A rare frameshift mutation (K306fs) in LIMA1 (also known as EPLIN or SREBP3), which encodes the LIM domain and actin-binding protein 1 (LIMA1) causes reduced cholesterol absorption in the gut and low levels of serum LDL cholesterol. The mutation was identified in a Chinese family of Kazakh ethnicity. In mice, LIMA1 was found to be expressed mainly in the brush border membrane of the small intestine. LIMA1 binds to NPC1-like intracellular cholesterol transporter 1 (NPC1L1) and facilitates cholesterol uptake. Mice with intestine-specific LIMA1 deficiency had reduced cholesterol absorption and were resistant to diet-induced hypercholesterolaemia, recapitulating the phenotype of the LIMA1-K306fs variant in humans. The researchers suggest that inhibiting LIMA1 might provide a therapeutic approach to lowering LDL-cholesterol levels that is complementary to the use of statins, ezetimibe (which inhibits NPC1L1), or PCSK9 inhibitors.
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Zhang, Y.-Y. et al. A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption. Science 360, 1087–1092 (2018)
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Lim, G.B. LIMA1 variant influences cholesterol absorption. Nat Rev Cardiol 15, 502 (2018). https://doi.org/10.1038/s41569-018-0054-4
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DOI: https://doi.org/10.1038/s41569-018-0054-4