Liver Biochem Flashcards
What do you call the segments that make up hepatic lobes?
Hepatic lobules - shaped like hexagon
What structures do you find in a Hepatic Lobule?
At the center is a Central Vein
At the outside of the lobule, there are triads of vessels. they are Interlobular Arteries, Interlobular Veins, and Interlobular Bile Ducts
Interlobular Veins and Interlobualr Arteries joint together into a common vessel called a Hepatic Sinusoid (carries both portal vein blood and arterial blood) - this blood travels from the exterior of the lobule toward the central vein
Between the sinusoids are hepatocytes, which also surround Bile Canaliculi. The canalicui collect hepatocyte generated bile and send it to the exterior of the Lobule (to the Interlobular bile ducts; opposite the direction of blood flow)
What different cells types are found in the Liver?
Hepatocytes Endothelial cells Kupffer cells Hepatic Stellate Cells Pit cells (lymphocytes) Cholangiocytes
What are hepatocytes?
Liver cells that make up 80% of the organ, responsible for majority of metabolic functions, and are capable fof regeneration
What are liver endothelial cells?
Cells that allow for the exchange of materials between the blood and liver
Exchange occurs through pores and fenestrations (discontinous membrane)
What are Kupffer Cells?
Macrophages that protect the liver, have well developed endocytic/phagocytic function
Protect liver from gut derived microbes
Remove damaged/dead RBCs
Orchestrate immune response
Secret Cytokines
They are found in the sinusoid
What are Cholangiocytes?
Cells that form the bile ducts
They also control the bile flow rate and bile pH
What are Hepatic Stellate Cells?
Act as storage sites for Vitamin A and other lipids
Located in the Space of Disse
What are Pit Cells?
Natural Killer Cells (NTCs)
Protect liver against viruses and tumor cells
What is the space of disse?
Space between endothelial cells and hepatocytes
What are the main functions of the liver?
Primary Receiving, Distribution, and recycling center
Carbohydrate Metabolism
Lipid Metabolism - steroids, cholesterol, bile, bile salts
Nucleotide biosynthesis
Amino Acid Metabolism - Ammonia and Urea Cycle
Protein and Amino Acid Metabolism
Synthesis of Blood Proteins
Billirubin Metabolism
Waste Management
What are some unique features of liver-blood barrier?
Endothelial Cells have no basement membrane
There are no gap junctions between adjacent endothelial cells or between adjacent hepatocytes
There are gaps between endothelial cells
Apical membrane of endothelial cells is porous (fenestrations)
These features exist to allow greater access and increased contact between the liver and blood
What are isoprenoids?
Molecules that are precursors for steroids and lipid soluble vitamins
Isoprenoids are formed from IPP
What is IPP and how is it generated?
Isopentenyl Pyrophosphate is an isoprenoid precursor.
It is a five-carbon molecule formed from 3 Acetyl Coa molecules
What is a sterane ring and what is it generated from?
Sterane ring is the backbone of most steroids, including cholesterol
It is a tetracyclic molecule (4 rings)
it is formed from 6 IPP molecules
What are the components of a molecule of cholesterol
Sterane ring
Hydroxyl group (-OH) at C3
Eight-member hydrocarbon chain at C17
What is special about cholesterol?
It is very abundant
It is found in plasma membranes
it is the precursor of steroid hormones
It is the precursor for Vitamin D
Most importantly, it is the precursor for Bile and Bile salts
How many Acetyl CoA molecules does it take to make one molecule of Cholesterol?
16 molecules of Acetyl CoA
What is the first phase of Cholesterol synthesis, and what are the important steps/enzymes involved?
The first phase is the synthesis of IPP from 3 acetyl CoA moleucles
Acetyl CoA –> AcetoAcetyl CoA –> HMG-CoA –>Mevalonate –> IPP
(HMG = hydroxymethylglutaryl)
The rate limiting step is the reduction of HMG-CoA to Mevalonate
- The enzyme active during this step is HMG-CoA Reductase
The enzyme that converts Acetoacetyl CoA to HMG-CoA is HMG-CoA Synthase
What is the second phase of cholesterol synthesis, and what are the
The second phase is the synthesis of cholesterol
6 IPP –> Squalene (shark liver) –> Lanosterol –> Cholesterol
What is target of regulatory signals in cholesterol synthesis?
HMG-CoA reductase enzyme (rate-limiting step)
What are important features of HMG-CoA reductase?
It is an integral membrane protein found in the Endoplasmic Reticulum membrane
It passes through the membrane 8 times
It has two sites of Ubiquitination (sites where ubiquitin can bind, leading to the destruction of the enzyme)
Its catalytic domain is in the cytosolic side of the membrane
What do statins do?
They are cholesterol lowering drugs
They inhibit HMG-CoA reductase, preventing synthesis of cholesterol
All statins are named with “-statin” as a suffix
Ex: Simvastatin
They are STRONG COMPETITIVE INHIBITORS of HMG-CoA Reductase
What is a myotoxic effect of statin usage?
Statins block reduction of HMG-CoA reductase. This also prevents the generation of Ubiquinone (Coenzyme Q10, which is vital in ATP generation in the mitochondria), causing a depletion CoQ10 levels in muscle
How else can cholesterol levels be depleted aside from use of statins?
Hypocholesteromia can also be caused by an increase in SREBP (Sterol Regulatory Element Binding Protein) maturation.
SREBP promotes transcription of LDL receptor mediated endocytosis, which causes an increase in clearance of Cholesterol
How is HMG-CoA reductase regulated by Covalent modification?
When HMG-CoA reductase is in its phosphorylated form it is inactivated; when in dephosphorylated form it is activated
Low energy conditions, high cAMP promote phosphorylation (deactivation
Insulin (fed state) promotes dephosphorylation (activation)
Glucagon and Thyroxine PREVENT DEPHOSPHORYLATION; keeping the enzyme in its phosphorylated form (deactivated)
How is HMG-CoA reductase regulated by transcriptional control?
Transcription factors bind to promoter on HMG-CoA Reductase gene
mRNA levels increase
How is SREBP involved in transcriptional regulation of Cholesterol Synthesis during a low cholesterol state?
SREBP-SCAP complex in a low cholesterol state is translocated from the ER membrane to the Golgi.
At the golgi, the SREBP is cleaved from SCAP (integral membrane protein). The N-Terminus of SREBP is released and forms a dimer with another SREBP N-teminus forming a Transcription factor that binds and activates the HMG-CoA reductase gene.
How is SREBP involved in transcriptional regulation of Cholesterol Synthesis during a low cholesterol state?
SREBP-SCAP complex during a high cholesterol state remains in the ER membrane.
SREBP-SCAP complex becomes anchored to ER membrane by binding with INSIG integral membrane protein
In this state, transcription of cholesterol is very slow
What are antimycotics and what do they do?
Antifungal, also a late-stage cholesterol synthesis inhibitor
In mammals, it inhibits the enzyme that converts lanosterol to cholesterol
What are antiestrogens and what do they do?
Late stage cholesterol synthesis inhibitor
Prevents conversion of desmosterol to cholesterol
What are Epileptogenic drugs and what do they do?
Late stage cholesterol synthesis inhibitor
Prevents conversion of squalene to lanosterol; impairs cholesterol trafficking.
What are antipsychotic drugs and what do they do?
Late stage cholesterol synthesis inhibitor
induce dyslipidemia (increased cholesterol in blood)
How is cholesterol recycled in the liver?
Since NO ENZYME can degrade the sterane ring of cholesterol, it is converted into bile acids and stored in bile.
What do bile acids and bile salts do?
Helps emulsify fats
Helps with absorption of fat soluble vitamins
Helps with digestion and absorption of dietary fats
Helps with prevention of cholesterol precipitation
Helps with cholesterol elimination
What are important steps in the synthesis of bile acids from cholesterol?
Cholesterol is converted to 7-alpha-Hydroxycholesterol via 7alpha-hydroxylase enzyme
This is the committed step and the rate-limiting step. The cholesterol molecule (which already has a hydroxyl group on C3), gets a second hydroxyl group added to it on C7 thanks to 7alpha hydroxylase enzyme
Then a carboxylic acid group is added to the end of the hydrocarbon chain at C17 forming Chenodeoxycholic acid (2 hydroxyl groups; 1 carboxylic acid group)
Then Chenodeoxycholic acid can undergo oxidation (adding a Hydroxyl group) again at the other end of the hydrocarbon chain on C17, forming Cholic Acid (3 hydroxyl groups; 1 carboxylic acid group)
What is the purpose of forming conjugated bile acids, and how are they made?
Conjugated bile acids have a lower pka, and thus are more ionized. The more ionized the molecule, the greater the detergent effect.
Cholic acid has a CoA group added to it with the help of ATP, forming Cholyl CoA
Cholyl CoA can then be conjugated with wither Glycine or Taurine, forming Taurocholic Acid and Glycocholic Acid
Same occurs with Chenodeoxycholic Acid, forming Glycochenodeoxycholic Acid and Taurochenodeoxycholic Acid
How do bile acids and conjugated bile acids become bile salts?
De-protonation of the carboxylic acid group
How are bile salts recycled?
Bile salts are used in the duodenum to emulsify lipids. While in the gut, bacteria will deconjugate and dehydroxylate the bile salts, forming primary and secondary bile acids.
These primary and secondary bile acids are ABSORBED BY THE ILEUM and will either ultimately be excreted in feces (5%) or recycled in the liver via enterohepatic circulation.
What are Bile Acid-Binding Resins?
A form of cholesterol-lowering drug.
Bile acid-binding resin is non-absorbable and binds to bile acids in the duodenum. This causes an increase in Bile acid excretion in feces.
The resulting decrease in reabsorbed bile causes 7alpha hydroxylase to increase the synthesis of bile using liver cholesterol, which eventually runs out.
Liver then proceeds to uptake circulating cholesterol, decreasing plasma cholesterol levels.
What is steatorrhea?
Excretion of abnormally large amounts of fat in the feces due to reduced ability to absorb fats.
What is cholelithiasis?
Insuffiecient secretion fo bile salts or phospholipids into the gallbladder, or excess of cholesterol secretion into the bile
Causes gallstones
What waste materials does the liver remove?
Metabolites (end products of metabolism)
Xenobiotics (ingested compounds with no nutritional value, potentially toxic)
What is the first phase of detoxification process?
The purpose is to increase the polarity of the molecule, producing a primary metabolite.
Involves Reduction, Oxidation, Hydroxylation, and Hydrolysis
What is the second phase of detoxification process?
The purpose of the second phase is to make the primary metabolite suitable for excretion. This is done so by conjugating the functional groups on the molecule, forming a secondary metabolite
Involves Conjugation, sulfation, methylation, and glucuronidation
What is Cytochrome P450?
It is a family of enzymes that contains heme
It co-localizes with a molecule called Cytochrome P450 Reductase (4 CYP : 1 CYPR)
Play a key role in metabolizing hydrophobic materials
CYP1, CYP2, and CYP3 are responsible for drug metabolism
What is the main function of Cytochrome P450 enzymes?
To detoxify pharmacological agents; including Statins
CYP inhibitors will increase plasma drug levels
CYP promoters will decrease plasma drug levels
What are some examples of CYP inhibitors?
Clarithomycin, Itraconozole, cyclosporine, citrus juices, and grapefruit juices
All of these substances will increase statin levels in plasma as well as other drugs
What are some examples of CYP promoters?
Rifampicin, carbamazepine, and St. Johns Wort
All of these substances will decrease Statin plasma levels as well as other drugs
What is hepatitis?
Inflammation of the liver; can be acute or chronic
Can be caused by infection, alcohol consumption, or drug use
What is Jaundice?
Excess of pigment, billrubin, causes yellowing of skin.
Can be due to Pre-hepatic condition, intra-hepatic condition, or post-hepatic condition
What is viral hepatitis?
Inflammation of the liver due to viral infection
Hepatitis A, Hepatitis B, Hepatitis C
What is liver cirrhosis?
Fibrosis of he liver lobules, is a clinical result of hepatitis.
Fibrosis can cause an increase in resistance to blood flow in the liver resulting in Portal Hypertension
