Targets for treatment of hypercholesterolemia
View Patent ↗In certain embodiments this invention pertains to the discovery that inhibition of myosin light chain interacting protein (Mylip) can mitigate one or more symptoms of hypercholesterolemia. Methods of treating hypercholesterolemia and methods of screening for agents to treat hypercholesterolemia are provided.
1. A method of screening for an agent that inhibits low density lipoprotein (LDL) receptor degradation, or that promotes LDL uptake, or that inhibits low density lipoprotein (LDL) receptor degradation and promotes LDL uptake in a mammal, said method comprising:
contacting a plurality of test agents, each to a plurality of cells;
detecting the expression or activity of myosin light chain interacting protein (Mylip) in said cells; and
scoring test agents that decrease Mylip expression or activity, as compared to the expression or activity of myosin light chain interacting protein (Mylip) in a control as test agents that inhibit LDL receptor degradation, or that promote LDL uptake, or that inhibit LDL receptor degradation and promote LDL uptake in a mammal.
2. The method of claim 1 , wherein said detecting comprises detecting expression of a reporter gene whose expression is regulated by the Mylip promoter.
3. The method of claim 1 , wherein the expression of Mylip is detected by detecting Mylip mRNA from said cell.
4. The method of claim 3 , wherein said level of Mylip mRNA is measured by hybridizing said mRNA to a probe that specifically hybridizes to a Mylip nucleic acid.
5. The method of claim 1 , wherein said detecting the expression or activity of myosin light chain interacting protein (Mylip) comprises detecting the activity of Mylip on an LDL receptor.
6. The method of claim 1 , wherein said detecting the expression or activity of myosin light chain interacting protein (Mylip) comprises detecting Mylip auto-degradation.
7. The method of claim 1 , wherein said detecting the expression or activity of myosin light chain interacting protein (Mylip) comprises detecting LDL uptake where an increase in LDL uptake is an indicator of Mylip inhibition.
8. A method of screening for an agent that inhibits low density lipoprotein receptor (LDLR) degradation and/or promotes low density lipoprotein (LDL) uptake in a mammal, said method comprising:
contacting an LDLR or a fragment thereof comprising the amino acid residues that interact with an Idol protein or a fragment thereof comprising a FERM domain (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) with a test agent;
detecting interaction or binding of the LDLR with said Idol protein or fragment; and
scoring moieties that reduce or block LDLR/Idol interaction or binding as agents that inhibit LDL receptor degradation and/or promote LDL uptake in a mammal.
9. The method of claim 1 , wherein said test agents are small organic molecules.
10. The method of claim 9 , wherein said test agent is a small organic molecule.