胆固醇代谢平衡调控

一.胆固醇合成途径
胆固醇合成负反馈调控: SREBPs-膜结合的转录因子
Wang X, Briggs MR, Hua X, Yokoyama C, Goldstein JL, Brown MS. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. II. Purification and characterization. J Biol Chem. 1993 Jul 5;268(19):14497-504.
谢 谢！
胆固醇的生物学功能
Polar head group
Phospholipid
Saturated Unsaturated
Modified from Molecular Biology of the Cell, 1994
Fatty Acid
caveolae
胆固醇代谢异常与疾病
Cardiovascular disease
Dietary Cholesterol
Biliary Cholesterol
胆固醇代谢平衡调控途径
1. SREBPs转录水平调控 一.胆固醇合成途径 (负反馈调控) 2. 胆固醇合成关键限速酶HMGCR蛋白降解调控
1. 低密度脂蛋白受体（LDLR）介导的胆固醇吸收
二.胆固醇吸收途径 2. NPC1L1介导的肝肠内游离胆固醇的吸收 三.胆固醇外排途径
SREBPs调控的目的基因
胆固醇合成途径限速酶－HMGCR
(HMGCR)
HMGCR
Lanosterol是调节HMGCR的内源分子
Song BL et al, Cell Metab, 2005
HMGCR通过泛素蛋白酶体途径降解
A C
B
Sever N*, Song BL*, Yabe D* et al., JBC, 2003 Song and Debose-boyd, JBC, 2004 No Addition
LDLR突变----黄色瘤
LDLR突变----眼底脂质渗出
FH患者
正常人
LDL来源胆固醇在溶酶体中的运输
Hyock Joo Kwon, et al., Cell, 2009
NPC1的拓扑结构
Joanna P. Davies, JBC, 2000
NPC疾病的细胞学表型
Eugene D. Carstea, et al, Science, 1997
NPC疾病 (Niemann-Pick Disease Type C)临床表型
NPC is one of several inherited diseases of cholesterol metabolism.
Symptom: 1) Enlarged liver and spleen 2) Progressive loss of motor skills, learning problems, feeding difficulties, dementia, and seizures 3) Progressive central nervous system degeneration
胆固醇代谢平衡调控
胆固醇的化学结构式
Nobel laureates:
1928 Windans 阐明胆固醇的结构 1964 Bloch & Lynen 阐明胆固醇从头合成途径
1985 Michael S. Bຫໍສະໝຸດ Baiduown & Joseph L. Goldstein
发现低密度脂蛋白受体，阐明胆固醇代谢的调节机制
Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS. SREBP-1, a basic-helixloop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell. 1993 Oct 8;75(1):187-97. Wang X, Sato R, Brown MS, Hua X, Goldstein JL. SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell. 1994 Apr 8;77(1):53-62.
家族性高胆固醇血症（低密度脂蛋白受体突变） (Familial Hypercholesterolemia, FH)
杂合子患者血清总胆固醇较正常人高出1～2倍
纯合子患者血清总胆固醇较正常人高出6～8倍
杂合子患者发生率为1/500
纯合子患者发生率为1/1,000,000
杂合子患者男性30～40岁时，患CAD， 23% 患者在50岁以前 死于CAD，>50% 患者在60岁时明显的CAD症状； 纯合子患者十几岁时，有严重的心血管事件甚至死亡
+ Sterol
泛素蛋白酶体途径
甾醇调控HMGCR降解的分子机制
Cao, J., Wang, J., et al., Cell Metab, 2007
二.胆固醇吸收途径
细胞内胆固醇的动态运输平衡
Frederick R. Maxfield and Ira Tabas, Nature, 2005
NPC1L1介导的胆固醇在小肠中的吸收过程
NPC1L1的拓扑结构
Wang, J., Chu, B.B., et, al., JLR, 2009
NPC1L1在细胞内循环转运与介导胆固醇吸收的分子机制
Wang and Song, 2012, BBA
Xie et al., 2012, JLR Ge et al., 2011, PNAS Xie et al., 2011, JBC Zhang et al., 2011, JBC Chu et al., 2009, JBC Wang et al., 2009, JLR Ge et al., 2008, Cell Metabolism
Abnormal of cholesterol metabolism
Gall-stone
Obesity
脂肪肝-Fatty liver
胆固醇代谢平衡
Acetyl CoA
600-900 mg
Bile Acids
500-600 mg
300-500 mg
Cholesterol Pool ~100 g
600 mg
The majority (~95%) of the patients have been classified as npc1.
NPC1L1在胆固醇吸收过程中发挥重要作用
A B
C
Xie et al., JLR, 2012
Scott W. Altmann, et al, Science, 2004