5 Liver Biochemistry Flashcards
Cell types of the liver and fx of each (5)
Hepatocytes: main cell; metabolically active with rough ER
Cholangiocytes: line bile ducts; control bile flow rate and bile pH
Endothelial cells: line the sinusoids; allow exchange of material
Kupffer cells: macrophages
Hepatic stellate cells: storage of lipids; full of vitamin A; aid in contractility of the liver
Pit cells: NK cells; protect against viruses and tumor cells
Functions of the liver
Primary receiving, monitoring, synthesizing, modifying, distribution, and recycling center (detoxification)
Bile is secreted into the ____ in the liver.
Liver divided into lobes separated by what?
Sinusoids are in direct contact with the ____.
Bile canaliculi
Sinusoids
Hepatocytes
Carbohydrate metabolism of the liver
Glycolysis
Glycogenesis
Glucogenolysis
Gluconeogenesis
Glucostasis***: maintains a constant glucose level during fed/fasting/starvation (ketone bodies) states
Lipid metabolism of the liver
Biosynthesis and export of triacylglycerols, phospholipids, steroids (cholesterol, bile acids, bile salts), lipoproteins (VLDL, LDL, HDL)
Degrade TAG and plasma lipoproteins
Maintain concentration of free fatty acids (FFA)
Breakdown FFA by beta oxidation to release energy
Nucleotide biosynthesis
Synthesis of blood proteins like ____.
Amino acid metabolism by _____.
Bilirubin metabolism: RBC release ____ converted to _____.
Albumin, IgGs, apoproteins, fibrinogen, prothrombin, blood coagulation factors, C-reactive protein, antitrypsin, antichymotrypsin (acute phase proteins)
Degradation of AA; converting ammonia to urea
Hemoglobin; bilirubin
Waste management of the liver
Inactivation and detoxification of metabolites and xenobiotics
Liver lacks ____ junctions and basement membrane between hepatocytes and ____ cells.
Why?
Tight
Endothelial
Allow greater access and increased contact between liver and blood
5 carbon compound derived from three acetyl CoA
Fx?
Isoprenoid (IPP)
Serves a as building block for synthesis of isoprenoids like steroids, lipid-soluble vitamins, phenyl groups that attach proteins to plasma membrane
Sources of acetyl CoA
Generated in the ____.
Transported into the cytoplasm by ____ shuttle.
Oxidative decarboxylation of pyruvate
Beta oxidation of FA
Breakdown of AA
Mitochondria
Citrate shuttle
What forms the backbone of the steroids?
Six units of IPP form a tetracyclic (4-ring) sterane ring
Cholesterol is a component of the ____ membrane.
Synthesize what?
Produced by what?
Biosynthesis of cholesterol is regulates by ____.
Plasma
Bile acids and bile salts, vitamin D, steroid hormones
Liver, SI, adrenal cortex, ovaries, testes, skin
Dietary intake
Phase 1 of cholesterol synthesis of cholesterol begins with two ____.
Acetoacetyl-CoA to HMG-CoA by ____.
What is the rate limiting step?
Mevalonate to ____.
Acetyl-CoA
HMG CoA synthase
HMG-CoA to Mevalonate by HMG CoA reductase***
IPP
What is the target for the regulation of cholesterol synthesis?
By what class of drugs?
What do they do?
Examples?
HMG-CoA reductase (rate limiting step)
Statins
Lower cholesterol by inhibiting HMG-CoA reductase
Lovastatin, simvastatin, pravastatin, atorvastatin
Inhibitory effect of statins on cholesterol also caused increased transcription of the ____ receptor.
Caused enhanced clearance of _____ by LDL-receptor mediated endocytosis.
Mytotoxic side effects of long-term statin use are decreased formation of ____.
LDL
Cholesterol
Ubiquinone (CoQ) and prenylated proteins—> can cause myopathy and rhabdomolysis)
Late stage cholesterol synthesis inhibitors include _____ that treat fungal infections.
How do they inhibit cholesterol synthesis?
Antimycotics including miconazole, ketoconazole
Inhibit enzyme converting lanosterol to cholesterol
_____ is eliminated by being converted to bile acids and bile salts which form ____ that increase the ____ of lipids exposed to lipases.
Hepatic cholesterol
Strong detergents (micelles)
Surface area
HMG CoA reductase is enhanced by ____.
Inhibited by ____.
Insulin, thyroxine
Glucagon, sterols, high AMP, vitamin E, statins
Synthesis of bile acids begin with conversion of cholesterol to 7 alpha-hydroxycholesterol by ____ which is dependent on ____.
7 alpha-hydroxylase (rate limiting step***)
Cytochrome P450
Addition of OH groups to 7 alpha-hydroxycholesterol forms ____.
These acids have a ____ pKa that is protonated and insoluble in the duodenum.
Need to be ____ to become soluble.
Chenodeoxycholic acid and cholic acid
High
Conjugated
Conjugation of bile acids leads to better what?
Why?
What AA aid in the conjugation of bile acids?
Emulsifiers
Conjugation lowers the pKa so that the acids are now ionized and soluble in the duodenum and can emulsify.
Taurine and glycine
Bile salts are reabsorbed and returned to the liver for ____.
____ deconjugate and dehydroxylate bile salts.
Recycling
Gut bacteria
Cholesterol lowing drug that is a non-absorbable bile-acid resin; can be used instead of statins.
Causes a large increase in excretion of ____ (not absorbed by enterocytes); therefore _____ the rate of bile acid synthesis by induction of _____.
Cholestyramine
Bile acids
Increases
7 alpha hydroxylase
Crystals made of bile supersaturated with cholesterol
Insufficient secretion of bile salts of phospholipids or excess cholesterol secretion
Treatment?
Gallstones
Cholelithiasis
Ursodeoxycholic acid (secondary bile acid) that reduces the cholesterol secretion into bile and dissolves small stones.
Disturbance in bile salt metabolism leads to ____.
Malabsorption syndromes (steatorrhea), deficiency in fat soluble vitamins
Liver is the site for degradation of ____ and ____.
Metabolites: compounds made in the body (end products of metabolism)
Xenobiotics: compounds ingested from the outside (pharm agents, drugs, food additives)
Two phases and fx of inactivation and detoxification of xenobiotics
By what enzymes?
Phase 1: increase the polarity to make a primary metabolic
Phase 2: conjugate the functional groups to make a secondary metabolite and make them less reactive and safe for excretion
Cytochrome P450 enzymes (CYP)
Processes of phase 1 and phase 2 of xenobiotic detoxification
1: Reduction, oxidation, hydroxylation, hydrolysis
2: Conjugation, sulfation, methylation, glucuonidation
Cytochrome P450 is a ____ protein that binds to the ___ itself.
What transfers the electron?
All cytochrome P450 enzymes do what?
Heme containing protein
Drug
Cytochrome P450 reductase
Oxidize the substrate on which they act
Function of CYP
What inhibits CYP?
What activate CYP?
Detoxify pharmacological agents (inactivated statins)
Itraconozole, clarithromycin, cyclosporine, citrus juices, grapefruit juice (inhibit the inactivation of statins/increase statin levels—> lead to toxic side effects of statin like myopathy and rhabdomyolysis***)
Rifampicin, carbamazepine, St. John’s wort (decrease statin levels)
The majority of blood plasma proteins include what?
Albumin and fibrinogen
What is the primary effect of statins on hepatocytes?
Why?
Upregulation of cell surface LDL receptors
Statins decrease cholesterol synthesis. Decreased cholesterol causes upregulation of LDL receptors to increase LDL uptake.
Cholesterol synthesis can be inhibited at the synthesis of squalene by inhibiting squalene synthase with ____.
Lapaquistat
Statins inhibit the formation of cholesterol, but also inhibit the formation of what substances?
t-RNA, ubiquinone, heme A, Ras
Cholesterol ___ 7 alpha-hydroxylase
Bile acids ____ 7 alpha-hysroxylase
Affect of cholestyramine?
Activates
Inhibits
Prevents bile acids form being recycled; less bile means less inhibition (enhance breakdown of cholesterol into bile acids)
Ethanol can induce ____ of Tylenol metabolism.
How?
Acceleration
Ethanol induces CYP; when excessive NAPQ is produced from overconsumption of acetaminophen, NAPQ is not readily detoxified; it binds to proteins and inactivates them, leading to hepatocyte death (hepatotoxicity)
