主页: http://mypage.zju.edu.cn/luoyan2012 骆严 Yan LUO 主页: http://mypage.zju.edu.cn/luoyan2012 电邮：luoyan2011@zju.edu.cn 手机: 18757136369 浙江大学基础医学院 浙江大学肿瘤研究所

肝胆胰系统的 生物化学 Biochemical Aspects of the Hepatobiliary and Pancreatic Systems

The digestive system contains alimentary tract: mouth, pharynx, esophagus, stomach, small intestines, large intestines, rectum, anus accessory organs Salivary glands, liver, gall bladder, pancreas

Liver 肝 is the 2nd largest organ in the body. The liver is divided into two major lobes and two smaller lobes on the surface. Functions: Secretion Synthesis of bile Synthesis of plasma protein storage Detoxification Excretion Carbohydrate metabolism Protein metabolism filtering

双重供血系统 双重输出通道 例：血清清蛋白（serum albumin） 由肝脏合成后经过肝静脉进入血液循环； 占总血清蛋白的~50% 70-75%来自门静脉（ hepatic portal vein ） 25-30%来自肝动脉（ hepatic artery ） 双重输出通道 例：血清清蛋白（serum albumin） 由肝脏合成后经过肝静脉进入血液循环； 占总血清蛋白的~50% 例：胆汁酸由肝脏合成在胆囊储存浓缩； 经过胆道进入肠道促成消化 肝静脉 ( hepatic vein ） 胆道 (bile tract)

Gall bladder 胆囊 Major functions: Bile storage Bile concentration, modification

正常人每天平均分泌胆汁300~700ml 胆汁（bile） 肝 胆 汁 从肝脏初分泌的胆汁，透明澄清，固体物含量 较少。呈桔黄色或金黄色。 从肝脏初分泌的胆汁，透明澄清，固体物含量 较少。呈桔黄色或金黄色。 肝 胆 汁 Hepatic bile 胆汁（bile） 肝胆汁进入胆囊后，胆囊壁吸收肝胆汁中的水、盐及其它一些成分，并分泌粘液渗入胆汁，使胆汁浓缩，成为胆囊胆汁，呈暗褐色或棕绿色。 胆囊胆汁 Gallbladder bile 正常人每天平均分泌胆汁300~700ml

胆汁酸的生理作用 * 胆汁酸具有亲水和疏水的两个侧面，是一种很强的乳化剂。 功能： 促进脂类的消化与吸收； 增加胆固醇在胆汁中的溶解度，防止胆固醇析出形成结石； 相关基因/功能缺陷产生胆结石家族史。 9

脂类的消化和吸收 10

胆汁酸来自胆固醇的转化 初级胆汁酸：在肝脏由胆固醇直接转变生成的胆汁酸。包括游离型和结合型。胆汁酸合成的限速酶是7--羟化酶。 次级胆汁酸：初级胆汁酸经胆道系统排入肠道，在肠道细菌作用下的产物。 胆汁酸可以经过肠肝循环重新利用

Composition of Bile water (~85%) bile salts (~10%) 胆汁的组成 Composition of Bile  water (~85%)  bile salts (~10%) mucus and pigments (~3%) fats (~1%) inorganic salts (~0.7%) cholesterol (~0.3%)

两种胆汁的百分组成 肝胆汁 胆囊胆汁 比重 1.009～1.013 1.026～1.032 pH 7.1～8.5 5.5～7.7 水 96～97 80～86 固体成分 3～4 14～20 无机盐 0.2～0.9 0.5～1.1 粘蛋白 0.1～0.9 1～4 胆汁酸盐 0.5～2 1.5～10 胆色素 0.05～0.17 0.2～1.5 总脂类 0.1～0.5 1.8～4.7 胆固醇 磷脂 0.05～0.08 0.2～0.5

Bile acids Bile acids are the end products of cholesterol metabolism Bile acids are steroid acids found predominantly in the bile of mammals Bile salts: are bile acids compounded with a cation, usually sodium

Types of bile acids free bile acids (游离胆汁酸) conjugated bile acids (结合胆汁酸) cholic acid 胆酸 deoxycholic acid 脱氧胆酸 chenodeoxycholic acid 鹅脱氧胆酸 lithocholic acid 石胆酸 Conjugated bile acids are more efficient at emulsifying fats because, at intestinal pH, they are more ionized than unconjugated bile acids.

Free bile acids deoxycholic acid (脱氧胆酸) cholic acid (胆酸) chenodeoxycholic acid (鹅脱氧胆酸) lithocholic acid (石胆酸)

Conjugated bile acid CONHCH2CH2SO3H taurocholic acid(牛磺胆酸) CONHCH2COOH glycocholic acid (甘氨胆酸) CONHCH2COOH

primary bile acids（初级胆汁酸）: are synthesized in the liver and conjugated with taurine or glycine before secretion via bile into the intestine. cholic acid 胆酸 chenodeoxycholic acid 鹅脱氧胆酸 secondary bile acids（次级胆汁酸） : are derived from the primary bile acids by the enzymatic action of intestinal bacteria through the process of deconjugation and dehydroxylation. deoxycholic acid 脱氧胆酸 lithocholic acid 石胆酸

primary bile acid secondary bile acid cholic acid chenodeoxycholic acid deoxycholic acid lithocholic acid secondary bile acid 7alpha-dehydroxylation

Function of bile acids eliminating cholesterol from the body driving the flow of bile to eliminate catabolites from the liver emulsifying lipids and aids the process of  digestion of  lipids in the small intestine facilitate the intestinal absorption of fat-soluble vitamins.

Hydrophobic side Hydrophilic side glycocholic acid

胆汁酸的生成 （一）初级胆汁酸的生成 部位：肝细胞胞液和微粒体 原料：胆固醇 限速酶：胆固醇7α-羟化酶

（甘氨胆酸、牛磺胆酸、甘氨鹅脱氧胆酸、牛磺鹅脱氧胆酸） 胆固醇 7α—羟胆固醇 初级游离胆汁酸（胆酸、鹅脱氧胆酸） 初级结合型胆汁酸 （甘氨胆酸、牛磺胆酸、甘氨鹅脱氧胆酸、牛磺鹅脱氧胆酸） 7α—羟化酶 加氢，羟化，侧链氧化，断链 牛磺酸 甘氨酸结合

胆汁酸代谢的调节 ① 受胆汁酸反馈调节 7α-羟化酶是限速酶 ② 受胆固醇的调节 胆固醇合成与胆汁酸合成具有协同关系 胆固醇合成限速酶 HMG CoA还原酶被胆汁酸抑制； 高胆固醇膳食抑制此酶而激活7α-羟化酶 ① 受胆汁酸反馈调节 7α-羟化酶是限速酶 ② 受胆固醇的调节 胆固醇合成与胆汁酸合成具有协同关系 ③ 受糖皮质激素和生长激素调节 促进7-α羟化酶活性

（二） 次级胆汁酸的生成 部位：小肠下段和大肠 过程： 初级胆汁酸 次级胆汁酸 肠菌 水解、脱羟

（三）胆汁酸的肠肝循环 胆汁酸随胆汁排入肠腔后，约95%胆汁酸可经门静脉重吸收入肝，在肝内转变为结合胆汁酸,并与肝新合成的胆汁酸一道再次排入肠道，此循环过程称胆汁酸的肠肝循环 (enterohepatic circulation of bile acid) 。 意义： 将有限的胆汁酸反复利用以满足人体对 胆汁酸的生理需要。

* 胆汁酸的肠肝循环 胆汁酸排入肠道后，大部分结合胆汁酸在回肠部主动重吸收，其余在各部被动吸收。肠道吸收的胆汁酸经门静脉入肝，肝细胞将重吸收的游离型胆汁酸重新转变为结合型胆汁酸，并与新合成的初级胆汁酸一起再排入肠道，这一过程称为胆汁酸的肠肝循环。

机体内胆汁酸储备的总量称为胆汁酸库(bile acid pool)。 胆汁酸肠肝循环的过程

Liver 肝 is the 2nd largest organ in the body. The liver is divided into two major lobes and two smaller lobes on the surface. Functions: Secretion Synthesis of bile Synthesis of plasma protein storage Detoxification Excretion Carbohydrate metabolism Protein metabolism filtering

Remember Miller Experiment?

TCA

Pancreas 胰脏 Makes pancreatic juices and hormones

Function The pancreas is both an exocrine and endocrine gland. The exocrine portion of the gland produces a secretion that contains enzymes that are capable of hydrolyzing proteins, fats, and carbohydrates The endocrine portion of the gland, the pancreatic islet, produces the hormones insulin and glucagon that play a key role in carbohydrate metabolism

Pancreatic juice Pancreatic juice is clear, colorless and watery solution; pH is slightly basic 8.0-8.3 Contains 1.5% solids 2/3 of solids : inorganic matter 1/3 of solids : organic matter

inorganic matter HCO3: content is very high ( 5 times more than the plasma). Cl Na K small amounts of Phosphate, Ca, Mg

Organic matter: enzymes/proenzymes Enzymes are produced, stored and released as their inactive precursors so that they don’t digest and destroy the pancreas itself. Main pancreatic enzyme : protease trypsin chymotrypsin elastase Carboxypeptidase pancreatic lipase Amylase

Trypsin (胰蛋白酶) Inactive : trypsinogen. Activated by enteropeptidase ( 肠激酶）. Properties : Alkaline pH 8.0-9.0 Endopeptidase Activates other pancreatic proenzyme is active against the peptide bonds in protein molecules that have carboxyl groups donated by Arg and Lys Trypsin inhibitor is present in the pancreatic juice as well as in the plasma

Chymotrypsin (胰凝乳蛋白酶) secreted in the inactive form. Activated by trypsin. Endopeptidase pH 8-9 is active against the peptide bonds in protein molecules that have carboxyl groups donated by Tyr,Phe,Trp,Met and Leu

Pancreatic lipase It is water soluble and can act only on the surface of fat globules after their emulsification. Acts only in the presence of bile salts which seems to activate it. Activity is increased by certain proteins and amino acids. Optimum pH is 8.2- 9.2.

 Zymogen Activation by Proteolytic Cleavage

Regulation of pancreatic juice secretion secrtin (促胰液素） cholecystokinin (CCK, 胆囊收缩素)

End of the lecture