ESPEYB15 12 Type 2 Diabetes, Metabolic Syndrome and Lipid Metabolism New Genes (1 abstracts)
12.15 A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption
Zhang Y-Y , Fu Z-Y , Wei J , Qi W , Baituola G , Luo J , Meng Y-J , Guo S-Y , Yin H , Jiang S-Y , Li Y-F , Miao H-H , Liu Y , Wang Y , Li B-L , Ma Y-T & Song B-L
To read the full abstract: Science 2018;360:1087-1092
During the Cardiovascular Risk Survey in western China, a Kazakh family with inherited low levels of LDL-C was identified. The Kazakhs are mainly descendent from the Turkic and medieval Mongol peoples, they live in isolated regions and usually marry within their own ethnic group. They exhibit often unique differences in single nucleotide variants (SNVs) across their genomes. To identify the causal SNV(s), samples from three subjects exhibiting low LDL-C (38-70 md/dl) and one exhibiting normal LDL-C were analyzed by whole-exome sequencing. A frameshift mutation in the LIMA1 gene was identified. Given that LDL-C is influenced by both endogenous cholesterol biosynthesis and intestinal cholesterol absorption, the campesterol to lathosterol ratio was measured. The LIMA1 mutation was associated with a significantly lower Ca:L ratio than in non-carriers, suggesting that LIMA1-mutation carriers have reduced intestinal cholesterol absorption.
In a mice model, LIMA1 was highly expressed in the small intestine, mainly localized on the brush border membrane, and modestly expressed in the liver. Oral administration of radiolabeled cholesterol to intestine-specific Lima1-deficient (I-Lima1−/−) mice showed lower cholesterol uptake than in wild-type (WT) littermates. In diet induced hypercholesterolemia mice, the cholesterol contents in VLDL, LDL and HDL were all markedly lower in I-Lima1−/− than in WT mice.
The absorption of cholesterol in the intestine is mediated by the key transmembrane protein Niemann-Pick C1-like 1 (NPC1L1). In intestine-specific Lima1 deficient (I-Lima1−/−) mice, LIMA1 was specifically depleted from the mouse intestine without affecting the level of NPC1L1. To reveal the mechanism by which LIMA1 mediates dietary cholesterol absorption, the LIMA1-containing complex from WT mouse intestinal epithelial cells was immunoprecipitated and its binding proteins were identified by tandem mass spectrometry. LIMA1 was found to bind NPC1L1 and myosin, suggesting that LIMA1 may bridge myosin to NPC1L1, forming a triplex that facilitates cholesterol absorption. Ezetimibe, a drug that lowers plasma cholesterol levels by decreasing cholesterol absorption in the small intestine, reduces enterocyte uptake and absorption of cholesterol by binding to NPC1L1. Pharmacological targeting through the LIMA1 pathway might provide a new strategy to improve cardiovascular health.
Volume 15
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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