Liver Biochemistry (Zaidi) Flashcards
(39 cards)
1
Q
Describe the structure of the liver:
A
- largest solid organ in the body
- ~3% body weight, weighs ~1500 g
- consists of 2 lobes subdivided into multiple lobules and sinusoids
- covered by a capsule of CT
- blood supply: 75% by portal vein, 25% by hepatic artery
- biliary component made of bile ducts and gallbladder
2
Q
Describe blood flow through the liver:
A
- two ways in: oxygen rich blood flows into liver through hepatic artery (25%), nutrient rich blood coming from bowel flows into liver through portal vein (75%)
- one way out: blood flows out of liver through 3 hepatic veins into inferior vena cava
- bile: flows out of liver through bile duct
3
Q
- 60% of liver cells
- carry out most of the metabolic funcitons of the liver
- responsive to hormones, have receptors and transporters to carry out signaling pathways, capable of regeneration
- all other cells below 40%
A
hepatocytes
4
Q
- cells present in the lining of sinusoids
- do not form a tight basement membrane w/ hepatocytes
- present loosely, have pores and fenestrations in plasma membrane to allow exchange of material from liver to blood and vice versa
A
endothelial cells
5
Q
- cells present in the lining of sinusoids
- macrophages that protect liver from gut derived microbes, remove damaged/dead RBCs, and upon stimulation orchestrate immune response by secreting cytokines
- have endocytic and phagocytic functions, lysosomes present in these cells
A
Kupffer cells
6
Q
- lipid-filled cells that serve as primary storage site for vit A
- ~5-20 of these cells per 100 hepatocytes
- control the turnover of hepatic CT and extraceullar matrix and regulate conntractility of sinusoids
- during liver cirrhosis, they are stim by various signals to increase syn of extracellular matrix material, which in turn diffusely infiltrates liver eventually interfering w/ function of hepatocytes
A
hepatic stellate cells
(perisinusoidal or Ito cells)
7
Q
natural killer cells, serve as defense mechanism against invasion of liver by potentially toxic agents such as tumor cells or viruses
A
Pit cells
(liver associated lymphocytes)
8
Q
line the bile ducts and control bile flow rate and bile pH
A
cholangiocytes
9
Q
What are the main functions of the liver? (~9-10)
A
- primary receiving, distribution, and recycling center
- carb metabolism
- lipid metabolism
- nucleotide biosyn
- protein and AA metabolism
- removal of nitrogen generated by AA metabolism via urea cycle (impaired clearance of ammonia causes brain damage)
- synthesis of blood proteins
- bilirubin metabolism
- waste management
10
Q
Describe the receiving, distribution, and recycling functions as they relate to the liver:
A
- liver receives nutrient rich blood from enteric circ through portal vein
- all compounds that enter GI go through liver on their way to tissues
- has first access to nutrients to fulfill specific functions
- first access to ingested toxins and potentially harmful compounds
- also receives ox rich blood from hepatic artery
- arterial and venous blood mixes in sinusoids
- mixing: gives liver access to metabolites ingested and prod in periphery ans secreted into peripheral circ (glucose, AAs, proteins, iron (transferrin complexes), and waste metabolites which could be potential toxins prod during substrate mblsm)
- major role: monitoring, synthesizing, recycling, distributing, and modifying metabolites
- ingested material that may be useful for body is retrieved by liver and converted to useful form
- any harmful product that is ingested/prod by body converted to a safe product and excreted
11
Q
Describe carb metabolism as it relates to liver:
A
- role in glucose metablosm, specifically in maintaining optimal levels of circ blood glucose
- maintains glucostasis
- synthesizes and stores glucose in form of glycogen (glycogen syn)
- releases glucose when blood glucose levels low (glycogenolysis)
- has glucose 6 phosphatase which permits release of free glucose into the blood (unlike muscle which keeps glucose 6 phosphate for its own use)
- can syn glucose from non-carb sources, principally through breakdown of body’s proteins (gluconeogenesis)
12
Q
Describe lipid metabolism as it releates to liver:
A
- biosyn of TAGs, phospholipids, steroids (cholesterol, bile acids, bile salts) lipoproteins (VLDL, LDL, HDL)
- degradation of TAG and plasma lipoproteins
- reg of free fatty acid mblsm
- breakdown of FFA via beta oxidation to release energy
- under conditions of starvation, syn ketone bodies for use as energy source
13
Q
Describe synthesis of blood proteins as it relates to liver:
A
- syn of albumin, IgGs, apoproteins (lipid transport proteins), fibrinogen, prothrombin, blood coagulation factors V, VII, IX, and X (blood clotting proteins)
- syn of acute phase proteins (response encompasses all systemic changes in response to infection/inflammation), which include C-reactive protein and protease inhibitors (α-1 Antitrypsin and α-1 Antichymotrypsin)
14
Q
Describe waste management as it relates to liver:
A
inactivation, detoxification, and biotransformation of metabolites and xenobiotics
15
Q
What is unique regarding hepatic circulation?
A
- receives blood from enteric circ (via portal vein) and from periphery (via hepatic artery)
- two sources mix together in sinusoids
- low portal blood pressure
16
Q
What are the structural feature adaptations of the liver?
A
- lack of basement membrane and absence of tight junctions between hepatocytes and endothelial cells
- gaps between endothelial cells
- fenestrations (pores) in endothelial cell membrane
- allow greater access and increased contact between liver and blood
17
Q
What are the cellular adaptations of the liver?
A
- 10 different cell types
- hepatocytes: well developed plasma membrane and ER, lots of lysosomes, metabolic enzymes
- endothelial cells: allow free exchange of materials
- immune cells: protect liver from pathogens
18
Q
Describe what bile acids/salts are, what their functions are, how they are stored, and how they are released:
A
- bile made of bile acids, bile salts, cholesterol, phospholipids, fatty acids, proteins, bile pigments, and inorganic salts
- functions: emulsification of fats, absorption of fat-soluble vitamins, digestion and absorption of fats, prevention of cholesterol precipitation, elimination of cholesterol
- they are strong detergents: amphipathic, w/ polar and non-polar regions; help to form micelles that increase surface area of lipids thus expose them to lipases
- synthesized from hepatic cholesterol
- made in hepatocytes, released into bile canaliculi, stored/concentrated in gallbladder
- released into duodenum in reponse to food
19
Q
What are the structural differences between bile acids and salts?
A
- acids are the protonated form (COOH)
- salts are the de-protonated form (COO-)
20
Q
Describe the process of emulsification by bile salts:
A
- cholic acid ionizes to give its cognate bile salt
- hydrophobic surface of bile salt molecule a/w TAG and several of these complexes aggregate to form a micelle
- hydrophillic surface of bile salt faces outward, allowing micelle to a/w pancreatic lipase/colipase
- hydrolytic action of lipase/colipase frees FA’s to associate in much smaller micelle that is absorbed through intestinal mucosa
21
Q
What is the first step of the primary pathway within bile acid synthesis?
A
cholesterol > 7-α-hydroxycholesterol > (several steps) cholic acid and chenodeoxycholic acid
1st step: cholesterol > 7-α-hydroxycholesterol
- 7α-hydroxylase (CYP7A, present in ER of hepatocytes)
- committed step
- needs: NADPH > NADP+ + H+; and vit C
- what happens: OH group added to 7 carbon
22
Q
How is cholesterol converted to bile acids?
A
cholesterol > 7-α-hydroxycholesterol > (several steps) cholic acid and chenodeoxycholic acid
cholesterol > (7α-hydroxylase) > 7α-hydroxycholesterol
7α-hydroxycholesterol > (reduction, hydroxylation, and conversion of hydroxyls to α) > 3α,7α-diol
3α,7α-diol > chenodeoxycholic acid
3α,7α-diol > (oxidation of side chain) > 3α,7α,12α-triol
3α,7α,12α-triol > cholic acid
differences between primary bile acids: cholic acid has 12 OH group and chenodeoxycholic acid does not
23
Q
What is the regulation on primary bile acid synthesis?
A
7α-hydroxylase (CYP7A)
(+): cholesterol
(-): bile acids
24
Q
Describe the process of conjugation of bile acids:
A
colic acid (CA) and chenodeoxycholic acid (CDA) converted to:
- glycocholic acid and glycochenodeoxycholic acid by glycine
- taurocholic acid and taurochenodeoxycholic acid by taurine
(conjugate bile acids: K+ and Na+ salts of conj bile acids are bile salts)
CA specifically:
CA > cholyl CoA (pKa 6) > (3:1 in favor of glycine) > glycocholic acid (pKa 4) and taurocholic acid (pKa 2)
25
What is the purpose of conjugating bile acids prior to secretion?
- conjugate bile acids have a lower pKa than primary bile acids
- when conj bile acids enter duodenum (pH ~6) w/ a lower pKa, this allows them to become deprotonated, w/ negative charge (**ionized**), and thus are **more polarized**
- this allows conj bile acids to be better **emulsifiers** w/ a **better detergent effect**
26
Describe the synthesis of secondary bile acids:
- CA and CDA \> (bacterial 7α-dehydroxylase) \> **deoxycholic acid** (CA) and **lithocholic acid** (CDA)
- bacteria **deconjugate** and **dehydroxylate** primary bile salts into primary and secondary bile acids, which are absorbed by the **distal ileum** and then: excreted in feces (5%) and recycled to liver via **enterohepatic circulation** (95%)
- **difference between primary and secondary bile acids**: secondary has 7α OH removed compared to primary bile acids
27
Describe the mechanism of cholesterol-lowering drugs:
- medication used to lower cholesterol in patients w/ hypercholesterolemia
- ~20-30g of bile acids enter enterohepatic circ qd
- ~95% reabsorbed and 5% excreted out
- non-absorbable bile acid binding resins (**cholestyramine**) cause **large increase in excretion of bile acids**
- **rate of bile acid syn** is increased by **induction of 7α-hydroxylase**
- **depletion of liver cholesterol pool**
- increase in hepatic uptake of LDL cholesterol from circulation
- **lower plasma cholesterol levels**
28
- **crystals** made of **bile supersaturated** w/ **cholesterol**
- insufficient secretion of bile salts or phospholipids into gallbladder or excess cholesterol secretion into bile
- chronic disturbance in bile salt metabolism leads to **malabsorption syndromes (steatorrhea)** and **deficiency in fat soluble vitamins**
gallstones (cholelithiasis)
29
Liver is the primary site for conversion and/or degradation of:
- **xenobiotics**: compounds ingested from outside (w/ no nutritional value, potentially toxic) (e.g. pharmacological agents, recreational drugs, components of food)
- **metabolites**: compounds made in body (intermediates and/or end prod of metabolism)
30
Describe the process of inactivation and detoxification of xenobiotics:
- **phase I reactions**: polarity increased; catalyzed by **cytochrome P450 (CYP) enzymes**
- **phase II reactions**: functional groups are conjugated to make molecule more amenable for safe excretion
31
Describe drug metabolism as it relates to liver:
- most drugs metabolized in liver
- **increases hydrophilicity** and ability to be excreted
- most drug **metabolites are less pharmacologically active** than parent drug
- some drugs are inactive when administered but converted to **active form after metabolism** in liver (prodrugs)
- hepatic enzymes can deal w/ infinite range of molecules that can be administered
- achieved by **responsible enzymes** having **low substrate specificity**
32
What is the main group of enzymes that play a key role in liver drug metabolism?
- **cytochrome P450 enzymes** superfamily
- made of **18 families** and 43 sub families containing **57 genes**, **3 families** responsible for most of phase I drug metabolism (**CYP1, CYP2, CYP3**)
- **CYP3A4 isoform accounds for 30-40% of CYP450 enzymes** in liver and metabolizes greatest number of drugs in humans
- CYP's are heme containing proteins present in ER
- CYP's co-localize w/ **NADPH** (cytochrome P450 reductase, CYPR)
- ratio of CYP to CYPR is 4:1, making CYPR rate limiting
- play key role in metabolism of **multiple hydrophobic compounds**
- operate via electron transfer system
33
Describe how CYP's function in liver drug metabolism:
- **CYP's detoxify pharmacological agents**
- inducible by their substrate
- certain drugs/xenobiotic agents increase rate of phase I rxns
- certain drugs that form stable complex w/ particular CYP inhibit metabolism of other drugs that are normally substrates for that CYP
- agents that **inhibit CYP** will cause **increase in drug levels** in plasma
- agents that **stimulate CYP** will cause **decrease in drug levels** in plasma
- may lead to toxic side effects (myopathy and rhabdomylosis)
34
Describe induction and competitive inhibition as it relates to CYPs:
- **CYP inhibitors**: itraconozole, clarithromycin, cyclosporine, **citrus juices, grapefruit juice** (example: if patient regularly takes statins w/ grapefruit juice there will be **increase in statin levels** in plasma)
- **CYP inducers**: rifampicin, carbamazepine, **St. John's Wort** (example: if patient takes statins and St. John's Wort there will be **decrease in statin levels** in plasma)
35
Describe personalized medicine as it relates to CYP liver enzymes:
- allelic variation and **polymorphisms of CYPs** exist in individuals
- influences catalytic activity of CYPs
- **infuences drug metabolism**
- **genotyping CYPs** to identify gene-relevant polymorphisms may become more common in order to personalize an individual's response to particular drug
36
- a drug that is toxic to liver in excess
- sometimes it is toxic in certain individuals and not in others
- may be due to **genetic or immunologic** causes
- elimination of this drug occurs via **conjugation w/ glucuronic acid or sulfate** which are then excreted via kidney
- in overdose, **capacity for nml conjugation is overwhelmed**
- it is oxidized by liver **CYP3A4 to N-acetyl benzoquinoneimine (NABQ1)**
- NABQ1 causes free radical-mediated peroxidation of membrane lipids and damages hepatocytes
- serious enough to lead to **hepatic failure and death**
- **NABQ1 detoxified by glutathione**, in overdose these stores become depleted
- sulphydryl compound, **N-acetyl cysteine**, can be given as **antidote**
tylenol (acetaminophen) hepatoxicity
37
What are the major diseases of the liver?
- hepatitis: acute or chronic
- jaundice: pre-hepatic, intra-hepatic, post-hepatic
- viral hepatitis: A, B, and C
- alcohol induced hepatitis
- drug induced hepatitis
- liver cirrhosis: result of chronic hepatitis, characterized by fibrosis of liver lobules
38
What is the underlying etiology of most liver diseases and what does this lead to?
- **major change**: nml leaky basement membrane between endo cells and hepatocytes replaced by high density membrane containing fibrillar collagen
- spaces between endo cells and fenestrations in plasma membrane lost
- increased stiffness of hepatic vascular channels creates resistance to free flow of blood through liver \> elevated intra-sinusoidal pressure \> portal htn
_- **causes**: impairment of free exchange of material between hepatocytes and blood_
39
What parts of the liver function/metabolic panel are indicative of liver function?
- albumin
- transaminases: alanine amino transferase (ALT) and aspartate amino transferase (AST)
- alkaline phosphatase
- prothrombin time (PT)
- bilirubin (unconjugated and conjugated)
- urea (BUN)
- glucose
- TAG
- cholesterol (total, VLDL, LDL, HDL)
