyslipidemia also includes mixed dyslipidemia (ApoE allelic variation results in a decrease in the ability to exclude chylomicrons and VLDL residual particles from circulation, and lipid exchange of residual particles with LDL and HDL particles causes them to become abnormal cholesterol, and these abnormalities Cholesterol causes atherosclerosis.); dyslipidemia dominated by HDL-C reduction (HDL-C is an important form of cholesteryl ester transport, and its abnormalities can manifest lipid or sterol metabolism).

Clinical significance

With the development of next-generation sequencing technology, more and more lipid metabolism-related genes have been discovered. Further understanding of the causes and progression of cardiovascular disease can be achieved by performing functional verification of these genes. This is helpful for finding new diagnostic and therapeutic targets for dyslipidemia and cardiovascular disease, and also provides a new theoretical basis for early prevention of cardiovascular disease.

References:

  1. Khera AV, et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol. 2016,67:2578-2589.
  2. Van der Velde AE, Brufau G, Groen AK. Transintestinal cholesterol efflux. Curr Opin Lipidol. 2010, 21:167-171.
  3. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003,111:1795-1803.
  4. Andersen LH, et al. Familial defective apolipoprotein B-100: A review. J Clin Lipidol. 2016,10:1297-1302.
  5. Awan Z, et al. APOE p.Leu167del mutation in familial hypercholesterolemia. Atherosclerosis. 2013, 231:218-222.
  6. Maciejko JJ. Managing cardiovascular risk in lysosomal acid lipase deficiency. Am J Cardiovasc Drugs. 2017,17:217-231.

Research Area

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