Biochemistry, LDL Cholesterol

Apolipoproteins serve a structural role in phospholipid membranes, acting as ligands for lipoprotein receptors, guiding the formation of lipoproteins, and serving as activators or inhibitors of enzymes involved in the metabolism of lipoproteins. Lipoproteins are critical for absorption and transport of dietary lipids by the small intestine and moving lipids from the liver to peripheral tissues and back from peripheral tissues to the liver and intestine. They are also crucial for the transport toxic foreign hydrophobic and amphipathic compounds, including bacterial endotoxin from areas of invasion and infection. [6]

The LDL receptor is on the liver and most other tissues. It recognizes Apo B 100 and Apo E, mediating the uptake of LDL, chylomicron remnants, and IDL, through endocytosis. After internalization, the lipoprotein particle is degraded in lysosomes and cholesterol is released. When cholesterol enters the cell, HMG CoA reductase activity increases, then synthesizes cholesterol and modulates the expression of LDL receptors. LDL receptors on the liver determine plasma LDL levels. When there is a low number or receptors, less LDL can be taken up from the blood by the liver, leading to high plasma LDL levels. Conversely, when there are more LDL receptors, more LDL is taken up from the blood by the liver, leading to low plasma LDL levels.

Levels of cholesterol regulate the number of LDL receptors in the cell. If the cell senses a decrease in cholesterol levels, the transcription factor SREBP is transported from the endoplasmic reticulum to Golgi where proteases cleave and activate SREBP which moves to the nucleus and increases expression of LDL receptors. When cholesterol levels are low in the cell, high SREBP remains in the endoplasmic reticulum in an inactive form, and expression of LDL receptors is decreased. [7]

In testing for hypercholesterolemia, a fasting lipid panel should be ordered, along with labs to rule out secondary causes.[8] In the fasting lipid panel, a total cholesterol of greater than 200 mg/dL and LDL cholesterol greater than 130 mg/dL is considered abnormal.[9] Secondary causes of hyperlipidemia should be ruled out through testing of fasting blood glucose, hemoglobin A1c, thyroid stimulating hormone, alkaline phosphatase, and urinalysis to assess for proteinuria.[10]

Hypercholesterolemia occurs due to excess cholesterol from diet, bile, or intestines. The liver releases triglycerides into the plasma in the form of VLDLS.[11] The intestines release triglycerides into the plasma in the form of chylomicrons. Once in the plasma, the VLDL is converted into LDL. LDL in the plasma then interacts with the LDL receptor on cells in various tissues.[12]

Increased LDL is associated with an increased risk of cardiovascular disease.[13] It is commonly associated with diabetes, hypertension, hypertriglyceridemia, and atherosclerosis.[14] Through typically asymptomatic, hypercholesterolemia could present with metabolic syndrome, in which the patient would present with hypertension. In more severe hypercholesterolemia, patients may present with xanthomas with yellow nodules or plaques on the Achilles tendon; for example, xanthelasma on the eyelids or corneal arcus with white rings lining the cornea.[15]

For this reason, LDL is clinically significant as it is crucial to monitor levels of LDL in patients with hypertension and diabetes. Lifestyle modifications are crucial in overweight patients in order to lose weight, through both exercise and diet control. Diets with lower saturated fats and aerobic exercise can help reduce LDL for patients. Pharmacologic modalities can also be utilized to decrease LDL levels, primarily HMG-Coa Reductase inhibitors, such as pravastatin and lovastatin, help significantly decrease serum LDL levels by inhibiting the conversion of HMG Coa to Mevalonate, which is a precursor to cholesterol. [16] PCSK 9 inhibitors, such as Evolocumab and Alirocumab, also significantly decrease serum LDL levels by inactivation the degradation of LDL receptors on target tissues. With this, more LDL receptors remain on target tissue as they are not degraded, increasing removal of LDL from the bloodstream. [17]