Liver Biochemistry Flashcards
What is the blood supply to the liver?
75 percent from hepatic portal V.
25 percent from proper hepatic A.
What is the main cell type in the liver and what are they responsible for?
hepatocytes (80 percent of liver cells)
- carry out most of the metabolic fxn of the liver
- can regenerate
What do the endothelial cells of the liver do?
-allow exchange of material from liver to blood and vice versa via pores and fenestrations in the plasma membrane
What are characteristics of the Kupffer Cells in the liver?
- within the sinusoids (in the lining)
- have well-developed endocytic and phagocytic fxn
- lots of lysosomes in these cells
What is the function of Kupffer Cells in the liver?
-macrophages that protect the liver from gut-derived microbes, removed dead RBC, orchestrate immune response, secrete cytokines
What do the hepatic stellate cells do?
-serve as storage site for vitamin A and other lipids
What are Pit Cells in the liver?
- lymphocytes and natural killer cells
- protect liver against viruses and tumor cells
What are cholangiocytes?
they line the bile ducts and control the rate of bile flow and control the bile pH
What processes are carried out by the liver in regards to carbohydrate metabolism?
- glucostasis = maintains blood glucose levels
- glycogenesis
- glycogenolysis
- gluconeogenesis (d/t presence of G6P-ase)
- makes ketone bodies during starvation
What processes are carried out by the liver in regards to lipid metabolism?
- synthesis of TAG’s, phospholipids, steroids (cholesterol, bile), lipoproteins (VLDL, LDL, etc)
- lipolysis (degradation or TAG’s, plasma lipoproteins; beta-oxidation; regulation of FFA metabolism)
True or False: liver conducts nucleotide biosynthesis
True
What cycle dealing with amino acid metabolism only occurs in the liver?
- urea cycle (removal of nitrogen)
- impaired clearance of ammonia leads to brain damage
What blood proteins are synthesized by the liver?
-albumin, antibodies, apoproteins (for lipid transport), fibrinogen, prothrombin, clotting factors (V, VII, IX and X)
- acute phase response proteins (C-reactive protein)
- protease inhibitors (alpha1 antitrypsin)
True or False: liver metabolizes bilirubin
True
What is the liver’s role (overall big picture) in waste management?
-inactivation, detoxification, and biotransformation of metabolites and xenobiotics
How is the liver’s circulation unique?
- receives blood from enteric circulation via portal V.
- receives blood from periphery via hepatic A.
- low portal blood pressure
What major structural adaptation aids the liver in its function?
- lack of basement membrane and absence of tight junctions b/w hepatocytes and endothelial cells
- pores allow greater access and increased contact b/w liver and blood
What are the cellular adaptations and characteristics of hepatocytes that aid the liver in its function?
- well-developed plasma membrane
- well-developed ER (smooth and rough)
- lots of lysosomes
- lots of metabolic enzymes
What are the steps in the synthesis of primary bile acids?
–7alpha-hydroxylase changes cholesterol into 7alpha-hydroxycholesterol
–the side chain is snipped and a COOH is added to make chenodeoxycholic acid or cholic acid
What must happen to chenodeoxycholic acid and cholic acid prior to being secreted?
they must be conjugated
How are chenodeoxycholic acid and cholic acid conjugated?
- CoA is added
- then CoA is removed and replaced by an amino acid
- -taurine or glycine
- –taurochenodeoxycholic acid or taurocholic acid
- –glycochenodeoxycholic acid or glycocholic acid
Which primary conjugated bile acid is a better emulsifier?
-taurocholic acid with a pKa of 2
versus
–glycocholic acid with a pKa of 4
What is the rate-limiting step in bile acid synthesis?
the creation of 7alpha-hydroxycholesterol from cholesterol by 7alpha-hydroxylase
What is the cofactor used by 7alpha-hydroxylase?
vitamin C
How are primary conjugated bile acids changed into secondary bile acids?
by gut bacteria that deconjugate and dehydroxylate
What are the secondary bile acids?
- deoxycholic acid from cholic acid
- lithocholic acid from chenodeoxycholic acid
Once the bile acids are released, what happens to them?
- 95 percent is absorbed by the ileum and recycled by the liver
- 5 percent is excreted in the feces
How do bile acids and bile salts emulsify fats?
- the hydrophobic surfaces of bile salts associate with TAG’s and form a micelle
- hydrophilic surface of bile salts faces outward, allowing interaction w/ pancreatic lipase
What is the mechanism of digestion by pancreatic lipases?
pancreatic lipases free fatty acids from large micelles in to a smaller micelle that can be absorbed through intestinal mucosa
Clinical Correlation: Gallstones
- result from supersaturation of bile /cholesterol
- cholesterol crystals form
What is are the causes of cholelithiasis?
- insufficient secretion of bile salts that are required for the cholesterol to stay in solution
- excess cholesterol secretion into bile
What are some consequences of chronic disturbance in bile salt metabolism?
- malabsorption syndromes
- steatorrhea (fat in feces)
- deficiency in fat-soluble vitamins
What is the mechanism behind how cholesterol-lowering drugs such as cholestyramine work?
-bind to bile acids and prevent it from being reabsorbed
–bile is excreted
-decreased inhibition of 7alpha-hydroxylase
(bile normally inhibits 7alpha-hydroxylase)
-bile must be synthesized using up more cholesterol
What is a difference between hepatic metabolic enzymes versus others?
-low substrate specificity b/c they have to be able to deal w/ an infinite range of molecules
What are the phases of inactivation of xenobiotics?
Phase I - reduction, oxidation, hydroxylation, or hydrolysis increases the polarity (catalyzed by CYPs)
Phase II - conjugation, sulfation, methylation, glucuronidation makes them soluble enough to excrete
What is the rate-limiting enzyme in metabolism catalyzed by CYPs (most commonly CYP1, CYP2, and CYP3)?
CYPR
cytochrome P450 reductase
Name a couple things that inhibit CYPs and the result of inhibition.
- itraconozole and citrus juice
- increase in drug plasma levels
Name a couple things that stimulate CYPs and the result of stimulation.
- rifampicin and St. John’s Wort
- decrease in plasma drug levels
How does “personalized medicine” play into drug metabolism?
- there are many polymorphisms of CYPs
- -influences the way drugs are metabolized
-the CYPs of an individual patient can be genotyped
Clinical Correlation: Tylenol Toxicity
- normally conjugated with glucuronic acid or sulfate
- in overdose, capacity for conjugation is overwhelmed
- excess Tylenol oxidized by CYP3A4 into NABQ1
- -a free radical that causes hepatic failure and death
- tx by glutathione or N-acetyl cysteine
What are the mechanisms of liver disease?
- endothelial cells pack more tightly together
- membrane contains collagen
- stiff hepatic vasculature resists free flow of blood
- impairs exchange of material bw hepatocytes and liver
How can liver fxn be assessed using blood albumin levels?
- lack of albumin causes edema
- albumin provides the osmotic pressure
- low albumin means the liver isn’t making enough
How can liver fxn be assessed using AST and ALT levels?
- they’re normally in hepatocytes, NOT blood
- damaged hepatocytes release AST/ALT into blood
- ALT is more sensitive b/c it’s cytosolic
- ALT and AST are both in hepatocyte mitochondria
- req’d for conversion of amino acids into ketoacids
How can liver fxn be assessed using prothrombin time (PT)?
- liver makes prothrombin
- increased prothrombin time means liver isn’t making enough prothrombin
