• Explain the mechanism by which autosomal recessive disorder ARH contributes to elevated levels of LDL cholesterol in the bloodstream, and describe the role of elevated LDL in promoting the formation of atherosclerotic lesions that cause coronary heart disease.
ARH is the abbreviation for the autosomal recessive hypercholesterolaemia protein
Autosomal recessive hypercholesterolaemia is a rare disorder affecting ~one individual in five million.
In 2001, Garcia et al discovered a rare autosomal recessive form of hypercholesterolaemia, where there were no mutations in the LDL receptor, ApoB100, or iPCSK9, but where all family members had mutations in a gene encoding a putative adaptor protein, called ARH1. Since then, several mutations have been mapped to the ARH gene on chromosome 1. The age of onset, and clinical features, of ARH tend to phenocopy the less severe (Class 4) internalisation defective mutations which occur in the LDL receptor.
Mutations in ARH1, such as the introduction of a stop codon at 657-659, leads to defective uptake of LDL by the LDL receptor, whereas retroviral expression of ARH1 can rescue LDL receptor internalisation – confirming the functional defect caused by loss of ARH1.
ARH1 is an adaptor protein which connects the LDL receptor to the endocytic machinery; it has homology to Dab1 and Dab2, which are ‘Disabled’ proteins that have phosphotyrosine binding domains that preferentially bind to the NPXY internalisation sequence on the LDL receptor. ARH1 also binds to clathrin, via its clathrin consensus sequence (amino acids 212-216), the C-terminal of ARH1 binds to the beta2 adaptin subunit of AP2 (a clathrin adaptor), and it also binds phosphoinositides which regulate the assembly of clathrin ‘buds’ at the plasma membrane. Since ARH is an autosomal recessive disorder, it is clear that if one ARH1 allele is functional it can compensate for the loss of the other. However, when both copies of ARH1 are mutated, LDL internalisation via the hepatic LDL receptor is much less efficient, leading to the build up of LDL in the bloodstream.
Elevated levels of LDL in the bloodstream are strongly linked with the development of atherosclerosis and coronary heart disease. High levels of LDL can activate the endothelium, triggering the expression of adhesion molecules such as VCAM-1 and ICAM-1, and the output of chemotactic chemokines, such as Monocyte Chemotactic Protein-1. In turn, this leads to the recruitment of white blood cells from the circulation (lymphocytes, monocytes, neutrophils) to the site of inflammation.
The endothelium becomes more ‘leaky’, allowing LDL to accumulate within the intima of the vessel wall, wherein it can become modified (oxidized) to mildly oxidized LDL – a key trigger for further monocyte recruitment – or highly oxidized LDL. The latter is recognized by macrophage ‘scavenger’ receptors, allowing the unregulated uptake of oxidized LDL. The cholesterol derived from oxidized LDL accumulates within the cytosol of the macrophages as ‘foamy’ droplets of cholesteryl ester (esterified via ACAT), the storage form of cholesterol. Macrophage ‘foam’ cells are hallmarks of early fatty streak lesions, found in infants, children and teenagers.
Macrophage ‘foam’ cells contribute to further lesion development by releasing inflammatory cytokines, growth factors and matrix metalloproteases. These last two can facilitate entry of smooth muscle cells to the lesion, and their phenotypic shift from contractile to synthetic. However, matrix metalloproteases can also contribute to destabilisation of lesions, particularly if macrohages accumulate towards the ‘shoulder’ regions of lipid-rich lesions. The lesion can undergo ‘cycles’ of inflammation, leukocyte recruitment and accumulation of lipoprotein cholesterol, eventually leading to necrosis or apoptosis of macrophages, and the deposition of a lipid rich extracellular ‘core’ .
Our Service Charter
Excellent Quality / 100% Plagiarism-FreeWe employ a number of measures to ensure top quality essays. The papers go through a system of quality control prior to delivery. We run plagiarism checks on each paper to ensure that they will be 100% plagiarism-free. So, only clean copies hit customers’ emails. We also never resell the papers completed by our writers. So, once it is checked using a plagiarism checker, the paper will be unique. Speaking of the academic writing standards, we will stick to the assignment brief given by the customer and assign the perfect writer. By saying “the perfect writer” we mean the one having an academic degree in the customer’s study field and positive feedback from other customers.
Free RevisionsWe keep the quality bar of all papers high. But in case you need some extra brilliance to the paper, here’s what to do. First of all, you can choose a top writer. It means that we will assign an expert with a degree in your subject. And secondly, you can rely on our editing services. Our editors will revise your papers, checking whether or not they comply with high standards of academic writing. In addition, editing entails adjusting content if it’s off the topic, adding more sources, refining the language style, and making sure the referencing style is followed.
Confidentiality / 100% No DisclosureWe make sure that clients’ personal data remains confidential and is not exploited for any purposes beyond those related to our services. We only ask you to provide us with the information that is required to produce the paper according to your writing needs. Please note that the payment info is protected as well. Feel free to refer to the support team for more information about our payment methods. The fact that you used our service is kept secret due to the advanced security standards. So, you can be sure that no one will find out that you got a paper from our writing service.
Money Back GuaranteeIf the writer doesn’t address all the questions on your assignment brief or the delivered paper appears to be off the topic, you can ask for a refund. Or, if it is applicable, you can opt in for free revision within 14-30 days, depending on your paper’s length. The revision or refund request should be sent within 14 days after delivery. The customer gets 100% money-back in case they haven't downloaded the paper. All approved refunds will be returned to the customer’s credit card or Bonus Balance in a form of store credit. Take a note that we will send an extra compensation if the customers goes with a store credit.
24/7 Customer SupportWe have a support team working 24/7 ready to give your issue concerning the order their immediate attention. If you have any questions about the ordering process, communication with the writer, payment options, feel free to join live chat. Be sure to get a fast response. They can also give you the exact price quote, taking into account the timing, desired academic level of the paper, and the number of pages.