Biochemistry, LDL Cholesterol


Article Author:
Yasaman Pirahanchi


Article Editor:
Martin Huecker


Editors In Chief:
Linda Lindsay


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
1/16/2019 10:20:03 PM

Introduction

LDL cholesterol, or low-density lipoprotein cholesterol, is a fat that circulates in the blood, moving cholesterol around the body to where it is needed for cell repair and depositing it inside of artery walls. Because cholesterol and triglycerides are insoluble in water, they must be associated with proteins to flow through the hydrophilic blood. [1]

Fundamentals

The LDL particle is made of a monolayer of phospholipid, unesterified cholesterol forms the surface membrane, and fatty acid esters of cholesterol make up the hydrophobic core. One copy of the hydrophobic apo-B protein is embedded in the membrane, mediating the binding of LDL particles to specific cell-surface receptors. [2]

Issues of Concern

LDL receptor function is needed for uptake of LDL from the blood into hepatocytes.

Defects in LDL receptor function can cause hypercholesterolemia, known as familial hypercholesterolemia, an autosomal dominant disorder. Because LDL receptors on the surface of hepatocytes are necessary for the binding and subsequent uptake of LDL molecules in the blood, a genetic decrease in LDL receptor number would cause a decreased ability of hepatocytes to absorb LDL and would increase LDL in the blood. If this mutation is heterozygous, some LDL receptor will be present on the hepatocytes thus LDL is usually around 300 mg/dL. However, a homozygous mutation will result in the complete absence of LDL receptors on hepatocytes, increasing the LDL cholesterol levels up to 1000 mg/dL. [3]

Cellular

The liver produces Very low-density lipoprotein (VLDL), which is metabolized to IDL by lipoprotein lipase (LPL). IDL is then converted to LDL by hepatic triglyceride lipase (HTGL). LDL and a portion of IDL particles are cleared from the circulation via the LDL receptors (LDL-Rc) expressed in the liver and other cells. [4]

The LDL receptor consists of a single chain glycoprotein and is 839 amino acids long. It is comprised of a 320 residue N-terminal exoplasmic domain that contains the LDL-binding site and consists of disulfide-bonded cysteine residues, a C-terminal cytosolic domain which traps the LDL receptor in clathrin-coated pits, and a sequence of 22 hydrophobic amino acids within the plasma membrane in the form of an alpha helix. [5]

Molecular

LDL particles bind to an LDL receptor on the plasma membrane, forming a receptor-ligand complex that is internalized in a clathrin-coated pit that pinches off to become a coated vesicle. After endocytosis, the LDL particle and its receptors are internalized by receptor-mediated endocytosis and degraded in the lysozyme. The clathrin coat depolymerizes, forming an early endosome which fuses with a late endosome where the low pH causes the LDL particles to dissociate from the LDL receptors. In the lysozyme, the apo-B protein of the LDL is degraded to amino acids, and cholesterol esters are hydrolyzed to fatty acids and cholesterol. [2]

Function

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]

Mechanism

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]

Testing

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]

Pathophysiology

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]

Clinical Significance

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] 


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Biochemistry, LDL Cholesterol - Questions

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Which lipid level has a desirable level of < 130 mg/dL?



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A 55-year-old obese male patient is initiated on a therapy that inhibits the conversion of HMG-CoA to mevalonate. What substance would this most significant decrease in the blood?



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An experiment deletes the gene for apo-B100. Levels of what substance would most likely subsequently decrease in the liver?



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A 10-year-old male has a defective gene for the LDL receptor. What disease would this most likely cause?



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Biochemistry, LDL Cholesterol - References

References

Pejic RN, Familial hypercholesterolemia. The Ochsner journal. 2014 Winter     [PubMed]
Feingold KR,Grunfeld C, Introduction to Lipids and Lipoproteins null. 2000     [PubMed]
Kornilova ES, Receptor-mediated endocytosis and cytoskeleton. Biochemistry. Biokhimiia. 2014 Sep     [PubMed]
Miyajima C,Iwaki T,Umemura K,Ploplis VA,Castellino FJ, Characterization of Atherosclerosis Formation in a Murine Model of Type IIa Human Familial Hypercholesterolemia. BioMed research international. 2018     [PubMed]
Berberich AJ,Hegele RA, The complex molecular genetics of familial hypercholesterolaemia. Nature reviews. Cardiology. 2018 Jul 4     [PubMed]
Rahman MS,Woollard K, Atherosclerosis. Advances in experimental medicine and biology. 2017     [PubMed]
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Chandra A,Rohatgi A, The role of advanced lipid testing in the prediction of cardiovascular disease. Current atherosclerosis reports. 2014 Mar     [PubMed]
Feingold KR,Grunfeld C, Utility of Advances Lipoprotein Testing in Clinical Practice null. 2000     [PubMed]
Moin DS,Rohatgi A, Clinical applications of advanced lipoprotein testing in diabetes mellitus. Clinical lipidology. 2011 Aug 1     [PubMed]
Bays HE,Jones PH,Orringer CE,Brown WV,Jacobson TA, National Lipid Association Annual Summary of Clinical Lipidology 2016. Journal of clinical lipidology. 2016 Jan-Feb     [PubMed]
Hevonoja T,Pentikäinen MO,Hyvönen MT,Kovanen PT,Ala-Korpela M, Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL. Biochimica et biophysica acta. 2000 Nov 15     [PubMed]
Packard C,Caslake M,Shepherd J, The role of small, dense low density lipoprotein (LDL): a new look. International journal of cardiology. 2000 Jun 30     [PubMed]
Shimano H, SREBPs: physiology and pathophysiology of the SREBP family. The FEBS journal. 2009 Feb     [PubMed]
Cox RA,García-Palmieri MR, Cholesterol, Triglycerides, and Associated Lipoproteins null. 1990     [PubMed]
The complex molecular genetics of familial hypercholesterolaemia., Berberich AJ,Hegele RA,, Nature reviews. Cardiology, 2018 Jul 4     [PubMed]
Yandrapalli S,Gupta S,Andries G,Cooper HA,Aronow WS, Drug Therapy of Dyslipidemia in the Elderly. Drugs & aging. 2019 Jan 7     [PubMed]
Monami M,Sesti G,Mannucci E, PCSK9 inhibitor therapy: A systematic review and meta-analysis of metabolic and cardiovascular outcomes in patients with diabetes. Diabetes, obesity & metabolism. 2018 Nov 28     [PubMed]

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