Liver Biochem Flashcards
Blood flow through the liver
O2 rich blood flows IN through hepatic artery
Nutrient rich blood flows IN through portal vein
Blood flows OUT through 3 hepatic vv. into IVC
Blood entering liver from hepatic arteries and portal vein mixes as it enters ________ which parallel bile ducts (with opposite direction of flow).
Sinusoids
Sinusoids are lined by _______ cells which have tiny gaps between them leading to ________ which line the bile canaliculi
The sinusoids lead to the ______ vein
Endothelial; hepatocytes
Central hepatic
Which cell type makes up most of the adult liver and conducts most liver functions
Hepatocytes
Which liver cell type lines bile ducts, controls bile flow rate, and bile pH?
Cholangiocytes
What liver cell type is a specialized macrophage?
Kupffer cells
What liver cell type maintains the EC matrix, stores retinol, and aids liver regeneration and fibrosis?
Stellate cells
What liver cell type forms the vasculature and facilitates open communication of blood with hepatocytes?
Endothelial cells (sinusoidal endothelial cells specifically)
What are pit cells?
Liver-specific NK cells
Functions of the liver in terms of carb metabolism
Glycolysis
Glycogenesis and glycogenolysis
Gluconeogenesis
Glucostasis
Functions of the liver in terms of lipid metab
Biosynthesis and export of TAGs, phospholipids, steroids (cholesterol, bile acids, bile salts), lipoproteins
Degradation of TAG and plasma lipoproteins
Regulation of free fatty acids
Breakdown of free fatty acids via beta ox
Functions of the liver in general
Carb metabolism Lipid metabolism Nucleotide biosynthesis Blood protein synthesis Amino acid metabolism Bilirubin metabolism Wate management (metabolites and xenobiotics)
What types of blood proteins are made in the liver?
Albumin IgG Apoproteins Fibrinogen Prothrombin Blood coagulation factors Antichymotrypsin (APP)
T/F: the liver has abundant tight junctions and basement membrane between endothelial cells and hepatocytes to allow strict regulation of exchange
False! No tight junctions or basement mebrane to allow GREATER access and increased contact between liver and blood
Describe cellular characteristics of hepatocytes
Well developed PM with endocytic/exocytic system
Well developed ER (smooth and rough)
Metabolically active with large # of endosomes, mitochondria, and lysosomes
3 ______ are used to generate _________, a 5-carbon building block for the synthesis of all isoprenoids, including steroids and lipid soluble vitamins as well as prenyl groups that attach proteins to plasma membrane
Acetyl CoA; isopentenyl pyrophosphate (IPP)
Acetyl coA is generated in the mitochondria from various pathways such as oxidative decarboxylation of _______, beta oxidation of _______, or breakdown of _______
It is transported into _____ via the citrate shuttle
Pyruvate; fatty acids; amino acids
Cytoplasm
Six units of IPP form a tetracyclic ______ ring which is the backbone of most steroids
Sterane
Cholesterol is an allicyclic compound made up of 4 fused _____ rings, a ______ chain, and a hydroxyl group at C___
It has _____ carbons total
Sterane; hydrocarbon; 3
27
Precursor of bile acids, bile salts, vitamin D, steroid hormones like progesterone, aldosterone, cortisol, testosterone, or estradiol
Cholesterol
How is cholesterol biosynthesis regulated by dietary intake?
Inverse relationship!
The less you consume, the more the liver will make
Cholesterol requires many resources to make, what are some of the “ingredients” to make cholesterol?
18 Acetyl CoA
18 ATP
16 NADPH
During phase 1 of cholesterol synthesis, acetoacetyl coA is converted to ______ via ______ enzyme
That product is then converted to _______ via ______ enzyme, which is rate-limiting
HMG CoA; HMG CoA synthase
Mevalonate; HMG CoA reductase
What are positive vs. nevative regulators of the rate limiting enzyme HMG CoA reductase in phase 1 of cholesterol synth
Positive: insulin, thyroxine
Negative: glucagon, sterols, high AMP, vitamin E, statins
In phase II of cholesterol synthesis, 6 mevalonate-derived IPPs are converted to squalene, then lanosterol, then cholesterol via a series of many steps. Of note are the negative regulators of lanosterol —> cholesterol. What are these late-stage inhibitors of cholesterol synthesis?
Antifungal meds, anti-estrogen meds, anti-epileptic drugs
HMG CoA reductase is the target for regulation of cholesterol synthesis
It is a transmembrane protein in the _____ of the cell with its catalytic domain on the ______ side
ER; cytosol
_____ = strong competitive inhibitors of HMG CoA reductase d/t much higher affinity than HMG CoA.
Its hypocholesterolemic action is also d/t an increase in SREBP maturation which leads to _______ transcription of LDL receptor and subsequent ______ clearance of cholesterol via LDL receptor mediated endocytosis
Consequently, there is ______ translation of the HMG CoA reductase protein
Statins
Increased; enhanced
Increased
What are the myotoxic side effects of statins? Why are these significant?
Decreased formation of ubiquinone (CoQ 10) and prenylated proteins
Ubiquinone is needed to make quinol, and formation of heme A is also impaired
Prenylated proteins are needed to attach proteins to their substrates in cell membranes
Fate of cholesterol in all tissues
Incorporated into cellular membrane
Fate of choleserol in liver
Used to synthesize bile acids or packaged into VLDL and released into blood
Fate of cholesterol in adrenal glands, ovaries, and testes
Used to synthesize steroid hormones
Fate of cholesterol in skin
Used to synthesize vitamin D
Methods of regulation on cholesterol synthesis
Regulated via effects on HMG coA reductase by:
- direct inhibition
- covalent modificaiton (hormones)
- transcriptional control
- translational control
- posttranslational control
What enzyme degrades the sterane ring of cholesterol?
NO ENZYME CAN DEGRADE IT
Most cholesterol is converted to bile acids and stored in bile
The synthesis of bile acids begins with cholesterol which is converted to ____________ by 7-alpha hydroxylase, a reaction which gives off/recycles _________
7-alpha hydroxycholesterol; cytochrome P450
After cholesterol is converted to 7-alpha hydroxycholesterol, it is converted to ____and _____ which are bile acids
Chenodeoxycholic acid; cholic acid
In the conjugation process of cholic acid, a bile acid, it is converted to cholyl CoA, which can be converted to ______ and/or ______, which can then be converted to ____ or ______ (respectively)
Taurine; glycine; taurocholic acid; glycocholic acid
What is the pKa difference between cholyl CoA, taurocholic acid, and glycocholic acid?
Cholyl coA = 6
Taurocholic acid =2
Glycocholic acid = 4
If someone cannot tolerate statins, what is the next drug of choice for lowering cholesterol? What is its MOA?
Bile acid-binding resins like cholestyramine
These cause a large increase in excretion of bile acids which increases the rate of bile acid synthesis via induction of 7ahydroxylase. This leads to a depletion of the liver cholesterol pool as well as an increase in hepatic uptake of LDL cholesterol from serum by receptor mediated and receptor independent mechanism
Gallstones are made up of cholesterol-based crystals. _____ = insufficient secretion of bile salts or phospholipids or excess cholesterol secretion
Cholelithiasis
What may result from chronic disturbance in bile salt metabolism?
Steatorrhea and deficiency in fat soluble vitamins
The liver is the primary site for degradation of metabolites as well as ________, which are compounds ingested from outside with no nutritional value and are potentially toxic such as pharm agents, rec drugs, or food additives
Xenobiotics
General scheme of xenobiotic detoxification
Phase 1 reactions increase polarity by reducing/oxidizing/hydroxylating/hydrolyzing to get a primary metabolite
Phase 2 reactions conjugate primary metabolite via sulfation/methylation/glucuronidation etc. to a secondary metabolite suitable for excretion
Cytochrome p450 enzymes are ____containing proteins that co-localized with cytochrome p450 reductase. They are inducibleby their substrate.
____, ____, and ____ are responsible for drug metabolism d/t their broad specificity
Heme
CYP1, CYP2, and CYP3
Agents that inhibit CYP will have what effect on statin levels in plasma?
Inhibition of CYP causes increase in statin levels in the plasma, leading to toxic side effects of myopathy and rhabdomyolysis
[inhibitors include antifungals, clarithromycin, cyclosporine, grapefruit juice]
Drinking grapefruit juice while taking statin can lead to potentially devastating side effects. This is caused by a component of grapefruit juice doing which of the following?
A. Interfering with the hepatic uptake of statins
B. Accelerating the conversion of statins to a more toxic form
C. Inhibiting the inactivation of statins
D. Upregulating the HMG CoA reductase
E. Downregulating the HMG CoA reductase
C. Inhibiting the inactivation of statins
What types of nutrients are stored in the liver in excess?
Glucose
Vitamin A
Vitamin D
Iron
Some toxic substrates acted on by the liver are lactic acid, hydrogen peroxide, and ammonia. How are these dealt with?
Lactic acid from cellular respiration is detoxified to glucose
Hydrogen peroxide from FA metabolism is detoxified to hydrogen and oxygen
Ammonia from amino acid metab is detoxified to urea
Fairly predictable changes occur in the various metabolic pathways of lipid metabolism in patients with moderately advanced hepatocellular disease. Which of the following would you expect to see under these conditions?
A. Increased activity of plasma lecithin cholesterol acyltransferase (LCAT)
B. Serum cholesterol esters are increased
C. Hepatic triglyceride lipase activity is increased
D. Serum triacylglycerols are increased
E. Serum non-esterified FA levels are decreased
D. Serum triacylglycerols are increased
Because of reduced hepatic triglyceride lipase activity
T/F: endogenous production of cholesterol can be inhibited at multiple steps
True; statins inhibit HMG coa reductase; lapaquistat inhibits squalene synthase
Much of statin myopathy may be caused by depletion of muscle levels of ubiquinone (CoQ10) and resultant impairment of mitochondrial function. Inhibitors of ______ ______ should increase levels of CoQ10 by shunting
Squalene synthase
HMG CoA reductase inhibitors (statins) are the most effective drugs available for reducing LDL levels. Statins cause several downstream effects by inhibiting the RL step in hepatic cholesterol synthesis. What is the primary effect of statins on hepatocytes?
A. Decrease hepatic production of LDL
B. Decrease production of triglycerides
C. Downregulation of cell surface LDL receptors
D. Increase production of HDL
E. Upregulation of cell surface LDL receptors
E. Upregulation of cell surface LDL receptors
What are the 2 main safe ways of metabolizing acetaminophen?
Glucuronidation —> renal excretion
Sulfation —> renal excretion
[note that acetaminophen can also be excreted in an unchanged state]
Describe the CYP450 pathway for acetaminophen metabolism
Metabolized to NAPQI (a toxic product) which can then be conjugated with glutathione to APAP-mercaptate for safe renal excretion
What happens to acetaminophen metabolism in overdose?
Safe metabolism gets overwhelmed, so it is no longer glucuronidated or sulfonated. It is converted via CYP450 to toxic NAPQI, and eventually stores of glutathione are diminished so the toxic product binds other hepatic macromolecules and hepatic necrosis ensues
Which of the following characteristics of cytochrome P450 enzymes is correct?
A. They are all found in golgi apparatus and are referred to as microsomal enzymes
B. They all contain a flavin-containing reductase unit that uses NADH and not NADPH as a source of electrons
C. They are all inducible by oxygen, which binds to the iron of the cytochrome
D. They all oxidize the substrate on which they act
E. They all generate a free radical compound as a final product of the reaction
D. They all oxidize the substrate on which they act
They require NADPH and are located in the ER membrane. Oxygen does not induce all cytochrome p450 members, and although they proceed via free radical mechanism, that is not the final product
After a 2-week alcohol binge, a patient ingested some tylenol to help with a headache. She took 3x the suggested dose because of the severity. Within 24 hrs she became very lethargic, vomited frequently, and developed severe abdominal pain. The symptoms this patient is developing are due to which of the following?
A. Hypoglycemia
B. Ethanol induced inhibition of tylenol metabolism
C. Hyperglycemia
D. Ethanol induced acceleration of tylenol metabolism
E. Acetaminophen inhibition of VLDL secretion by the liver
D. Ethanol induced acceleration of tylenol metabolism
Ethanol induces the CYP system which converts acetaminophen to NAPQI, the toxic intermediate
