Metabolic functions of the liver Flashcards
What does the liver protect?
→ Major vessels from direct contact with dietary nutrients
How does the liver contribute to the removal of glucose?
→ regulating the flux into pathways that remove free glucose
How does the liver store glucose?
→ As glycogen
How does the liver restore blood glucose levels?
→ Glycogenolysis
→ Gluconeogenesis
What is the liver a major site of synthesis for?
→ Serum proteins such as albumin and blood clotting factors
What does the liver do to excess amino acids during gluconeogenesis?
→ Degrades them
What do glucogenic amino acids become?
→ Sugars
What do ketogenic amino acids become?
→ Ketone bodies
What does the liver do to amino acids?
→ Transaminate and deaminates them
What happens to ammonia in the liver?
→ Gets detoxified
Describe the glucose alanine cycle
→In the muscle, branched amino acids are taken and broken down.
→The carbon skeleton is used for energy production.
→ the NH4 can be used to convert to pyruvate to Alanine. Alanine is then exported into the blood and travels to the liver.
→ alanine is then converted to glutamate via transamination (reacting with α-ketoglutarate) also producing a pyruvate.
→The pyruvate can enter the gluconeogenic pathway to form glucose, and the glucose can be transported in the blood back to the muscle where it can be used for energy.
→The glutamate will then be used along with the CO2 generated to produce urea in the liver.
Where does synthesis of fatty acids take place?
→ In the cytosol of hepatocytes
Where is the cholesterol in the body made?
→ 50% made by the liver
→ rest is made in the intestines, adrenal cortex and reproductive tissue
What is cholesterol made from and what enzyme is used?
→ HMG- CoA reductase
→ Acetyle CoA is used
How is cholesterol transported from the liver as?
→ VLDL
How is cholesterol disposed of and why?
→ The body cannot degrade cholesterol
→ Disposed of by the biliary system as cholesterol or converted to bile acids or salts
What are the two routes of metabolism of ethanol?
→ Oxidation through alcohol dehydrogenase - 90%
→ Microsomal oxidation using cytochrome P450 - 10-20%
How much alcohol does the body metabolize per hour?
→ 10g
What is methanol metabolized to and why is this bad?
→ Formaldehyde
→ Toxic and associated with paralysis, loss of consciousness, blindness
What is the Km of ALDH2 ?
→ low
What are the symptoms for ethanol intolerance?
→ Vasodilation
→ Facial flush
→ tachycardia
→ Nausea
What is the consequence of alcohol metabolism not being regulated by negative feedback?
→ Large quantities of Acetyl CoA, NADH and ATP are formed
What are the pathways inhibited by the metabolism of ethanol?
→ Acetyl CoA, NADH and ATP are formed which inhibits glucose metabolism by inhibiting PFK and pyruvate dehydrogenase
→ NADH inhibits the TCA cycle
→ Acetyl CoA results in ketone body formation and stimulation of fatty acid synthesis
→ Fatty acids are esterified to TG to transport as VLDL
What does the second route of metabolism of ethanol involve?
→ Oxidation of ethanol by members of cytochrome P450 enzymes
What does the MESO system use?
→ NADPH which is needed for the synthesis of antioxidant glutathione
What happens to acetaldehyde with excess alcohol intake?
→ Acetaldehyde builds up
What happens in the liver if acetaldehyde builds up?
→ Reduction in secretion of both serum protein and VLDL
What can acetaldehyde enhance?
→ Free radical production
→ Leads to tissue damage such as inflammation or necrosis
How can cirrhosis cause death?
→ Ammonia accumulates resulting in neurotoxicity, coma and death
What are xenobiotics?
→ Compounds with no nutritional value
→ Plant metabolites
→ Drugs
→ Food additives
What compounds can be excreted easily in the urine?
→ Water compounds
What is the livers aim with xenobiotics?
→ Make them harmless
→ More readily disposed of
What are the three phases of xenobiotic metabolism?
→ Oxidation
→ Conjugation
→ Elimination
What does Phase I of xenobiotic metabolism do?
→ Oxidation is the most common modification there is also hydroxylation and reduction
→ Modification increases solubility
→ It introduces functional groups which enable participation in further reactions
Where are P450 enzymes found?
→ In the endoplasmic reticulum
What kind of proteins are P450 enzymes?
→ Haem proteins that are related to mitochondrial enzymes
What are P450 enzymes inducible by?
→ Their own substrates
Describe Phase II of xenobiotic metabolism
→ Modified by the addition of groups such as
→Glutathione
→ Glucuronic acid
→ Sulphate
What does modification in Phase II do?
→ Increases solubility and targets them for excretion
Why is drug metabolism important?
→ Part of the bodies natural defences
→ Body cannot distinguish between harmful and beneficial compounds such as therapeutic drugs
→A drug taken orally will pass through the liver first
→ Modifications made by the liver can significantly reduce the effectiveness of a drug
→ Advantageous because the liver can activate the drug
What do statins inhibit and what are they degraded by?
→ HMG- CoA reductase
→ Degraded by CYP3A4
What is aflatoxin produced by and what are its effects?
→ Produced by the fungus aspergillus flavus
→ Aflatoxin is activated by P450 leading to epoxide formation
→ Hepatocarcinogenesis occurs
