Melancholé: The Dark Side of Bile Acids and Its Cellular Consequences.
Melancholé: The Dark Side of Bile Acids and Its Cellular Consequences.
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忧郁：胆汁酸的阴暗面及其细胞后果。
DOI：
10.1016/j.jcmgh.2022.02.003
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发表时间：
2022
影响因子：
7.2
通讯作者：
Anakk, Sayeepriyadarshini
中科院分区：
文献类型：
--
作者：
Zhou, Weinan;Anakk, Sayeepriyadarshini
1848年从牛胆囊中发现了第一个胆汁酸胆酸，奥托·维兰德（Otto Wieland）解决了胆汁酸结构，获得了1927年诺贝尔化学奖。1初级胆汁酸在肝脏中由胆固醇合成，并与牛磺酸或甘氨酸结合用于胆汁分泌。胆汁酸的合成由大约17种酶通过经典或替代途径催化。经典的胆汁酸合成途径是由胆固醇7a-羟化酶（CYP 7A 1）启动，然后是固醇12 a-羟化酶（CYP 8B 1）。另一方面，旁路途径起始于固醇27-羟化酶（CYP 27 A1），然后是氧固醇7 α-羟化酶（CYP 7 B1）。在分泌到肠道中时，微生物群通过7 α-脱羟酶的活性使牛磺酸或甘氨酸缀合的胆汁酸解缀合，从而产生次级胆汁酸。1-3羟基在24-碳类固醇核心上的定位使得胆汁酸亲水或疏水。1-3具有高疏水指数的胆汁酸，如石胆酸、脱氧胆酸和鹅脱氧胆酸，是有毒的并引起肝损伤。相反，亲水性胆汁酸，如熊去氧胆酸，刺激胆汁排泄毒性胆汁酸，并保护免受氧化应激和细胞死亡。1-4胆汁酸除了是脂肪消化和吸收所必需的，还是多方面的信号分子，可以激活以下：（1）钙/钙调蛋白依赖性蛋白激酶（2）环磷酸腺苷/蛋白激酶A（PKA）;（3）蛋白激酶C（PKC）;（4）核受体，如法尼醇X受体（FXR）和维生素D受体;或（5）G蛋白偶联受体，包括Takeda G蛋白偶联受体5、鞘氨醇-1-磷酸受体2和毒蕈碱受体，以调节许多细胞过程。1-8在这篇文章中，我们列举了这些信号通路的致病性激活所引发的有害影响的例子（图1）。许多肝脏疾病导致胆汁淤积，这被定义为胆汁酸在肝脏内的积累。胆汁淤积的病因包括遗传性疾病、激素失衡、免疫介导的胆管破坏、药物诱导或病毒损伤以及胆道梗阻，例如可能由胆结石或肿瘤引起。2，4胆道闭锁会破坏新生儿的胆道系统，9而进行性家族性肝内胆汁淤积是由于胆汁酸转运蛋白（胆汁盐输出泵）、胆汁酸受体FXR、磷脂转运蛋白（多药耐药蛋白3）、紧密连接蛋白2或肌球蛋白5 B的遗传缺陷所致。2相反，原发性胆管炎发生胆管的自身免疫性破坏，而胆管的炎症和纤维化导致原发性胆管炎。
The first bile acid, cholic acid, was discovered in 1848 from ox gallbladder, and the bile acid structure solved by Otto Wieland was recognized with the 1927 Nobel Prize in Chemistry. 1 Primary bile acids are synthesized in the liver from cholesterol and conjugated to taurine or glycine for biliary secretion. Bile acid synthesis is catalyzed by approximately 17 enzymes via the classic or alternative pathways. The classic bile acid synthesis pathway is initiated by cholesterol 7a-hydroxylase (CYP7A1), followed by sterol 12a-hydroxylase (CYP8B1). On the other hand, the alternative pathway initiates with sterol 27-hydroxylase (CYP27A1), followed by oxysterol 7a-hydroxylase (CYP7B1). Upon secretion into the gut, microbiota deconjugate the taurine or glycine conjugated bile acids via the activity of 7a-dehydroxylase, thus generating secondary bile acids. 1–3 The positioning of the hydroxyl groups on the 24-carbon steroid core renders the bile acid either hydrophilic or hydrophobic. 1–3 Bile acids with a high hydrophobic index, such as lithocholic acid, deoxycholic acid, and chenodeoxycholic acid, are toxic and cause liver injury. In contrast, hydrophilic bile acid, such as ursodeoxycholic acid, stimulates biliary excretion of toxic bile acids and is protective against oxidative stress and cell death. 1–4 In addition to being essential for fat digestion and absorption, bile acids also are multifaceted signaling molecules that can activate the following:(1) calcium/calmodulin-dependent protein kinase (Ca2+/CaM-PK);(2) cyclic adenosine monophosphate/protein kinase A (PKA);(3) Protein Kinase C (PKC);(4) nuclear receptors, such as Farnesoid X receptor (FXR) and vitamin D receptor; or (5) G-protein–coupled receptors, including Takeda G-protein–coupled receptor 5, sphingosine-1-phosphate receptor 2, and muscarinic receptors to regulate many cellular processes. 1–8 In this article, we cite examples of the harmful effects triggered by pathogenic activation of these signaling pathways (Figure 1).Many liver diseases result in cholestasis, which is defined as the accumulation of bile acids within the liver. The etiology of cholestasis ranges from genetic disorders, hormonal imbalances, immune-mediated destruction of bile ducts, drug-induced or virus-based injuries, and biliary obstruction, such as can be caused by gallstones or tumors. 2, 4 Biliary atresia destroys the biliary tree in neonates, 9 while progressive familial intrahepatic cholestasis is the result of genetic defects in the bile acid transporter (bile salt export pump), the bile acid receptor FXR, phospholipid transporters (multidrug resistance protein 3), tight junction protein 2, or Myosin 5B. 2 In contrast, autoimmune destruction of bile ducts occurs in primary biliary cholangitis, whereas inflammation and fibrosis in bile ducts result in primary
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影响因子：
17.1
作者：
Lorent K;Gong W;Koo KA;Waisbourd-Zinman O;Karjoo S;Zhao X;Sealy I;Kettleborough RN;Stemple DL;Windsor PA;Whittaker SJ;Porter JR;Wells RG;Pack M
通讯作者：
Pack M
影响因子：
6.7
作者：
de Vries, Elsemieke;Mazzetti, Marta;Beuers, Ulrich
通讯作者：
Beuers, Ulrich
影响因子：
4.7
作者：
Theise, Neil D.;Crawford, James M.;Quaglia, Alberto
通讯作者：
Quaglia, Alberto
影响因子：
4.8
作者：
Zhou, Yong;Maxwell, Kelsey N.;Levental, Ilya
通讯作者：
Levental, Ilya
DOI：
10.1002/hep.29905
发表时间：
2018-09
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Bezerra JA;Wells RG;Mack CL;Karpen SJ;Hoofnagle JH;Doo E;Sokol RJ
通讯作者：
Sokol RJ