Liver Biochemistry Flashcards
What is the largest solid organ in the body?
liver
3% body weight
How many lobes are there?
2 main lobes which are subdivided into multiple lobes and sinusoids
What is the liver covered by?
capsule of CT
What is the blood supply of the liver
75% portal vein
25% hepatic artery
What is the biliary components made of?
bile ducts and gall bladder
Describe hepatic circulation
- oxygen rich blood flows into the liver through the hepatic artery (25%)
- nutrient rich blood coming through the bowel flows into the liver through the portal vein (75%)
- bile flows out of the liver through the bile duct
- blood flows out of the liver through 3 hepatic veins into a big vein called the IVC
What can be seen in a cross section of a liver lobe?
- hepatic sinusoid
- hepatocyte
- central vein
- interlobar bile duct
- interlobar vein
- interlobar artery
What types of cells are in the liver?
- hepatocytes
- endothelial cells
- Kupffer cells
- hepatic stellate cells
- pit cells (lymphocytes)
- cholangiocytes
What are hepatocytes?
80% of liver cells, carry out most of the metabolic functions of the liver, capable of regeneration
What do endothelial cells do in the liver?
allow exchange of material from liver to blood and vice versa via pores and fenstrations in plasma membrane
What are Kupffer cells?
- present in the lining of the sinusoids
- 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
What are hepatic stellate cells?
serve as storage site for vitamin A and other lipids
What are pit cells?
lymphocytes
-NK cells, protect liver against viruses and tumor cells
What are cholangiocytes?
line bile ducts
control bile flow rate and bile pH
What are the functions of the liver?
- primary receiving, distribution, and recycling center
- carbohydrate metabolism
- liver metabolism
- neucleotide biosynthesis
- amino acid metabolism, ammonia, and urea cycle
- protein and amino acid metabolism
- synthesis of blood proteins
- bilirubin metabolism
- waste management
How does the liver participate in carbohydrate metabolism?
- glycolysis
- glycogenesis and glycogenolysis
- gluconeogenesis
- glucostasis (maintains glucose levels under fed, fasting, and starvation state)
How does the liver participate in lipid metabolism?
- biosynthesis of triacylglycerols (TAGs), phospholipids, steroids (cholesterol, bile acids, and bile salts), lipoproteins (VLDL, LDL, HDL)
- degredation of TAG and plasma lipoproteins
- regulation of free fatty acid (FFA) metabolism
- breakdown of FFA via beta oxydation to release energy
What are the blood proteins the liver synthesizes?
- albumin
- IgGs
- apoproteins
- fibrinogen
- prothrombin
- blood coagulation factors V, VII, IX, and X
- CRP
- alpha 1 antitrypsin
- alpha 1 antichymotrypsin (acute phase proteins)
How is the liver involved in waste management?
-inactivation, detoxification, and biotransformation of metabolites and xenobiotics
What is a majory role fo the liver?
monitoring, synthesizing, recycling, distributing, and modifying metabolites
What does the liver do to useful ingested material and harmful products?
useful: retrieved by the liver and converted into a useful form
harmful: converted into a safe product and excreted
Describe the unique circulation of the liver
- liver receives blood from enteric circulation via portal vein and from periphery via hepatic artery
- low portal blood pressure
Does the liver have basement membrane?
NO
Does the liver have tight junctions between hepatocytes and endothelial cells?
NO
What is between endothelial cells of the liver?
gaps
What is unique about the endothelial cell membrane in the liver?
fenstrations
What allows greater access and increased contact between liver and blood?
- lack of basement membrane
- absence of tight junctions btwn hepatocytes and endothelial cells
- gaps btwn endothelial cells
- fenstrations in endothelial cell membrane
How many acetyl CoA are used to generate one isopentenyl pyrophosphate (IPP)?
3
IPP serves as a building block for synthesis of all ____
isoprenoids
What are examples of isoprenoids?
lipid-soluble vitamins, prenyl groups attach proteins to plasma membrane, steroids
How many carbons in isoprene?
5
Where is acetyl CoA generated?
mitochondria
- oxidative decarboxylation of pyruvate
- beta oxidation of fatty acids
- breakdown of amino acids
How is acetyl CoA transported into cytoplasm?
citrate shuttle
What is a sterane ring?
six units of IPP form tetracyclic sterane ring
- backbone of most steroids
- cholesterol and cholic acids
What is the structure of cholesterol?
- allicyclic compound made of 4 fused rings (sterane)
- MW of 386 g/mol
- 27 carbons (sterane ring, side chain, one hydroxyl group at C3)
What is the most abundant sterol?
cholesterol
0.05% of body weight
What is cholesterol a component of?
plama membranes and precursor of biologically active compounds:
- bile acids and bile salts
- vitamin D
- steroid hormones (progesterone, aldosterone, cortisol, testosterone, estradiol)
What is the recommended daily intake of cholesterol?
<300 mg
What is the daily production of cholesterol?
0.75-1.0 g (mostly in liver, small intestine, adrenal cortex, ovaries, testes, and skin)
What is the daily excretion of cholesterol?
5% excreted, 95% reabsorbed
biosynthesis of cholesterol is inversely proportional to _____
dietary intake
What is the chemical equation for cholesterol synthesis?
18 AcetylCoA + 18 ATP + 16 NADPH + 16H+ + 4O2 –> cholesterol + 16 NADP+ + 18 ADP + 18 Pi
What are the steps of phase I of cholesterol synthesis?
acetyl CoA –> acetoacetyl CoA -HMG CoA synthase->HMG CoA -HMG CoA reductase, insulin, thyroxine, glucagon, sterols, high AMP, vit E, statin-> mevalonate–>IPP
What is the rate limiting enzyme in cholesterol synthesis?
HMG CoA reductase
What are the steps in phase II of cholesterol synthesis?
6 IPP –> squalene –> lanosterol -azoles, KCN, tamoxifen, morpholine, triparanol-> cholesterol
What is the target for the regulation of cholesterol synthesis?
HMG CoA reductase in the membrane of the ER
What inhibits HMG CoA reductase?
statins: lovastatin, simvastatin, pravastatin, atorvastin
What are statins used for?
to reduce cholesterol levels significantly (20-60%), prevent CV disease
What are statins?
strong competitive inhibitors of HMG CoA reductase (rate limiting reaction in cholesterol biosynthesis)
Hypocholesterolemic action also due to increase in SREBP maturation which leads to ____ and subsequent enhanced _____ via LDL receptor mediated ____
transcription of LDL receptor; clearance of cholesterol; endocytosis
What are myotoxic side effects? What causes this?
statin-mediated myopathy caused by depletion of muscle levels of ubiquinone (CoQ 10) and resultant impairment of mitochondrial function. inhibitors of squalene synthase (sequalestatins) increase levels of CoQ10.
What is the fate of cholesterol?
- packaged into VLDL and released into blood
- All tissues: cholesterol incorporated into cellular membranes
- liver: cholesterol used to synthesize bile acids
- adrenal glands, ovaries, testes: cholesterol used to synthesize steroid hormones
- skin: cholesterol used to synthesize vitamin D
What is cholesterol synthesis directly inhibited by?
- free fatty acids
- bile acids
- oxysterols
- statins
What covalent modification inactivates HMG CoA reductase?
phosphate inactivates
What conditions inactivate HMG CoA reductase?
- low energy
- high AMP
activates AMPK, phosphorylates enzyme
Does insulin activate or inactivate HMG CoA reductase?
activates by dephosphorylation
Does thyroxine activate or inactivate HMG CoA reductase?
inactivates by preventing dephosphorylation
Does glucagon activate or inactivate HMG CoA reductase?
inactivates by preventing dephosphorylation
Describe the transcriptional control of HMG CoA reductase
binding of transcription factors to promoter on the HMG CoA reductase gene increases its mRNA levels
Describe translational control of HMG CoA reductase
protein synthesis level
-reduced by gamma tocotrienol (member of vitamin E family) and oxylanosterols
Describe the post-translational control of HMG CoA reductase
protein turnover/degredation
-enhanced by sterols, oxysterols, and gamma tocotrienol
What is the family of transcription factors for HMG CoA reductase called?
sterol regulatory element binding protiens (SREBP)
What is the gene in the promoter for HMG CoA reductase?
sterol regulatory element (SRE)
What are late stage inhibitors of cholesterol synthesis?
- antimycotics (miconazole, ketoconazole) inhibit formation of ergosterol
- antiestrogens (triparanol, progesterone, tamoxifen) prevent conversion of desmoterol to cholesterol
- epileptogenic drug inhibits conversion of squalene to lanosterol and impairs cholesterol trafficking
- antipsychotic drugs (haloperidol, clozapine) induce dyslipidemia
What enzyme can degrade the sterane ring of cholesterol
NONE
cholesterol is converted to bile acids and stored in bile
some cholesterol and bile are excreted in feces
What is bile made from?
- bile acids
- bile salts
- cholesterol
- phospholipids
- fatty acids
- proteins
- bile pigments
- inorganic salts
What do bile acids and bile salts help in?
- emulsification of fats
- absorption of fat soluble vitamins
- digestion and absorption of fats
- prevention of cholesterol precipitation and its elimination
What are bile acids and bile salts synthesized from?
hepatic cholesterol
Where are bile salts and bile acids made? What is the process?
- made in hepatocytes
- released into bile canaliculi
- stored and concentrated in gallbladder
- released into duodenum in response to food
What is the commited step in the synthesis of bile acids?
cholesterol –7 alpha hydroxylase –> 7 alhpa hydroxycholesterol
What are the steps in the synthesis of bile acids?
cholesterol –> 7 alpha hydroxycholesterol –> chenodeoxycholic acid OR cholic acid after oxydation of side chain
coagulation of bile acids
cholic acid–>cholyl CoA pKa 6 –(Taurine) –> Taurocholic acid pKa 2
cholic acid–>cholyl CoA pKa 6 –(Glycine)–>glycocholic acid pKa4
primary bile acids and primary conjugated bile acids
chenodeoxycholic acid –glycine–>glycochenodeoxycholic acid
chenodeoxycholic acid –taurine–>taurochenodeoxycholic acid
cholic acid –taurine–>taurocholic acid
cholic acid –glycine–>glycocholic acid
What is the protonated form?
acid
What is the deprotonated form?
salt
What are primary bile salts used for?
in the duodenum to emulsify dietary lipids to aid in their digestion and absorption
What do bacteria do to primary bile salts?
bacteria deconjugate and dehydroxylate primary bile salts into primary and secondary bile acids, which are absorbed by the ileum and are then
- excreted in feces (5%)
- recycled to the liver via enterohepatic circulation (95%)
What are examples of secondary bile acids?
- deoxycholic acid derived from cholic acid
- lithocholic acid derived from chenodeoxycholic acid
What do non-absorbable bile-acid binding resins such as cholestyramine cause?
large increase in excretion of bile acids
What increases the rate of bile acid synthesis?
induction of 7-alpha hydroxylase
What are gallstones?
-crystals made up of bile supersaturated with cholesterol
What is 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 what?
malabsorption syndromes (steatorrhea) and deficiency in fat soluble vitamins
What reduces cholesterol secretion into bile?
oral administration of Ursodeoxycholic acid (secondary bile acid) dissolves small/medium sized stones
What are metabolites?
compounds made in the body (intermediates and/or end products of metabolism)
What are xenobiotics?
compounds ingested from outside (with no nutritional value, potentially toxic)
- pharmacological agents
- recreational drugs
- compounds of food (additives, processing)
What are phase I reactions of inactivation of detoxification of xenobiotics?
polarity is increased
What are phase II reactions of inactivation and detoxification of xenobiotics?
functional groups are conjugated for safe excretion
What are inactivation and detoxification of xenobiotics catalyzed by?
cytochrome P450 (CYP) enzymes
What are examples of phase I reactions?
- reductions
- oxidations
- hydroxylation
- hydrolysis
What are examples of phase II reactions?
- conjugation
- sulfation
- methylation
- glucuronidation
What are cytochrome P450 enzymes?
- superfamily of proteins containing heme
- colocalize with cytochrome P450 reductase
- play a key role in metabolism of multiple hydrophobic compounds
- operate via electron transfer system
- inducible by their substrate
- 12 gene families
- CYP1, CYP2, CYP3 responsible for drug metabolism
What is the effect of agents that inhibit CYP?
cause increase in drug levels in plasma
What is the effect of agents that stimulate CYP?
cause decrease in drug levels in plasma
What are the toxiic effects of statins?
- myopathy
- rhabdomyolysis
What are examples of CYP inhibitors?
itraconozole, clarithromycin, cyclosporine, citrus juices, grapefruit juice
What are examples of agents that induce CYP?
rifampicin, carbamazepine, St. John’s Wort
What are some diseases of the liver?
-hepatits
-jaundice
-viral hepatitis
-alcohol - induced hepatitis
-drug induced hepatitis
=liver cirrhosis
What is a major change of the liver with disease?
-normally leaky basement membrane btwn endothelial cells and hepatocytes replaced by high density membrane containing fibrillar collagen
-spaces btwn endothelial cells and fenstrations in plasma membrane lost
-increased stiffness of hepatic vascular channels offers resistance to free flow of blood through liver
-elevated intra-sinusoidal fluid pressure
PORTAL HTN
IMPAIRMENT OF FREE EXCHANGE OF MATERIAL BTWN HEPATOCYTES AND BLOOD
What are some tests for assessment of liver function?
- albumin
- transaminases: ALT and AST
- alkaline phosphatase
- lactate dehydrogenase
- urea BUN
- ammonia
- prothrombin time (PT)
- TAG levels
- cholesterol levels
- bilirubin levels
- serum glucose
