Metabolic Functions of the Liver Flashcards
How does the liver decrease Blood glucose levels?
By regulating flux into the pathways that remove free glucose, the liver contributes to lowering BGL
How do other organs contribute to lowering BGL?
Other organs (adipose tissue and muscle) also switch on their biosynthetic pathways to remove glucose from the blood
How does the liver maintain constant BGL?
- Removal of glucose from blood post meal
- Storing glucose as glycogen
- Restoring BGL via gluconeogenesis + glycogenolysis
- Regulating fluxes through glycolysis, pentose phosphate
cycle + gluconeogenesis
Which sugars does the liver metabolise?
The liver is involved in metabolism of other sugars e.g. fructose and galactose as well as glucose
What role does the liver play in protein synthesis?
The liver is the major site for serum protein synthesis
e.g. albumin and blood clotting factors
What is the fate of excess amino acids in the body?
The liver degrades excess amino acids especially during gluconeogenesis
What are glucogenic amino acids degraded into?
glucogenic amino acids → sugars
What are ketogenic amino acids degraded into?
ketogenic amino acids → ketone bodies
What role does the liver play in the removal of toxic ammonia?
Major site for transamination + deamination of amino acids and detoxification of ammonia
What is the significance of liver interaction with muscle?
Important in regulating BGL available to tissues
Important in converting metabolites → proteins / sources of energy
How does the liver regulate fats and lipids in the body?
The liver also plays a central role in the synthesis, transport and metabolism of lipids and fats
How does cholesterol enter the livers cholesterol pool?
- dietary
- de novo via extra-hepatic tissue
- endogenous (own production)
Where is the body’s cholesterol made from?
50% cholesterol made by liver
rest produced by intestine, adrenal cortex, and reproductive tissue
Made from acetyl coA (HMG CoA reductase)
Transported from liver as VLDL
How is cholesterol excreted from the body?
Body can’t degrade cholesterol
Disposed by biliary system in intestines as either cholesterol following conversion to bile acids/salts
Why is ethanol metabolism significant?
Need to metabolise ethanol as its present as a consequence of either diet or lifestyle
What are the 2 routes of ethanol metabolism?
- Oxidation (via alcohol dehydrogenase)
2. Microsomal Oxidation (via cytochrome p450)
Outline the metabolism of ethanol
ethanol → acetaldehyde →acetate
using enzymes alochol and actealdehyde dehydrogenases
What is the consequence of methanol metabolism?
Methanol→formaldehyde - v. toxic
associated with paralysis, loss of consciousness and blindness
Explain how certain ethnicities are intolerant to ethanol
40% of asians are intolerant to ethanol showing symptoms of:
- tachycardia, facial flush, vasodilation and nausea
What are the products of ethanol metabolism?
Oxidation of alcohol takes precedent over other nutrients and isn’t regulated by negative feedback so large quantities of NADH, ATP and acetyl CoA are formed
- can cause inhibition of certain metabolic pathways
Which pathways are inhibited due to ethanol metabolism?
Acetyl CoA, NADH + ATP
- inhibit glucose metabolism by inhibiting PFK + pyruvate
dehydrogenase
NADH
- inhibits tca cycle + acetyl CoA increases further
Acetyl CoA
- Causes ketone body formation + FA synthesis
stimulation
- FA esterified to TG for VLDL export
What does MESO stand for?
Microsomal Ethanol Oxidising System
What is MESO?
2nd route of metabolism
involves oxidation of ethanol by cytochrome P450 family
uses NADPH required for GSH synthesis
Outline features of acetaldehyde
- highly reactive (accumulates w/ excessive alcohol)
- can inhibit enzyme functions
- liver leads to reduce serum protein and VLDL secretion
- Can enhance free radical production →leads to tissue
damage e.g. inflammation + necrosis
What are the 3 stages of liver damage?
Stage 1: fatty liver
Stage 2: Alcoholic hepatitis, necrosis = inflammation
Stage 3: Cirrhosis, fibrosis, scarring and cell death
What is the consequence of cirrhosis?
As cirrhotic liver can’t function properly, ammonia accumulate resulting in neurotoxicity, coma and death
What are xenobiotics?
Compounds with no nutritional value
Give examples of xenobiotics
Plant metabolites Synthetic compounds Food additives Agro-chemicals Cosmetics By products of cooking drugs
What is the advantage of water soluble compounds in excretion?
Water soluble compounds are easily excreted in urine
Lipophilic compounds are harder to excrete
What are the three phases of xenobiotic metabolism?
- Oxidation
- Conjugation
- Elimination
Describe the effects of Phase 1: oxidation
Increases solubility
Introduces functional groups - allows further reactions
Promoted by Cytochrome p450
Where are cytochrome p450 enzymes found?
Found mainly in liver and intestinal Cells; ER
How are cytochrome p450 enzymes induced?
own substrates or related substrates activate cytochrome p450 enzymes - clinically significant
Explain how xenobiotic conjugation occurs
Xenobiotics are modified by addition of groups such as:
- Glutathionine
- Glucoronic acid
- Sulphate
compounds are often sequentially modified
What is the benefit of xenobiotic conjugation?
Modification with these groups increases solubility and targets them for excretion
What is the significance of liver drug metabolism?
Xenobiotic metabolism is part of the body’s natural defences but the body doesn’t distinguish between harmful and beneficial compounds e.g. therapeutic drugs
How does liver metabolism of drugs affect their effectiveness?
orally taken - passes through liver first
modifications made by the liver can significantly reduce effectiveness but this can also be advantageous
What is the function of statins?
inhibit HMG CoA Reductase
degraded by CYP3A4 (inhibited by grapefruit juice)
How is aflatoxin B1 produced?
By fungus aspergillus Flavus
Activated by P450 enzymes leading to epoxide formation and hepatocarcinogenesis
Explain the metabolism of paracetamol in the liver
Hepatic metabolism of paracetamol→reactive intermediate NAPQI formed
Under normal physiological conditions NAPQI is cleared via conjugation with GSH (glutathionine)
What is the effect of NAPQI if not cleared?
NAPQI forms NAPQI-protein adducts resulting in:
- oxidative stress
- mitochondrial dysfunction
- necrotic cell death
Why may NAPQI not be cleared?
Due to low GSH levels/ excessive alcohol consumption
→Activation of MESO (microsomal ethanol-oxidising
system) using NADPH which is required for GSH
synthesis
How does ethanol metabolism affect NAPQI clearance?
Ethanol metabolism →NADPH reduction = less GSH to clear NAPQI →NAPQI builds up causing liver damage
What is the fate of modified compounds?
Small water soluble compounds excreted via kidneys
Some actively transported in to bile → intestines
Explain what happens to compounds that are modified?
Fate of these is 3 fold
- digestion
- absorption
- reabsorption via enterohepatic circulation
How long does it take for 50% of a substance to be excreted fully?
t 1/2 is the time required for 50% of a substance to be lost
Explain the role the liver plays in carbohydrate metabolism
Regulates carbohydrate metabolism
- to maintain BGL
Explain the role the liver plays in fat metabolism
Regulates fat metabolism
- lipid synthesis
- beta oxidation
Explain how the liver regulates protein metabolism
plasma protein synthesis
detoxification of ammonia → urea formation
What roles does the liver play in regulating cholesterol?
Regulates cholesterol synthesis and excretion
