A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption

• Published in: Science (American Association for the Advancement of Science) Vol. 360; no. 6393; pp. 1087 - 1092
• Main Authors: Zhang, Ying-Yu, Fu, Zhen-Yan, Wei, Jian, Qi, Wei, Baituola, Gulinaer, Luo, Jie, Meng, Ya-Jie, Guo, Shu-Yuan, Yin, Huiyong, Jiang, Shi-You, Li, Yun-Feng, Miao, Hong-Hua, Liu, Yong, Wang, Yan, Li, Bo-Liang, Ma, Yi-Tong, Song, Bao-Liang
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 08.06.2018
• Subjects: Absorption; Animals; Asian Continental Ancestry Group - genetics; Bile; Cardiovascular disease; Cardiovascular diseases; China; Cholesterol; Cholesterol, LDL - blood; Cholesterol, LDL - metabolism; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Frameshift Mutation; Genetic factors; Genetic Variation; Hep G2 Cells; Humans; Hypercholesterolemia; Intestinal Absorption - genetics; Intestinal Mucosa - metabolism; Kazakhstan - ethnology; Lipid metabolism; Low density lipoprotein; Membrane Proteins - metabolism; Metabolism; Mice; Mice, Knockout; Minority & ethnic groups; Myocardial infarction; Myosin; Myosin Heavy Chains - metabolism; Myosin Type V - metabolism; Pedigree; Pharmacology; Phenotypes; Protein Binding; Protein Transport; Proteins; Risk factors; Rodents; Small intestine
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aao6575

Cholesterol is important for general health, but too much can build up in artery walls and cause cardiovascular disease. Low-density lipoprotein cholesterol (LDL-C) is often referred to as “bad cholesterol”; keeping LDL-C within stringent limits is recommended to reduce the risk of heart attack and stroke. Zhang et al. discovered that some individuals have an inherited frameshift mutation in the LIMA1 gene (also known as EPLIN or SREBP3 ). The gene has not been linked to lipid metabolism before, but altered LIMA1 was found to maintain low plasma LDL-C by reducing the absorption of cholesterol through the intestine. Pharmacological targeting through the LIMA1 pathway might thus provide a strategy to improve heart health. Science , this issue p. 1087 Human familial genetics reveals a new player in cholesterol physiology. A high concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease. Although LDL-C levels vary among humans and are heritable, the genetic factors affecting LDL-C are not fully characterized. We identified a rare frameshift variant in the LIMA1 (also known as EPLIN or SREBP3 ) gene from a Chinese family of Kazakh ethnicity with inherited low LDL-C and reduced cholesterol absorption. In a mouse model, LIMA1 was mainly expressed in the small intestine and localized on the brush border membrane. LIMA1 bridged NPC1L1, an essential protein for cholesterol absorption, to a transportation complex containing myosin Vb and facilitated cholesterol uptake. Similar to the human phenotype, Lima1 -deficient mice displayed reduced cholesterol absorption and were resistant to diet-induced hypercholesterolemia. Through our study of both mice and humans, we identify LIMA1 as a key protein regulating intestinal cholesterol absorption.