Explain the mechanism by which autosomal recessive disorder ARH contributes to elevated levels of LDL cholesterol in the bloodstre

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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 dis

• 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’ [544].