Biochemistry Flashcards
What is well developed in hepatocytes?
ER system; smooth for lipids and rough for proteins
Give a brief description of each of the following cells types: hepatocytes, endothelial cells, kupffer cells
- hepatocytes: carry out most metabolic functions of liver
- endothelial cells: allow exchange of materials between hepatocytes and blood
- kupffer cells: macrophages that line sinusoids and protect the liver from gut derived microbes
Give a brief description of each of the following cell types: hepatic stellate cells, pit cells, cholangiocytes
- hepatic stellate cells: storage site for vitamin A and other lipids
- pit cells: NK cells that protect against viruses and tumors
- cholangiocytes: line bile ducts, control bile flow rate and bile pH
Why does the liver have low portal blood pressure?
maximizes access of blood to hepatocytes - more time to take up nutrients
What is used to make a 5C isopentenyl pyrophosphate (IPP)?
3 acetyl CoA (2C compound)
What does IPP serve as the building block of?
isoprenoids
What are 3 examples of isoprenoids?
- steroids (cholesterol, bile acids, hormones)
- lipid soluble vitamins (ADEK)
- ubiquinone
What do 6 IPP molecules form?
tetracyclic (4 ring) sterane ring -> backbone of most steroids
Which carbon of a cholesterol compound has a hydroxyl group (OH)?
C3
What is cholesterol a precursor for (3)?
- bile salts and acids
- vitamin D
- steroid hormones
How are cholesterol biosynthesis and dietary intake related?
inversely proportional; if you ingest less cholesterol, your body makes more
What is the main purpose of the 2 phases of cholesterol synthesis?
phase 1: acetyl CoA -> IPP
phase 2: IPP -> cholesterol
What are the 5 intermediates of phase 1 of cholesterol synthesis?
acetyl CoA -> acetoacetyl CoA -> HMG CoA -> mevalonate -> IPP
What is the rate limiting step of cholesterol synthesis? What targets this step?
- HMG CoA reductase: HMG CoA -> Mevalonate
- targeted by statins
What are the 4 intermediates of phase 2 of cholesterol synthesis?
IPP -> squalene -> lanosterol -> cholesterol
What do azoles (antimycotics) inhibit?
inhibit fungal formation of cholesterol; can inhibit mammalian production at high doses and long term use (blocks lanosterol -> cholesterol)
How do statins work?
competitive inhibitors of HMG CoA reductase (rate limiting step) and lead to maturation of SREBP that transcribe LDL receptor that internalize cholesterol from plasma
What effect do statins have on ubiquinone (CoQ 10)
ubiquinone has a role in ETC in mitochondria -> long term statin use causes depletion of muscle levels of ubiquinone (fatigue)
What is the fate of cholesterol in the GI tract?
used to synthesize bile acids
What activates HMG CoA reductase?
insulin
What inhibits HMG CoA reductase?
thyroxine, glucagon, sterols, high AMP, vitamin E, statins, phosphorylation
What are SRE, SREBP, and SCAP?
- SRE - promotor of HMG CoA reductase
- SREBP - transcription factor
- SCAP - SREBP activating protein
Explain transcriptional control of HMG CoA reductase
- in cholesterol present, SREBP-SCAP bind to INSIG in ER
- when cholesterol absent, SREBP-SCAP released form ER -> cleaved to mature SREBP -> binds to SRE to promote cholesterol synthesis
What does ketoconazole do?
inhibits 7-a hydroxylase which is the RLS of the pathway that converts cholesterol to bile acids
What do epileptogenic drugs do?
inhibit conversion of squalene to lanosterol and impairs cholesterol trafficking
What is used to form bile acids and bile salts? Where are they synthesized?
hepatic cholesterol is used; made in hepatocytes
What is the rate limiting step in the synthesis of bile acids?
7a-hydroxylase: adds a 2nd -OH group to cholesterol
What are the 2 primary bile acids produced by hepatocytes?
cholic acid (3 OHs); chenodeoxycholic acid (2 OHs)
What 2 amino acids conjugate w/ bile acids?
Taurine and Glycine
What does it mean when a bile acid has a lower pKa?
lower pKa makes them more ionized and better at emulsifying fats in the small intestine (lower pH than small intestine)
What are the primary conjugated bile acids made from cholic acid?
glycocholic acid; taurocholic acid
What are the primary conjugated bile acids made from chenodeoxycholic acid?
glycochenodeoxycholic acid; taurochenocdeoxycholic acid
How are secondary bile acids made? What are the 2 secondary bile acids and what do they derive from?
- produced when bacteria in the gut deconjugate primary bile salts into secondary bile acids
- deoxycholic acid (from cholic acid)
- lithocholic acid (from chenodeoxycholic acid)
What do resins such as cholestryamine do?
bind to bile acids and make them non-absorbable -> cause large increase in excretion of bile acids in feces
How do resins result in lower plasma cholesterol levels?
more bile acids excreted -> rate of bile synthesis increases -> deplete liver cholesterol pool -> increase in hepatic uptake of LDL -> lower plasma cholesterol levels
What causes cholelithiasis?
insufficient secretion of bile salts or phospholipids into gallbladder or excess cholesterol secretion into bile
Metabolites vs Xenobiotics
- metabolites: compounds made in the body (intermediates or end products of metabolism)
- xenobiotics: compounds ingested from outside (pharmacologic agents, recreational drugs, food additives)
Explain the detoxification process of xenobiotics
- phase 1 reactions create a primary metabolite (more polar) using cytochrome P450 enzymes
- phase 2 reactions add a functional group to metabolite and conjugate it for safe excretion
What catalyzes the detoxification process for xenobiotics?
cytochrome P450 (CYP) enzymes -> helps make drugs more polar
What will be the effect of agents that inhibit and stimulate CYP?
- agents that inhibit CYP will increase drug levels
- agents that stimulate CYP will decrease drug levels
Heredity of Crigler Najjar syndrome? What enzyme is affected in this disease and type of bilirubin that builds up`?
AR; UGT1A1; uncojugated
What is the function of UGT1A1?
adds a sugar to bilirubin to conjugate it (makes it more polar and easily excreted)
Crigler Najjar Type I vs Type II
Type I: UGT1A1 completely absent - sx at birth - lethal
Type II: some UGT1A1 activity - survive to adulthood
What is kernicterus?
when uncojugated bilirubin builds up in brain; poor development/mental function; seen in crigler najjar type I
What is the tx for Crigler Najjar Type I and II?
Type I: plasmapheresis; liver transplant
Type II: phenobarbital (UGT1A1 inducer)
What is the cause of Gilbert’s syndrome? Type of bilirubin that builds up?
defect in gene promotor for UGT1A1; unconjugated
What generally causes flair ups of Gilbert’s syndrome?
fasting, stress, EtOH intake
What is the treatment for Gilbert’s syndrome?
no treatment needed; avoid irinotecan (anti-cancer drug detoxed by UGT1A1)
What is mutated in Dubin-Johnson syndrome and what is its funciton? What is the hallmark of Dubin-Johnson syndrome?
MRP2 -> moves conjugated bilirubin from hepatocytes to bile; hallmark = black liver
What is mutated in Rotor’s syndrome and what is its function? What sx is seen in Rotor’s syndrome and why?
Mutations in both OATP1B1 and OATP1B3 -> move bilirubin from blood into hepatocytes; bilirubinuria seen -> bilirubin backs up in blood and is excreted in urine
Urine coproporphyrin levels in Rotor’s and DJS?
- elevated in Rotor’s
- normal in DJS
What is mutated in Wilson’s disease and what is it’s function?
ATP7B -> transports copper from liver to bile -> accumulates in liver if not working
What is the function of ceruloplasmin?
transport protein for copper in blood -> free copper is toxic (similar to Fe)
What type of sxs are hallmark in Wilson’s disease?
CNS sxs: parkinson like sxs, hemiballismus (flailing of limbs), dementia
Kayser-Fleischer rings (multicolored concentric rings around irises)
What causes galactosemia? When in life is it seen?
deficiency in enzymes that transform galactose -> G6P (galactose builds up in blood) -> mainly GALT enzyme
- seen in newborns
What does fructokinase deficiency cause?
disruption of fructose metabolism -> fructosuria (fructose in urine)
What does aldolase B deficiency cause? How do pt’s present?
- causes build up of fructose and fructose 1-phosphate (damages liver and kidneys)
- pt’s have low serum levels of phosphorus and glucose
Von Gierke’s disease vs glycogen storage disease 1B?
- Von Gierke’s disease: deficiency of glucose 6 phosphatase (needed for release of glucose from liver)
- Glycogen storage disease 1B: deficiency is in transport protein that moves G6P to ER lumen where glucose 6 phosphatase is
What does PEPCK deficiency cause?
cannot catalyze conversion of OAA to PEP in carbohydrate metabolism -> academia (high acid levels in blood)
