Liver Function

Synthesis of cell membranes and contributes to the fluidity of membranes (lipid rafts) Precursor for the synthesis of several molecules including vitamin D, cortisol, aldosterone, progesterone, estrogen, testosterone, bile salts

Cholesterol is synthesized de novo and obtained from dietary sources Liver is a major site of cholesterol biosynthesis Synthesized from Acetyl Co-A Multi-step pathway to form cholesterol from Acetyl Co-A that can be divided into 3 major steps.

Squalene is synthesized from isopentenyl pyrophosphate Cyclization of squalene to form lanosterol Lanosterol goes through several steps to eventually form cholesterol.

Lipophilic molecule and does not dissolve well in aqueous environment Packaged with phospholipids and apolipoproteins to form a series of different lipoproteins Lipoproteins contain a lipid core (contain cholesterol esters and triglyercides) and a hydrophilic outer surface containing phospholipids, free cholesterol and apolipoproteins Main cholesterol carrying lipoproteins are low density and high density lipoproteins (LDL and HDLs)

Atherosclerosis is a progressive disease of large arteries and a leading cause of cardiovascular diseases and stroke Elevated levels of circulating LDL associated with the development of atherosclerosis Inhibitors of cholesterol synthesis used to treat atherosclerosis Statins inhibit HMG CoA Reductase in the cholesterol synthesis pathway

Liver receives blood from the gastrointestinal tract via the hepatic portal vein and oxygenated blood from the heart via the hepatic artery. Blood returns to the system circulation via the hepatic vein into the vena cava. Liver continuously produces bile into the bile duct that goes to the GI tract or gall bladder

Hepatocytes secrete hepatic bile into the bile canaliculi Hepatic bile also contains bile salts, bile pigments, cholesterol and lecithin (a phospholipid) Epithelial cells that line the bile ducts secrete a bicarbonate rich fluid that increase the volume of the bile Liver produces 600 – 1000 ml bile per day discharged into the duodenum or stored in gall bladder

Primary Bile acids (e.g. cholic acid) are synthesized from cholesterol and released into the intestine upon hormone stimulation Secondary bile acids (e.g. deoxycholic acid) are formed in the intestine by the action of bacteria flora.

Primary or secondary bile acids are conjugated to amino acids (e.g. glycine) to generate water soluble bile salts. Example cholic acid with glycine forms glycocholate Sometimes called bile salts Bile salts – hydrophobic and hydrophilic regions that aggregate to form micelles at a critical concentration Important for the emulsification of fats

The majority of bile salts are re-absorbed in the ileum (last segment of small intestine) Approx. 95% bile salts that enter intestine are recycled back to the liver via the portal vein. Uptake of bile salts from the portal blood into hepatocytes occurs via an active transport pathways. Recycling from the GI tract to the liver is known as the enterohepatic circulation5% are lost in faeces (but liver makes new bile from cholesterol to replace the lost bile) During digestion – Bile can be recycled several times via the enterohepatic circulation

Sphincter of oddi is a ring of smooth muscle found where the common bile enters the small intestine

Peptide hormone Produced by the small intestine Stimulus for release = amino acid, fatty acids in the intestine

Sphincter of oddi closed -> bile is diverted to the gall bladder Stores bile not required immediately for digestion of meals Concentrates the bile by removal of salts and water Can increase concentration of bile salts up to 20 fold

Bile pigments are breakdown product of heme portion of haemoglobin from erythrocytes broken down in the liver and spleen Bile contains approx 0.2 % bile pigments Responsible for characteristic colour of bile (greenish yellow) Major pigment is bilirubin found in bile and secreted into duodenum

Liver secretes large numbers of proteins Albumin: plasma protein, transport lipids and steroid hormones Globulins: approx 40% total plasma proteins; a- and b-globulins also transport lipids and steriod hormones Clotting factors: most are produced by liver e.g. fibrinogen and prothromin

Insulin like growth factor (IGF) is an important mediator of growth hormone (GH) action Liver synthesizes IGF-1 and -2 in response to growth hormone Structurally similar to pro-insulin Potent growth promoting effects. IGF-1 levels low in infancy, peak in puberty during growth and declines in adult IGF-2 important in fetal and neonatal growth

Cytochrome P450 enzymes are important Superfamily of related enzymes Population variation in P450 enzymes are important in terms of therapeutics Naturally occurring dietary substances can inhibit (e.g. grapefruit juice) or induce (brussels sprouts) P450 enzymes with impact on drug metabolism

The majority of clopidogrel is also inactivated by blood esterases so only 15% metabolised by hepatic P450 enzymes A two step metabolism phase leads to a delayed onset of action for clopidogrel Genetic mutations in P450 enzymes are associated with a reduced response to clopidogrel treatment

The liver is supplied by blood from both arteries and veins Portal blood is nutrient rich and carries pathogen derived molecules Kupffer cells are critical component of the mononuclear phagocytic system Found in the hepatic blood sinusoids where the scavenge microbes from the blood circulation Important for sensing and uptake of pathogenic material Other functional roles of Kupffer cells include removal of activated host cells (e.g., activated platelets, neutrophils)