Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Aufm Hennekamp 65, 40225 Duesseldorf, Germany.
Atherosclerosis. 2011 Sep;218(1):134-43. doi: 10.1016/j.atherosclerosis.2011.05.008. Epub 2011 May 18.
Alterations of lipid metabolism play a pivotal role in the development of atherosclerosis and its complications, today's major mortality risks. The predominant regulators controlling cholesterol- and fatty acids synthesis in liver are the sterol regulatory element-binding proteins (SREBPs), a family of transcription factors that were formerly identified as cholesterol sensor for LDLR gene expression. Variation of gene structure in these genes might therefore indicate a predisposition to develop complications like myocardial infarction and stroke.
We investigated 190 unrelated German subjects, including 69 subjects with LDL-cholesterol <55mg/dl, for mutations in SREBP genes SREBF-1 and SREBF-2 by direct sequencing. The impact on SREBP functionality was analyzed by protein biochemical analyses, promoter reporter gene assays and gene expression studies.
A missense mutation in SREBF-1 (c.332 C>T; P111L) was identified in a subject with LDL-cholesterol <5mg/dl. Examination of the subject's family confirmed the mutation in two of three siblings. Detailed clinical evaluation of these subjects disclose a novel form of primary combined hypolipidemia only in SREBP-1a P111L carriers, characterized by low levels of apoB and apoA1, low triglyceride, LDL-cholesterol and HDL-cholesterol levels. Functional analyses indicated that the mutation abolishes phosphorylation of SREBP-1. As a consequence transcriptional activation of classical target genes, i.e. LDLR, HMG-CoAR, FAS, ABCA1, but also MTTP, was dramatically reduced.
Phosphorylation of SREBP-1, the master regulator of genes for central rate limiting enzymes of cholesterol and lipid metabolism, appears to be a biological principle with clinical implications.
脂质代谢的改变在动脉粥样硬化及其并发症的发展中起着关键作用，这些并发症是当今主要的死亡风险。控制肝脏中胆固醇和脂肪酸合成的主要调节因子是固醇调节元件结合蛋白（SREBPs），这是一组转录因子，以前被确定为 LDLR 基因表达的胆固醇传感器。这些基因结构的变异可能表明存在发生心肌梗死和中风等并发症的倾向。
我们通过直接测序研究了 190 名无关的德国受试者，包括 69 名 LDL-胆固醇<55mg/dl 的受试者，以检测 SREBP 基因 SREBF-1 和 SREBF-2 的突变。通过蛋白生化分析、启动子报告基因测定和基因表达研究分析了突变对 SREBP 功能的影响。
在 LDL-胆固醇<5mg/dl 的受试者中发现了 SREBF-1 中的错义突变（c.332 C>T；P111L）。对该受试者的家族进行检查证实，该突变在三个兄弟姐妹中的两个中存在。对这些受试者的详细临床评估显示，仅在 SREBP-1a P111L 携带者中存在一种新型原发性混合性低脂蛋白血症，其特征为载脂蛋白 B 和载脂蛋白 A1 水平低、甘油三酯、LDL-胆固醇和 HDL-胆固醇水平低。功能分析表明，该突变会使 SREBP-1 的磷酸化作用丧失。因此，经典靶基因 LDLR、HMG-CoAR、FAS、ABCA1 的转录激活显著降低，但 MTTP 也如此。
SREBP-1 的磷酸化作用，即胆固醇和脂质代谢中心限速酶基因的主要调节因子，似乎是具有临床意义的生物学原则。
