Metabolic functions of the Liver Flashcards
Describe the regulatory and metabolic actions of the liver
- Regulation of carbs metabolism
- Maintains blood glucose
- Regulation of fat metabolism
- Synthesis
- B-oxidation
- Regulation of protein metabolism
- Plasma protein synthesis
- Detoxification of ammonia - Urea formation
- Cholesterol synthesis
- Synthesis of specialised molecules
- Bile acids
- Haemin
Describe the blood supply to the liver, its venous drainage and its duct drainage
- Receives deoxygenated blood from the GI tract (small intestines) via the portal vein, delivers major dietary nutrients e.g. proteins, carbs BUT NOT lipids. Also delivers drugs and potential toxins
- Empties directly into IVC, ensures rapid circulation of its products
- Bile duct empties directly into gut, influences digestive process
Describe the role of the liver in lipid metabolism
Long- chain FAs:
- Liver’s major fuel source during fasting
- Triglycerides from adipose tissue → FAs bound to albumin → liver → activated via fatty acyl CoA synthetases → fatty-acyl-CoA → fatty-acyl-carnitine → carnitine crosses inner mitochondrial membrane
- Enzymes in beta oxidation, FA activation specfiic for length of FA chains
How does the liver metabolise cholesterol?
- When there’s too much Acetyl CoA, it can enter 2 different pathways instead of TCA:
- Ketogenesis to form ketone bodies, taken up by the brain and muscles to produce ATP
- Cholesterol synthesis:
- 2 acetyl-CoA molecules react together and fuse via thialase enzyme. Forms acetoacetyl-coA, coA molecule is lost in this process
- Another acetyl coA feeds into reaction, binds to acetoacetyl-coA, another coA is lost. This forms H.M.G coA (beta hydrox, beta methylglutaryl-CoA), mediated by enzyme HMG coA synthase
- HMG coA converted into mevalonate, heavily regulated by HMG coA reductase, it’s the rate limiting step as we don’t want to make too much cholesterol. Also required reducing powers of NADPH. High levels of cholesterol inhibit HMG coA reductase, decreasing cholesterol lvls.
- Mevalonate converted into isopentyl pyrophase, which is then converted into isoprene units, which are then converted into squalene. That conversion is mediated by squalene synthase
- Squalane is converted into 7 dehydrocholesterol, and this is then converted into cholesterol
- The liver packages this cholesterol in LDLs and VLDLs, which are secreted into the circulation for transport to other tissues, and free cholesterol can be excreted as natural sterols into bile or transformed into bile acids. It can be esterified and stored in the liver as cholesterol esters as well.
- In cells, cholesterol will be used to stabilise the cell membrane, it’s incorporated into the phospholipid bilayer, decreases it’s fluidity (increases rigidness) and prevents phase transitions. It can also combine with glycosphingolipids in the membrane, forms a lipid raft.
- Cholesterol used for steroid hormones (aldosterone, testosterone, oestrogen etc.)
- Bile salts (cholic acid etc.), cholesterol helps with emulsification of lipid molecules, makes them more water soluble.
- Packaged into cholesterol esters/ lipoproteins
Describe the role of the liver in formation of ketone bodies
The liver is the only organ that can produce ketone bodies, it cannot use these for energy
- Ketone bodies formed when glucose lvls low, high rates of FA oxidation
- Ketone bodies = Major fuel source for CNS under starvation
- In liver:
- Fasting, uncontrolled diabetes + prolonged exercise stimulate FA breakdown, producing acetyl-CoA
- Metabolism shifts towards maintaining blood glucose leading to reduction in OAA
- Loss of OAA limits energy production from acetyl-CoA
- Excess acetyl-CoA used to form ketone bodies
- Ketone bodies are acetoacetate, 3-beta-hydroxybutyrate and acetone
- Synthesis ketone bodies regulated by insulin/glucagon ratio, ketogenesis high when ratio low, as this inhibits acetyl-CoA carboxylase
- Ketone bodies used preferentially by cardiac muscle and renal cortex, and brain during starvation
What is our main source of ethanol?
We ingest ethanol as a result of both diet and life-style choice
Describe the 2 main routes of the metabolism of ethanol
- Oxidation through activity of alchohol dehydrogenase (90%)
- Metabolism of acetaldehyde:
- Ethanol is converted into acetaldehyde. This is mediated by alcohol dehydrogenase, this process reduces NAD+ to NADH + H+. This happens in the cytosol.
- Acetaldehyde is converted into acetate. This is mediated by aldehyde dehydrogenase and in this process, NAD+ reacts with H2O to form NADH and 2H+. Acetate then goes on to form acetyl CoA and this is mediated by acetyl CoA synthase
- Caucasians have 2 isoforms of the enzyme aldehyde dehydrogenase, ALDH-1 and ALDH-2, 2 is mitochondrial with a low Km
- Most of the acetate produced enters blood, taken up by skeletal muscle and other tissues where it’s converted into acetyl CoA
- In the liver, acetyl coA synthase is cytoslic, so it’s used to synthesise FAs and cholesterol
- Non-hepatic tissue have high lvls of mitochondrial form of enzyme, so acetyl CoA can enter TCA cycle
- Metabolism of acetaldehyde:
- Microsomal oxidation using cytochrome P450 (10-20%) - This is known as MESO
- Inolves oxidation of ethanol by members of cytochrome P450 family of enzymes, this process generates acetaldehyde
- This system consumes NADPH required for the synthesis of antioxidant glutathione, resulting in increased oxidative stress
What is the rate limiting step for ethanol metabolism? What’s the major enzyme involved in ethanol metabolism?
Alcohol dehydrogenase (ADH)
This is the rate-limiting step, but NAD+ is also needed for ethanol to be metabolised
ALDH-2 is the major enzyme involved in ethanol metabolism, but 30-40% Chinese, Japanese, Mongolians, Koreans, Vietnamese, Indonesians and Native Americans only express ADLH1.
Why can aldehyde dehydrogenase be the rate limiting step in metabolism of acetaldehyde?
It’s not normally rate-limitng, but in some single amino acid substitutions (e.g. glu to lys), a dominant negative mutation is produced
What can alcoholics be treated with to manage symptoms?
ALDH inhibitors
What happens to NADH as it’s not a good negative inhibitor of ADH or ALDH?
NADH generated in the cytosol accumulates. This leads to the inhibition of the TCA cycle
Describe acetaldehyde
- Highly reactive, can accumulate with excessive ethanol intake
- Can inhibit enzyme function
- In the liver, can lead to reduction is secretion of both serum protein and VLDL
- Inhibition of secretion of VLDL will result in accumulation of fats within the liver- fatty liver
- Can also enhance free-radical production - leads to tissue damage such as inflammation and necrosis
What is methanol metabolised to?
Formaldehyde - This is very toxic and is associated with blindness, paralysis, loss of consciousness
Describe the 3 stages of alcohol related liver damage
- Stage 1 - Fatty liver
- Stage 2 - Alcoholic hepatitis, groups of cells die, results in inflammation
- Stage 3 - Cirrhosis which includes fibrosiss, scarring and cell death
- As cirrhotic liver cannot function properly, ammonia accumulates, resulting in neurotoxicity, coma and death
- Cirrhosis arises in 25% of alcoholics and 75% all cirrhosis is due to alcohol
Describe the consequences of high ethanol metabolism
- High NADH inhibits gluconeogenesis and stimulates conversion of pyruvate to lactate, leading to hypoglycaemia and lactic acidosis
- High NADH inhibits FA oxidation, stimulates FA synthesis and formation of triglycerides
- Acetyl CoA, NADH and ATP formed inhibit glucose metabolism by inhibiting PFK and pyruvate dehyrogenase
- NADH inhibits the TCA cycle and acetyl CoA increases this inhibition further
- Acetyl CoA results in ketone body formation and stimulation of FA synthesis
Outline the metabolism of Aflatoxin B1
- Produced by fungus Aspergillus flavus
- Aflatoxin activated by P450 isoenzymes leading to epoxide formation, hepato-carcinogenesis
Outline the metabolism of statins
- Inhibit HMG- coA reductate (main regulator of cholesterol synthesis)
- Degraded by CYP3A4
What juice inhibits CYP3A4 activity?
Grapefruit juice, statin lvls can rise 15 fold
Define xenobiotics
Compounds with no nutritional value such as:
- Plant metabolites
- Synthetic compounds
- Food additives
- Agrochemicals
- Cosmetics
- By-products of cooking etc.
- Drugs
Describe the role of the liver in xenobiotic metabolism
- Aim to make xenobiotic harmless and more readily disposed of by the kidney in urine OR gut in faeces
- Also involved are intestines and lungs
- Body doesn’t distniguish b/w harmful and beneficial compoudns, so metabolism of drugs by liver plays role in their effectiveness
- A drug taken orally will first pass through the liver
- Modifications made by the liver can significantly reduce the effectiveness of a drug, although this
Describe the 3 phases of xenobiotics metabolism
Phase I: Oxidation
- Oxidation is most common modification but also get hydroxylation and reduction
- Modification increases solubulity
- Introduces functional groups which enables participation in further reactions
- These reactions are promoted by family of enzymes called cytochrome P450
Phase II: Conjugation
- Xenobiotics are modified by addition of groups such as:
- Glutathione
- Glucuronic acid
- Sulphate
- Modification with these groups increase solubility and targets them for excretion
- Compounds sequentially modified
Phase III: Elimination
- Small water souble molecules can be removed by the kidney
- Actively transported into bile, then into intestines, and fate is 3 fold:
- Digestion
- Excretion
- Re-absorption via enterohepatic circulation
- t1/2 is time needed for 50% substance to be lost
Describe the metabolism of paracetamol
Most of paracetamol is conjugated with either glucoronate or sulphate and excrted by the kidney
Describe cytochrome P450 enzymes
- Found mainly in liver and cells of the intestine
- Make up a family of approx 50 diff enzymes, they are haem proteins and are related to the mitochondrial enzymes
- They are found in ER
- Example of their action would be hydroxylation of ibuprofen
- P450 enzymes are inducible both by their own substrates (5-10 fold) but also related substrates (2-4 fold)
- Clinically important
What do cytochrome P450 enzymes do?
Major xenobiotic metaboliser, oxidises substrates, adds oxygen to structures
Describe the role of the liver in the maintenance of blood glucose levels
Increased blood glucose:
- Insulin secreted by pancreas
- Increase uptake of glucose, amino acids by cells; inhibition of glycolysis, activation of glycogen synthesis
- Inhibition of gluconeogenesis, inhibition of glycogenolysis, inhibition of FA oxidation, decreased blood glucose
Decreased blood glucose:
- Increase breakdown of glyocgen
- Secretion of glucagon, activation of glycolysis, inhibition of glycogen synthesis, activation of gluconeogenesis, activation of glycogenolysis, activation of FA oxidation - Increased blood glucose
