Liver Biochemistry

Question 1

what is the blood supply to the liver? and what is the blood flow out

Answer 1

75 percent portal vein (coming from the GI tract)
-nutrient rich blood coming from the bowel flows into the liver

25 percent from the hepatic artery (oxygenated blood from the heart)
-Oxygen rich

Blood flows out of the liver through 3 hepatic veins into a big vein called the inferior vena cava

Question 2

how does the flow of blood meet up in the liver

Answer 2

Blood from the portal vein will travel down the sinusoid where it will meet up with the hepatic artery where the two contents will mix

the blood will continue to travel until reaching the central vein and leave the Liver

Question 3

how does bile flow in relation to blood?

Answer 3

bile will flow the opposite direction in the Bile canaliculi until it reaches the bile duct and leaves the liver

Question 4

Roll of the Hepatocytes?

Answer 4

80percent of liver cells and carriesout most of the metabolic functions of the liver capable of regeneration

Question 5

Roll of the Endothelial cells of the liver?

Answer 5

allow for exchange of material from liver to blood and vice versa via pores and fenestrations in plasma membrane

Question 6

roll of the Kupffer cells

Answer 6

Present in the lining of the sinusoids

they are macrophages that protect the liver from gut derived microbes, remove damaged/dead RBCs, orchestrate immune response, secrete cytokines

Have well developed endocytic and phagocytic functions, lots of lysosomes present in these cells

Question 7

roll of Hepatic Stellate cells?

Answer 7

Serve as storage site for Vitamin A and other Lipids

Question 8

Roll of Pit cells?

Answer 8

Lymphocytes, Natural killer cells

-protect liver against viruses and tumor cells

Question 9

Roll of Cholangiocytes?

Answer 9

Line the bile ducts and control the bile flow rate and bile pH

Question 10

What are the 9 main functions of the liver?

Answer 10

1) Primary receiving, distribution, and recycling center
2) Carbohydrate metabolism
3) Lipid Metabolism
4) Nucleotide Biosynthesis
5) Protein and Amino Acid metabolism
6) Removal of nitrogen generated by amino acid metabolism via the urea cycle
7) Synthesis of Blood proteins
8) Bilirubin Metabolism
9) waste Management: Inactivation, detoxification, and biotransformation of metabolites and xenobiotics

Question 11

How does the liver undergo Carbohydrate metabolism?

Answer 11

-Maintains optimal levels of circulating glucose
(GLucostasis: under fed, fasting, and starvation state)

• Glycogen synthesis (glucose to glycogen for storage)
• Glycogenolysis (breakdown of glycogen)
• Contains glucose 6 Phosphatase that permits release of free glucose to the blood
• make glucose from non-carbohydrate sources (gluconeogenosis)

Question 12

How does the liver undergo Lipid metabolism?

Answer 12

• Biosynthesis of TAGs, phospholipids, Steroids (cholesterol, bile acids and bile salts), Lipoproteins (VLDL, LDL, HDL)
• Degradation of TAG and plasma lipoproteins
• Regulation of free fatty fatty acid metabolism
• Breakdown of FFA via beta oxidation

Question 13

What happens if there is impaired clearance of ammonia?

Answer 13

Brain damage

Question 14

What are some blood proteins the the liver makes?

Answer 14

• Albumin, IgGs, Apoproteins, Fibrinogen, Prothrombin, Blood coagulation factors V, VII, IX, and X (blood clotting proteins)
• Acute phase proteins: acute phase response encompasses all systemic changes in response to infection or inflammation
• Liver synthesizes acute phase response proteins such as C-reactive protein and protease inhibitors such as alpha-1 antitrypsin and alpha-1 antichymotrypsan

Question 15

what structural adaptations of the liver allow for it to be good at being a receiving, distribution, and recycling center?

Answer 15

Unique circulation:

• liver receives blood from enteric circulation (via portal vein) and from the periphery (hepatic artery)
• low portal blood pressure

Structural features:

• lack of basement membrane and absence of tight junctions between hepatocytes and endothelial cells
• gaps between endotelial cells
• Fenestrations (pores) in endothelial cell membrane
• all these allow for greater access and increaed contact between liver and blood

Cellular adaptations:
-well developed plasma membrane and ER (rough and smooth) with lots of lysosomes, metabolic enzymes

Question 16

what 5 things do Bile acids and salts help in?

Answer 16

1) emulsification of fats
2) absorption of fat soluble vitamins
3) digestion and absorption of fat
4) prevention of ccholesterol precipitation
5) elimination of cholesterol

Question 17

what makes bile acis/salts a strong detergent?

Answer 17

amphipathic: polar and non polar regions

- help to form micelles which increase surface area of lipids thus exposing them to lipases

Question 18

where are bile acids/salts made and released?

Answer 18

made via hepatic cholesterol in hepatocytes

and are released into the bile canaliculi and stored and concentrated in gall bladder

released into duodenum in response to food

Question 19

what is the difference between a bile acid and a bile salt?

Answer 19

Acid is the pronated form:

• cholic acid
• glycocholic acid

Salt is the depronated form:

Question 20

4 step process of the Emulsification by bile salts

Answer 20

1) Cholic acid, a typical bile acid, ionizes to give its conjugate bile acid
2) the hydrophobic surface of the bile salt molecule associates with triacylglycerol and several such complexes aggregate to form a micelle
3) the hydrophilic surface of the bile salts faces outward allowing the micelle to associate with pancreatic lipase/colipase
4) the hydrolytic action of lipase/colipase frees fatty acids to associate in a much smaller micelle that is absorbed through the intestinal mucosa

Question 21

what is the committed step in the synthesis of bile acids

Answer 21

cholesterol to 7a-hydroxycholesterol
-addition of an OH at the 7 location

this is done by the 7a-hydroxylase

• uses O2 and makes watter
• needs Cytochrome P450 that is found in ER of hepatocytes

Question 22

what are the two bile acids that are made?

Answer 22

Chenodeoxycholic acid
-OH at the 3 and 7 position

Cholic acid
-OH at the 3, 7, and 12 possition

Question 23

what happens to bile acids before they are secreted?

Answer 23

they are conjugated with the addition of either a glycine or a Taurine
-ratio is 3:1 in favor of glycine

Question 24

what are the 4 main conjugated bile acids?

Answer 24

• GLycocholic acid
• Taurocholic acid
• glycochenodeoxycholic acid
• taurochenodeoxycholic acid

Question 25

what are the two secondary bile acids and how do they come about?

Answer 25

Deoxycholic acid (derived from cholic acid) Lithocholic acid (derived from chenodeoxycholic acid) these arise because when the primary bile acids are released in the duodenum bacteria will deconjugate them and dehydroxylate them to turn them into the secondary bile acids before they are reabsorbed

Question 26

how do bile acid binding resins decrease cholesterol?

Answer 26

since normally 95 percent of bile acid is reabsorbed and 5 percent is excreted out, Bile acid binding resins such as Cholestyramine will cause a large increase in excretion of bile acids - this will increase the rate of bile acid synthesis and is increased by induction of 7-a hydroxylase - depletion of liver cholesterol pool - increase in uptake of LDL cholesterol - Lower plasma cholesterol levels

Question 27

what are gall stones? Cholelithiasis? and what can it lead to?

Answer 27

-Crystals made up of bile supersaturated with cholesterol Cholelithiasis: insufficient secretion of bile salts or phospholipids into gall bladder or excess cholesterol secretion into bile Chronic disturbance in bile salt metabolism leads to malabsorption syndromes (steatorrhea) and deficiency in fat soluble vitamins

Question 28

what are the two things that the liver is the primary site for converssion and or degradation of?

Answer 28

MEtabolites: Compounds made in the body (intermediates and or end products of metabolism) Xenobiotics: Compounds ingested from outside (with no nutritional value, potentially toxic) - pharmacological agents - recreational drugs - componets of food (additives, processing)

Question 29

what is the two phase process of inactivation and detoxification of xenobiotics?

Answer 29

Phase I: - polarity is increased - done via reduction, oxidation, hydroxylation, hydrolysis - catalyzed by cytochrome P450 enzymes Phase 2: - Functional groups are conjugated for safe excretion - done via conjugation, sulfation, methylation, glucuronidation

Question 30

Process of Drug metabolism?

Answer 30

- Metabolized in the liver - increases the hydrophilicity of the liver to allow for excretion - generally drug metabolites are less pharmacologically active then parent drung - produrgs are inactive until processed by liver

Question 31

what are cytochrome P450 enzymes?

Answer 31

- CYPs are heme containing proteins - Present in ER - co-localize with NADPH: cytochrome p450 redunctase(normally rate limiting step) - Metabolism in multiple hydrophobic compounds - CYP1, CYP2, and CYP3 are important for phase 1

Question 32

how do drug interactions with CYPs affect their activity?

Answer 32

CYPs are inducible by their substrate - certain drugs can form a stable complex with a particular CYP that inhibits 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 decrease in drug levels in plasma

Question 33

what are examples of CYP inhibitors and CYP inducers?

Answer 33

inhibitors: itraconozole, clarithyromycin, cyclosporine, Citrus juices, grapefruit juice - therefore taking these with another drug will lead to more drug in the plasma Inducers: rifampicin, carbamazepine, st johns wort -patient takes a drug with these there will be a decrease in drug levels in plasma

Question 34

how can personalized medicine be utilized with CYPs?

Answer 34

CYPs have Allelic variations and polymorphisms -this will influence drug metabolism there genotyping CYPS can help create a personalized medicine that benefits an individual

Question 35

Drug Hepatotoxicity in the exampe of Tylenol

Answer 35

- A drug may be toxic in excess, and sometimes in certain individuals than others - Elimination of tylenol (acetaminophen) occurs via conjugating with glucuronic acid or sulfate and then excreted via kidney - in acetaminophen overdose, the capacity for normal conjugation is overwhelemed - it is oxidized by CYP3A4 to NABQ1 - NABQ1 has a free fadical mediated peoxidation of membrane lipids that damages hepatocytes therefore enough of this can cause helaptic failure and death - NABQ1 is detoxified by glutathione but the body can run out -a sulphydryl compound called N-acetyl cysteine given as an antidote to acetaminophen poisioning

Question 36

what are the major changes in diseases of the liver?

Answer 36

- Normally leaky basement membrane between endothelial cells and hepatocytes replaced by high density membrane containing fibrillar collagen - spaces between endothelial cells and fenestrations in plasma membrane lost - increased stiffness of hepatic vascular channels offers resistance to free flow of blood through liver, elevated intra-sinusoidal fluid pressure and portal hypertension Impairment of free exchange of material between hepatocytes and blood

Question 37

what is the assessment of liver function/metabolic panel checking levels of?

Answer 37

- Albumin - Transaminases: Alanine amino Transferase (ALT) and aspartate amino transferase (AST) - Alkaline phosphate - Prothrombin time (PT) - Bilirubin - Urea (BUN) - GLucose - TAG - Cholesterol

Question 38

ALT and AST and significance of test?

Answer 38

- ALT and AST involved in the interconversion of amino acids and kketo acids and are required for protein and carbohydrate metabolism - both located in mitochondria, ALT also found in cytosol - Serum activity of ALT and AST increased in liver disease as the enzymes released from damaged hepatocytes - ALT more sensitive since it is cytosolic