生理學教學課件：肝膽生理

1、肝膽生理（一）性質濃稠、味苦、有色液體。8001000ml/day肝膽汁金黃色、枯棕色，弱堿性，pH 7.4膽囊膽汁黃綠色、弱酸性，pH 6.8持續(xù)分泌、間歇排放，不含消化酶。二、膽汁 (bile)（二）成分和作用1. 膽鹽 (bile salt)促脂肪消化：乳化脂肪、增加酶作用面積;促脂肪吸收：與脂肪形成水溶性復合物;促脂溶性維生素（A、D、E、K）吸收;促膽汁的自身分泌：腸 - 肝循環(huán)。The Secretion of Canalicular Bile Is Active and Isotonic膽鹽進入小腸后，約95%被回腸末端黏膜吸收，通過門V又回到肝臟，再成為合成膽汁的原料，然后膽汁

2、又分泌入腸，這一過程稱為膽鹽的腸肝循環(huán)。返回肝臟的膽鹽有刺激肝膽汁分泌的作用。2. 膽固醇： 體內脂肪的代謝產(chǎn)物，也具有乳化功能.膽鹽、膽固醇和卵磷脂的適當比例是維持膽固醇成溶解狀態(tài)的必要條件。若膽固醇膽石癥。3. 膽色素 是血紅蛋白的降解產(chǎn)物.膽紅素是臨床上判定黃疸的重要依據(jù)，也是肝功能的重要指標。 2.體液調節(jié) 縮膽囊素 促胰液素 促胃液素 膽鹽食物(蛋白分解產(chǎn)物脂肪酸糖) 條件與非條件反射（純神經(jīng)機制迷走-促胃液素機制）肝臟膽汁分泌和排放。1.神經(jīng)調節(jié)（三）膽汁分泌和排放的調節(jié)IntroductionThe liver is the largest gland in the body,

3、weighs 1400 to 1600 gm, representing 2.5% of body weight.It performs an astonishingly large number of tasks that impact all body systems:catabolizing dietary amino acids , carbohydrates, lipids, and vitamins; synthesizing and secreting serum proteins; detoxifying the endogenous waste products and xe

4、nobiotics and excrete into bile.secreting bileThe liver is vulnerable to a wide variety of metabolic, toxic, microbial, and circulatory insultsIt has tremendous regeneration capacity Blood SupplyIncoming blood-25% of cardiac outputarrives via the Portal vein it is 60% to 70% of hepatic blood flow30%

5、 to 40% from hepatic artery through the hilum, the gateway of the liver (porta hepatis).Outgoing Blood- collected into ramifications of the hepatic vein, which exits by the back door of the liver into the closely apposed inferior vena cava.Circulation of liverHeptic artery carries oxygen-rich blood

6、from the aorta .The portal vein carries blood containing digested food from the small intestine. These blood vessels subdivide in the liver repeatedly, terminating in very small capillaries. Each capillary leads to a lobule. Zonal Flow of BloodLiver- FunctionsVascular functions, including formation

7、of lymph and the hepatic phagocytic system.Metabolic achievements in control of synthesis and utilization of carbohydrates, lipids and proteins.Secretory and excretory functions, particularly with respect to the synthesis of secretion of bile.Metabolic Functions of LiverThe liver is the central orga

8、n of glucose homeostasis,maintaining blood glucose levels by glycogenolysis and gluconeogenesis.Synthetic functionsMost serum proteins, including Albumin Blood coagulation factorsComplement, Acute phase reactants binding proteins for iron, copper, and vitamin APlasma Proteins synthesizedStorage Func

9、tionsThe liver is an important storage site for Glycogen, Triglycerides, Iron, copper, Lipid-soluble vitamins.Excretory Functions:The principal excretory product of the liver is bile, an aqueous mixture of conjugated bilirubin, bile acids, phospholipids, cholesterol electrolytes. Bile not only provi

10、des a repository for the products of heme catabolism but is also vital for fat absorption in the small intestine.Micro architectureClassically, the liver has been divided into 1- to 2-mm diameter hexagonal lobulesLobule oriented around terminal hepatic veins tributariesPortal tracts are at periphery

11、 of lobuleHepatocytes present at Centrilobular around central vein (HepaticPeriportal near the portal tractHepatic Parenchyma-1The hepatic parenchyma is organized into cribiform (pierced with holes as in a sieve ), anastomosing sheets or plates of hepatocytesHepatocytes immediately abutting the port

12、al tract are referred to as the limiting plate, forming a rim around the mesenchyme of the portal tract.There is a radial orientation of the hepatocyte cords around the terminal hepatic vein. Hepatocytes exhibit variation in size, Nuclei may vary in size, number, and ploidy, particularly with advanc

13、ing age. Uninucleate,Hepatic Parenchyma-2Between the cords of hepatocytes are vascular sinusoids. Blood traverses the sinusoids and exits into the terminal hepatic vein through orifices of vein wall. Hepatocytes are bathed on 2 sides by well-mixed portal venous and hepatic arterial blood.The sinusoi

14、ds are lined by fenestrated and discontinuous endothelial cells, which demarcate an extrasinusoidal space of Disse, into which protrude abundant microvilli of hepatocytes. Scattered Kupffer cells of theThere are scattered fat-containing perisinusoidal stellate cells in the space of Disse. They stell

15、ate cells play a role in metabolism of vitamin A and are transformed into collagen-producing myofibroblasts in inflammation Liver Cell platesSchematic liverSinusoid DiagramaticFUNCTIONAL ANATOMY OF THE LIVER AND BILIARY TREEHepatic Lobule, Portal Lobule & Portal AcinusPeriportal Hepatocytes Speciali

16、ze In Oxidative Metabolism; Pericentral Hepatocytes Detoxify DrugsPeriportal hepatocytes (zone I) are the most resistant to the effects of circulatory compromise, nutritional deficiency and other forms of cell injury and are the first to regenerate. Hepatocytes in the intermediate zone II and perice

17、ntral hepatocytes located near the terminal hepatic venule (zone III ) are exposed to progressively lower concentrations of nutrients and oxygen.Anatomy of Bile DuctsSinusoidal Uptake, Intracellular Transport, Chemical Modification and Canalicular SecretionHouse Keeping TransportersNa-K Pump at the

18、Basolateral Membrane Provides the Energy for Transporting a WideVariety of Solutes via Channels and TransportersSecretion of Bile Acids and SaltsThe primary bile acids are cholic or chenodeoxycholic acid, both synthesized by hepatocytes. Secondary bile acids form in intestinal tract via bacterial de

19、hydroxylation. Primary bile acids are near neutral, not very water soluble. Bile acids once deprotonated, are bile salts (BA-), which are far more water soluble.The liver conjugates primary bile acids and salts to glycine or taurine (BA-Z), as well as to sulfate or glucuronate (BA-Y). Most of the bi

20、le acids in bile are conjugated. Components of bile flowSecretion of an HCO3-rich fluid by cholangiocytes. The apical step of secretion by the duct cell is mediated by a Cl-HCO3 exchanger. The Cl- recycles back to the lumen through Cl- channels, such as CFTR. The basolateral step of secretion probab

21、ly is mediated in part by the uptake of through an electrogenic Na/HCO3 cotransporter. The uptake of CO2, combined with the extrusion of H+ through an Na-H exchanger and an H+ pump, generates the rest of the through carbonic anhydrase (CA). Secretin, glucagon, VIP, and gastrin-releasing peptide (GRP

22、) all are choleretics. Somatostatin either enhances fluid absorption or inhibits secretion.Isotonic fluid reabsorption by the gallbladder epithelium. The gallbladder epithelium performs the isotonic absorption of NaCl. The apical step is parallel Na-H exchange and Cl-HCO3 exchange. Because Na-H exch

23、ange is somewhat faster, net secretion of acid into the lumen occurs. The basolateral step of NaCl absorption is mediated by the Na-K pump and by Cl- channels. K+ channels provide a route for basolateral K+ recycling. Water follows passively through the tight junctions and through the basolateral me

24、mbrane.Excretion of Organic AnionsMajor Organic Molecules in Bile Include Bile Acids, Cholesterol and PhospholipidsBile has two important functions: (1) bile provides the sole excretory route for many solutes that are not excreted by the kidney, and (2) secreted bile salts and acids are required for

25、 normal lipid digestion and absorption.Both hepatic bile and gallbladder bile are complex secretions that are isosmotic with plasma (300 mosmole/kg) and consist of water, inorganic electrolytes, and a variety of organic solutes, including bilirubin, cholesterol, fatty acids, and phospholipids. The p

26、redominant cation in bile is Na+, and the major inorganic anions are Cl- and solutes whose presence in bile is functionally important include micelle-forming bile acids, phospholipids, and immunoglobulin A.Canalicular Bile Flow Driven by the Secretion of Small Organic Molecules and Bile AcidsTotal b

27、ile flow is the sum of the bile flow from hepatocytes into the canaliculi (canalicular flow) and the additional flow from cholangiocytes into the bile ducts (ductular flow). In most species, the rate of canalicular bile secretion (i.e., milliliters per minute) increases more or less linearly with th

28、e rate of bile acid secretion (i.e., moles per minute). Canalicular bile flow is the sum of two components: (1) a constant component that is independent of bile acid secretion (bile acid-independent flow) and (2) a rising component that increases linearly with bile acid secretion (bile acid-dependen

29、t flow). In humans, most of the canalicular bile flow is bile acid dependent. Intracellular Transport from Sinusoidal to Canalicular Membrane in Hepatocytes - Binding Proteins vs Vesicular RoutesBILE SALTS - three binding proteins identified: hepatic dihydrodiol dehydrogenase, glutathione-S-transfer

30、ase B and fatty-acid-binding protein. Intracellular sequestration may regulate bile acid synthesis. Transcellular diffusion can be detected in seconds after bile salts are applied to hepatocytes; a primary mode under basal conditions.Intracellular transport of bile salts may also follow the microtub

31、ule-dependent vesicular pathway, which is slower and used at higher bile-salt loads. The type of bile salt may influence its transcellular pathway, e.g. vesicular pathway for monoanionic bile salts and binding proteins for dianionic bile salts.Intracellular Transport from Sinusoidal to Canalicular M

32、embrane in Hepatocytes - Binding Proteins vs Vesicular RoutesBILIRUBIN - After sinusoidal uptake, unconjugated bilirubin is transported to the endoplasmic reticulum (ER), where it is conjugated to glucuronic acid. Because the resulting bilirubin glucuronide is markedly hydrophobic, its intra-cellula

33、r transport is probably mediated by binding proteins such as glutathione transferase B. Spontaneous transfer of bilirubin between phospholipid vesicles. Membrane-to-membrane flux of bilirubin is biased for higher cholesterol/phospholipid ratio. (the inherent gradient for cholesterol from the basolat

34、eral to the ER membrane).Bilirubin Secretion & MetabolismBilirubin Excretion & MetabolismMacrophages phagocytose senescent red blood cells and break heme down to bilirubin, which travels in the blood, bound to albumin, to the liver. The hepatocyte takes up bilirubin across sinusoidal membrane by thr

35、ee mechanisms and then conjugates the bilirubin with one or two glucuronic acids. The cell then exports this conjugated bilirubin into bile. Some bilirubin glucuronide is converted back to bilirubin by bacteria in the terminal ileum and colon. This bilirubin is further converted to the colorless uro

36、bilinogen.If remains in the colon, urobilinogen is further converted to stercobilin, which is the main pigment of feces. If the urobilinogen enters the plasma and is filtered by the kidney, it is converted to urobilin and gives urine its characteristic yellow color.In Phase I Biotransformation, Hepa

37、tocytes Use Cytochrome P-450; In Phase II Hepatocytes Conjugate the Phase I ProductsThe liver is responsible for the metabolism and detoxification of many endogenous and exogenous compounds. Some compounds (e.g., proteins and ligands) taken up by hepatocytes are digested within lysosomes. Specific c

38、arriers exist for the lysosomal uptake of sialic acid, cysteine, and vitamin B12. Lysosomal acid hydrolases cleave sulfates, fatty acids, and sugar moieties from larger molecules.Hepatocytes handle other compounds by biotransformation reactions that usually occur in two phases.Phase I reactions repr

39、esent oxidation or reduction reactions in large part catalyzed by the P-450 cytochromes, including hydroxylation, dealkylation and dehalogenation. The common feature is that one atom of oxygen is added to the substrate, making the substrate more polar, poised for further modification by a phase II r

40、eaction. Phase II reaction may increase the water solubility of ROH by conjugating it to a highly hydrophilic compound such as glucuronate, sulfate, or gluthathione:Finally, the conjugated compound is secreted into the blood or bile.Hepatic ConjugationHepatocytes used three conjugation reactions: gl

41、ucuronate, sulfate, or gluthathione.CONJUGATION TO GLUCURONATE uridine diphosphate glucuronosyl transferases (UGTs) reside in the SER of the liver. Family 1 UGTs catalyze the conjugation of glucuronic acid with phenols or bilirubin. Family 2 UGTs catalyze the glucuronidation of steroids or bile acid

42、s. Congenital absence of bilirubin-UGT activity results in jaundice from birth and bilirubin encephalopathy, as can be seen in Crigler-Najjar type I syndrome.CONJUGATION TO SULFATE The sulfotransferases-which are located in the cytosol catalyze the sulfation of steroids, catechols, and foreign compo

43、unds such as alcohol and metabolites of carcinogenic hydrocarbons.Sulfates are not toxic and are readily eliminated, with the exception of sulfate esters of certain carcinogens.Hepatic Conjugation - ContinuedCONJUGATION TO GLUTATHIONE. The first step is for glutathione-S-transferase to couple the ta

44、rget compound to the cysteine residue of GSH. MRP2 secrets GSH conjugate into the canalicular lumen.-glutamyl transpeptidase may remove the terminal glutamate residue. Alternatively, the conjugate may reach the blood and be filtered by the kidney where a -glutamyl transpeptidase at the brush border

45、and a dipeptidase generate a cysteine derivative. Acetylation yields the mercapturic acid derivative, which appears in the urine. Conjugation to GSH and formation of mercapturic acidsBile Acid Synthesis chemical structuresBile Acid Synthesis major enzymesBile Acid Secretion major membrane transporte

46、rsAlrefei and Gill, 2007Human liver synthesizes bile acid at 500-600 mg/day, maintains 2-3 g in transit, and due to enterohepatic circulation secretes 20-30 g of bile acids each day. The concentration of bile acids is 100-1000-fold higher in bile than in portal blood.Cholestasis is characterized by

47、diminished bile flow, which is associated with many intrahepatic and extrahepatic disorders. The causes can be classified as hereditary or acquired.Bsep-actinA: bright fieldB: anti-BsepC: anti-actinD: anti-BsepCai et al 2001Aller et al 2009The synthesis, secretion and reabsorption of bile acid in th

48、e liver and intestine is primarily regulated by FXR and FGF19FXR participates in the regulation of glucose and lipid metabolism體循環(huán)和門靜脈中的膽汁酸濃度膽酸細胞膜受體TGR5The TGR5 receptor (or GP-BAR1, or M-BAR) G-protein coupled receptor specific for bile acidsTGR5 組織表達以及不同的膽汁酸激活程度TGR5在不同組織中的功能脂肪肝模型 食物中添加的膽酸明顯地降低體重Th

49、e liver function as a source or a sink for glucose and is primarily regulated by insulin and glucagonAmino acid metabolism and urea formation in hepatocytesCholesterol metabolismCholesterol synthesisThe Liver Is the Prime Site for Metabolism and Storage of the Fat-Soluble Vitamins A, D, E, and K Vit

50、amin A (retinol and its derivatives)-like dietary vitamin D, as well as vitamins E and K-is absorbed from the intestine and is then transported in newly synthesized chylomicrons or VLDLs. After some peripheral hydrolysis of its triglyceride, the remnant chylomicrons are taken up by the liver. In the

51、 hepatocyte, retinyl esters may be hydrolyzed to release free retinol, which can then be transported into the sinusoids bound to retinol-binding protein (RBP) and prealbumin. Retinyl esters may be stored in the hepatocyte or transported as RBP-bound retinol to stellate (Ito) cells.Retinol may also u

52、ndergo oxidation to retinal and conversion to retinoic acid, which plays a key role in phototransduction. Retinoic acid is conjugated to glucuronide and is secreted into bile, where it undergoes enterohepatic circulation and excretion. The Liver Is the Prime Site for Metabolism and Storage of the Fa

53、t-Soluble Vitamins A, D, E, and K Skin cells, under the influence of ultraviolet light, synthesize vitamin D3. Dietary vitamin D can come from either animal sources (D3) or plant sources (D2). In either case, the first step in activation of vitamin D is the 25-hydroxylation of vitamin D, catalyzed b

54、y a hepatic cytochrome P-450 enzyme. This hydroxylation is followed by 1-hydroxylation in the kidney to yield a product (1,25-dihydroxyvitamin D) with full biological activity. Termination of the activity of 1,25-dihydroxyvitamin D also occurs in the liver by hydroxylation at carbon 24, mediated by

55、another cytochrome P-450 enzyme.The Liver Is the Prime Site for Metabolism and Storage of the Fat-Soluble Vitamins A, D, E, and K Vitamin E, a fat-soluble vitamin is absorbed from the intestine primarily in the form of - and -tocopherol. It is incorporated into chylomicrons and VLDLs with other prod

56、ucts of dietary lipid digestion. Reach the systemic circulation through the lymphatics and undergo some triglyceride hydrolysis. In the process, some vitamin E is transferred to other tissues. The - and -tocopherol remaining in the remnant chylomicrons is transported into the liver, which is the maj

57、or site of discrimination between the two forms. The -tocopherol is secreted again as a component of hepatically derived VLDL and perhaps HDL. The -tocopherol appears to be metabolized or excreted by the liver. A hepatic tocopherol-binding protein may play a role in this discriminatory process.The L

58、iver Is the Prime Site for Metabolism and Storage of the Fat-Soluble Vitamins A, D, E, and K Vitamin K is a fat-soluble vitamin produced by intestinal bacteria. This vitamin is essential for the -carboxylation-by the ER enzyme -glutamyl carboxylase-of certain glutamate residues in coagulation factors II, VII, IX, and X as well as anticoagulants protein C and protein S and certain other proteins. Intestinal absorption and handling of vitamin K-which is present in two forms, K1 and K2.Common causes of vitamin K deficiency, which can lead to