Familial Hypercholesterolemia Flashcards
CardioVascular Disease
Cardiovascular or heart disease is a class of disease that involves the heart or blood vessels (arteries, capillaries and veins). The most common type of heart disease,
Atherosclerosis
Caused by plaque building up along the inner walls of the arteries, which narrows the arteries and restricts blood flow.
Atherosclerotic plaques
Contain proteins, lipids and cholesterol
Cholesterol and function
Waxy and hydrophobic;
Integral part of cell membrane;
Precursor for hormones
Precursor for Vitamin D
Precursor for Bile acids
Cholesterol ester
Transfer form of Cholesterol
Sources of Cholesterol
Dietary cholesterol
Synthesis of cholesterol
Cholesterol synthesis pathway
HMGCoA reductase facilitates LDL synthesis
LDL
Low Density Lipoprotein
VLDL
Very Low Density Lipoprotein
HDL
High Density Lipoprotein
IDL
Intermediate Density Lipoprotein
What is the pathophysiology of FH?
Lack of LDL receptor expressed by hepatic cells in homozygotes
Reduced amount of LDL receptors
expressed by hepatic cells in heterozygotes
The MoA of Statin?
If there is less LDL in the hepatic cells, cells will upregulate LDL receptors to take up more LDLs
Statin blocks the HMGCoA reductase which will decrease the Cholesterol synthesis –> low LDL levels in the liver –> Liver upregulate LDL receptors –> Takes up more LDL from the bloodstream
HMGCoA reductase
HMG-CoA reductase is an enzyme found in the liver that plays a key role in the synthesis of cholesterol. It is responsible for converting HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) to mevalonic acid, which is a key intermediate in the biosynthesis of cholesterol and other important molecules such as CoQ10.
HMG-CoA reductase is the target of a class of drugs called statins, which are commonly used to lower cholesterol levels in people with high blood cholesterol levels. Statins work by inhibiting the activity of HMG-CoA reductase, which reduces the amount of cholesterol that is produced in the liver.
Adjusting the diet to eliminate the intake of dietary cholesterol can decrease the circulating cholesterol levels, but often has only minor effects. Explain why a no cholesterol diet can have such limited effects.
Cholesterol is an essential component of membranes, needed by all cells. If little or no cholesterol is being consumed, the cells of the liver (and other cells) will increase synthesis so that there is sufficient cholesterol available to all cells
Bile Acids
Bile acids are a group of steroid acids that are synthesized in the liver and secreted into the small intestine to aid in the digestion and absorption of fats. They are derived from cholesterol and are important for the solubilization and absorption of dietary lipids, including cholesterol, fatty acids, and fat-soluble vitamins such as A, D, E, and K.
Bile acids also play a role in the regulation of cholesterol metabolism, as they stimulate the synthesis of bile salts in the liver and inhibit the synthesis of cholesterol. Additionally, they are involved in the absorption and metabolism of drugs and other xenobiotics.
PCSK9 gene
Causes the degradation of the LDL receptors
The PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) gene is a gene that encodes a protein involved in the regulation of cholesterol metabolism. The PCSK9 protein is produced primarily in the liver and plays a key role in the regulation of low-density lipoprotein (LDL) cholesterol levels in the bloodstream.
PCSK9 protein binds to the LDL receptor on the surface of liver cells and promotes its degradation, which results in reduced clearance of LDL cholesterol from the bloodstream. This leads to increased levels of LDL cholesterol in the blood, which is a major risk factor for cardiovascular disease.
The MoA of Statin?
If there is less LDL in the hepatic cells, cells will upregulate LDL receptors to take up more LDLs
Statin blocks the HMGCoA reductase which will decrease the Cholesterol synthesis –> low LDL levels in the liver –> Liver upregulate LDL receptors –> Takes up more LDL from the bloodstream
(remember the distinctions of LDL in the liver and the bloodstream, we want less LDLs in the bloodstream and more LDLs in the liver for the liver to metabolized them)
