The acidic pathway of bile acid synthesis: Not just an alternative pathway☆.
The acidic pathway of bile acid synthesis: Not just an alternative pathway☆.
复制标题
DOI：
10.1016/j.livres.2019.05.001
复制
发表时间：
2019-05-21
期刊：
影响因子：
--
通讯作者：
Kakiyama, Genta
中科院分区：
文献类型：
--
作者：
Pandak, William M;Kakiyama, Genta
在过去二十年中，肥胖和代谢综合征（MS）如非酒精性脂肪性肝病（NAFLD）和2型糖尿病（T2 DM）的患病率急剧增加。胆汁酸作为其化学和信号性质的函数，在营养物的消化、吸收和身体对吸收的脂质的再分配中起主要作用。因此，人们对胆汁酸代谢途径重新产生了兴趣，并面临着深入了解这一快速增长的医疗保健问题的新治疗方法的挑战。在肝脏中胆汁酸合成的两个主要途径中，酸性（替代）途径的最重要作用是产生和控制调节氧化固醇的水平，从而帮助控制细胞胆固醇和脂质稳态。胆固醇通过类固醇生成急性调节蛋白（StarD 1）转运至线粒体固醇27-羟化酶（CYP 27 A1），以及随后通过氧固醇7 α-羟化酶（CYP 7 B 1）对氧固醇进行7 α-羟化是该途径的关键调节步骤。最近的观察表明CYP 7 B1是细胞氧固醇水平的最终控制者。本文综述了酸性途径及其对脂质、胆固醇、碳水化合物和能量稳态的作用。此外，还讨论了酸性途径的失调不仅导致其控制细胞胆固醇和脂质稳态的能力丧失，而且导致炎症。
Over the last two decades, the prevalence of obesity, and metabolic syndromes (MS) such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), have dramatically increased. Bile acids play a major role in the digestion, absorption of nutrients, and the body's redistribution of absorbed lipids as a function of their chemistry and signaling properties. As a result, a renewed interest has developed in the bile acid metabolic pathways with the challenge of gaining insight into novel treatment approaches for this rapidly growing healthcare problem. Of the two major pathways of bile acid synthesis in the liver, the foremost role of the acidic (alternative) pathway is to generate and control the levels of regulatory oxysterols that help control cellular cholesterol and lipid homeostasis. Cholesterol transport to mitochondrial sterol 27-hydroxylase (CYP27A1) by steroidogenic acute regulatory protein (StarD1), and the subsequent 7alpha-hydroxylation of oxysterols by oxysterol 7alpha-hydroxylase (CYP7B1) are the key regulatory steps of the pathway. Recent observations suggest CYP7B1 to be the ultimate controller of cellular oxysterol levels. This review discusses the acidic pathway and its contribution to lipid, cholesterol, carbohydrate, and energy homeostasis. Additionally, discussed is how the acidic pathway's dysregulation not only leads to a loss in its ability to control cellular cholesterol and lipid homeostasis, but leads to inflammatory conditions.