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载脂蛋白A1

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Apolipoprotein A-I
载脂蛋白A1
PDB rendering based on 1av1.
有效结构
PDB 直系同源检索:PDBe, RCSB
标识
代号 APOA1; MGC117399
扩展标识 遗传学107680 鼠基因88049 同源基因47900 ChEMBL: 5984 GeneCards: APOA1 Gene
RNA表达模式
更多表达数据
直系同源体
物种 人类 小鼠
Entrez 335 11806
Ensembl ENSG00000118137 ENSMUSG00000032083
UniProt P02647 Q00623
mRNA序列 NM_000039 NM_009692
蛋白序列 NP_000030 NP_033822
基因位置 Chr 11:
116.71 – 116.71 Mb
Chr 9:
46.23 – 46.23 Mb
PubMed查询 [1] [2]

載脂蛋白A1(英語:Apolipoprotein A1,簡稱ApoA1)為附著於高密度脂蛋白(HDL)及乳靡小球上的載脂蛋白,基因編碼為「APOA1[1][2]。載脂蛋白A1可以活化卵磷脂-胆固醇酰基转移酶英语Lecithin—cholesterol acyltransferase(Lecithin Cholesterol Acyltransferase,LCAT);當高密度脂蛋白運送組織中多餘的膽固醇回到肝臟細胞中時,載脂蛋白A1同時也可作為高密度脂蛋白的配體,在脂質代謝英语lipid metabolism中扮演重要角色。研究指出,APOA1的mRNA是由反義RNA轉譯出的內源性蛋白質所調控[3]

結構

APOA1基因位於第11對染色體上(11q23-q24),該基因包含4個外顯子[4]。载脂蛋白A1的質量為45.4 kDa ,含有 396 個胺基酸;質譜分析可觀察到蛋白質由21個胜肽片段組成[5][6]

功能

載脂蛋白A1(ApoA1)為構成血漿中高密度脂蛋白(HDL)蛋白質部分的主要成分。小腸腸道細胞所分泌的乳糜微粒中雖然也含有載脂蛋白A1,但在血流中很快就會被轉為HDL[7]。ApoA1可促進將周邊組織脂質及膽固醇回收至肝臟,並藉由膽管分泌至小腸。另外該蛋白也是卵磷脂-胆固醇酰基转移酶英语Lecithin—cholesterol acyltransferase(LCAT)的輔因子,製造了血漿中大多數的膽固醇脂英语cholesteryl esters。ApoA1同時也是前列环素(PGI2)的穩定因子,因此也具有抗凝血的作用[8]。如果編碼該蛋白的基因有缺陷,會導致個體體內缺乏HDL,導致包含Tangier disease英语Tangier disease在內的症狀,以及非神經性全身類澱粉變性[4]

由於ApoA1在體內脂質代謝的角色相當重要,因此常被視為預測個體冠心病風險的生物標記。有研究發現「apoB-100/apoA1」的比值預測心肌梗塞的效果比任何其他脂質標記更有效果[9]。ApoA1可利用ELISAnephelometry英语nephelometry檢驗。

臨床意義

已隱藏部分未翻譯内容,歡迎參與翻譯

Activity associated with high HDL-C and protection from heart disease

As a major component of the high-density lipoprotein complex (protective "fat removal" particles), apo A1 helps to clear fats, including cholesterol, from white blood cells within artery walls, making the WBCs less likely to become fat overloaded, transform into foam cells, die and contribute to progressive atheroma英语atheroma. Five of nine men found to carry a mutation (E164X) who were at least 35 years of age had developed premature coronary artery disease.[10]One of four mutants of apo A1 is present in roughly 0.3% of the Japanese population, but is found in 6% of those with low HDL cholesterol levels.

ApoA-1 Milano英语ApoA-1 Milano is a naturally occurring mutant of apo A1, found in a few families in Limone sul Garda, Italy, and, by genetic + church record family tree detective work, traced to a single individual in the 14th century. Described in 1980, it was the first known molecular abnormality of apolipoproteins.[11]Paradoxically, carriers of this mutation have very low HDL-C (HDL-Cholesterol) levels, but no increase in the risk of heart disease, often living to age 100 or older. This unusual observation was what lead Italian investigators to track down what was going on and lead to the discovery of apo A1 Milano (the city, Milano, ~160 km away, in which the researcher's lab was located). Biochemically, apo A1 contains an extra cysteine bridge, causing it to exist as a homodimer or as a heterodimer with apo A-II. However, the enhanced cardioprotective activity of this mutant (which likely depends on fat & cholesterol efflux) cannot easily be replicated by other cysteine mutants.[12]

Recombinant apo A1 Milano dimers formulated into liposomes can reduce atheroma英语atheromas in animal models by up to 30%.[13]Apo A1 Milano has also been shown in small clinical trials to have a statistically significant effect in reducing (reversing) plaque build-up on arterial walls.[14][15]

In human trials the reversal of plaque build-up was measured over the course of five weeks.[14][16]

Novel Haplotypes within apolipoprotein AI-CIII-AIV gene cluster

Lately, two novel susceptibility haplotypes i.e. P2-S2-X1 and P1-S2-X1 have been discovered in ApoAI-CIII-AIV gene cluster on chromosome 11q23, which confer approximately threefold higher risk of coronary heart disease in normal[17]as well as in the patients having non-insulin diabetes mellitus.[18]

Role in other diseases

A G/A polymorphism in the promoter of the apo A1 gene has been associated with the age at which patients presented with Alzheimer disease.[19]Protection from Alzheimer's disease by apo A1 may rely on a synergistic interaction with alpha-tocopherol英语alpha-tocopherol.[20] Amyloid deposited in the knee following surgery consists largely of apo A1 secreted from chondrocytes (cartilage cells).[21]A wide variety of amyloidosis symptoms are associated with rare Apo A1 mutants.

Apo A-I binds to lipopolysaccharide or endotoxin, and has a major role in the anti-endotoxin function of HDL.[22]

In one study, a decrease in apo A1 levels was detected in schizophrenia patients' CSF, brain and peripheral tissues.[23]

Epistatic impact of apo A1

Apolipoprotein A1 and APOE interact epistatically to modulate triglyceride levels in coronary heart disease patients. Individually, neither apo A1 nor apo E was found to be associated with triglyceride (TG) levels, but pairwise epistasis (additive x additive model) explored their significant synergistic contributions with raised TG levels (P<0.01). [24]

Factors affecting apo A1 activity

Apo A1 production is decreased by calcitriol, and increased by a drug that antagonizes it.[25]

Exercise or statin treatment may cause an increase in HDL-C levels by inducing apo A1 production, but this depends on the G/A promoter polymorphism.[26]

交互作用

載脂蛋白A1可與下列蛋白產生交互作用

Potential binding partners

Apolipoprotein A1 binding precursor, a relative of APOA-1 abbreviated APOA1BP英语APOA1BP, has a predicted biochemical interaction with Carbohydrate Kinase Domain Containing Protein英语CARKD. The relationship between these two proteins is substantiated by cooccurance across genomes and coexpression.[30]The ortholog of CARKD in E. coli contains a domain not present in any eukaryotic ortholog. This domain has a high sequence identity to APOA1BP. CARKD is a protein of unknown function, and the biochemical basis for this interaction is unknown.

交互作用途徑

点击基因、蛋白质和代谢产物的链接访问对应的介绍条目。 [§ 1]

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他汀类药物途径 编辑
  1. ^ 这个相互作用途径可以在WikiPathways上编辑: Statin_Pathway_WP430. 

參見

參考文獻

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外部連結