Liver Functions PDF

LIVER FUNCTIONS The liver provides a 1. Maintain homeostasis of nutrients broad array of Carbohydrates Gluconeogenesis functions that are Glycogenolysis necessary for Lipids...

LIVER FUNCTIONS The liver provides a 1. Maintain homeostasis of nutrients broad array of Carbohydrates Gluconeogenesis functions that are Glycogenolysis necessary for Lipids VLDL (fatty acid distribution) maintaining health (and HDL (cholesterol scavenging) life). These functions Ketones (“soluble” fatty acid analogs) Amino acids include: 2. Store nutrients Glycogen Lipids 3. Synthesize and release plasma proteins Clotting factors Albumin 4. Synthesize and release bile 5. Process and excrete bilirubin 6. Detoxification and excretion of drugs, hormones and toxins 7. Storage of vitamins A, D (including processing) and B12 8. Iron storage (Fe bound to apoferritin) 9. Synthesize and release somatomedins 10. Blood cleansing of bacteria  Maintain homeostasis of nutrients: The liver is the central regulator of blood nutrients, acting to assure there is a supply of glucose in the blood for neurons to use while also distributing fatty acid carbons in the form of ketones or packaged as triglycerides in very low density lipoproteins (VLDLs). – Carbohydrates: The liver can store glucose in the form of glycogen, and release glucose during the bad times via glycogenolysis and gluconeogenesis. In addition, the ~20% of dietary sugars that are galactose and fructose are primarily used by the liver, and their carbons fed into glycolysis or gluconeogenesis. Gluconeogenesis: This is the process of converting carbons from other chemicals (primarily amino acids, but also glycerol) into glucose molecules. This glucose will be used by neurons during the “Bad Times” of fasting. Glycogenolysis: The breakdown of glycogen during the “Bad Times” provides blood glucose to keep neurons functioning. While glycogen is stored in other cell types (notably skeletal muscle, which contains the greatest amount of glycogen in the body), glycogen concentrations in hepatocytes are higher than any other cell type in the body. – Lipids: Hepatocytes participate in lipid regulation by way of their ability to synthesize and release very low density lipoproteins (VLDLs), high density lipoproteins (HDLs), and by their ability to produce ketones from fatty acids: VLDL (fatty acid distribution): Covered in more detail in another lecture, VLDLs are made by hepatocytes which package triglycerides (made by the hepatocytes) to be sent out into the blood for distribution of the fatty acids to various cells of the body. HDL (cholesterol scavenging): High density lipoproteins are also made by hepatocytes and, as we shall see in another lecture, they function to scavenge cholesterol from the blood and peripheral tissues as well as providing a circulating reservoir of apoproteins for activating VLDLs and chylomicrons. Ketones (“soluble” fatty acid analogs): Hepatocytes can make ketones (acetoacetate and 3-OH-butyrate) from fatty acid metabolism. The significance of the ketones (there is a third, acetone, which is produced by spontaneous decarboxylation and which is useless to the body for metabolism) is that they are water soluble whereas fatty acids are poorly soluble. This allows the liver to distribute fatty acid carbons to cells throughout the body during the “Bad Times”, something that would be difficult to do with fatty acids alone.  – Amino acids: The relationship of the liver and amino acid handling in the body is significant in two ways: 1) The liver primarily uses amino acids from skeletal muscle proteolysis during the “Bad Times” to make glucose via gluconeogenesis; and 2) Hepatocytes are primarily responsible for the ability to synthesize a number of amino acids – causing them to be the NON-essential amino acids (the ones which are NOT PVT TIM HALL). NOTE: The removal of the amine groups from amino acids by hepatocytes during gluconeogenesis is the reason that the liver is the primary organ for producing urea – the primary nitrogenous waste product of our body  Store nutrients: One aspect of the liver which allows it to maintain homeostasis of nutrients during the “Bad Times” is its ability to efficiently store and process nutrients after eating (the “Good Times”). – Glycogen: The presence of glucokinase, an enzymatic relative of hexokinase, in hepatocytes allows the liver to efficiently synthesize glycogen during the “Good Times” (post-prandial state). This glycogen can then be used to fuel the brain during fasting. – Lipids: Lipids can be stored in the liver in the form of triglycerides, but this is more commonly associated with a disease state resulting from prolonged “Good Times”. The liver also tends to synthesize and accumulate cholesterol, which it can use for bile salt synthesis.  Synthesize and release plasma proteins: Pretty much all of the plasma proteins (except for the gamma globulins) are made by hepatocytes. While the plasma proteins perform many functions, two groups are of particular note here: – Clotting factors: The liver synthesizes many plasma proteins involved in regulating hemostasis, including: fibrinogen, prothrombin, Factor VII and others. The liver requires Vitamin K for the synthesis of several of these factors. Therefore, either a Vitamin K shortage or liver dysfunction will likely lead to prolonged bleeding. – Albumin: Albumin is the most abundant of the plasma proteins (easily so) and is a good non-specific reversible binder of hydrophobic compounds. This characteristic allows albumin to help distribute a broad variety of steroid hormones, drugs and other hydrophobic compounds throughout the body. Being the most abundant plasma protein, albumin also plays the major role in osmolality of the plasma – something that is critical in the dynamics of fluid movement between capillaries and interstitium. Liver dysfunction can result in a decrease in plasma osmolality and a resulting increase in tendency toward edema formation throughout the body.  Synthesize and release bile: Bile contains bile salts for emulsification of dietary fats. These bile salts/bile acids (taurocholate or glycocholate) have both a polar (taurine or glycine) and nonpolar (cholesterol) component to each molecule. This duality allows them to form micelles in the digestive tract, with dietary fats (triglycerides, phospholipids and cholesterol) occupying the core of the micelle. The ability to form micelles means that bile salts increase the surface area to volume ratio of fat globules, allowing greater efficiency of chemical digestion by pancreatic lipases. Bile also contains bilirubin and cholesterol. Process and excrete bilirubin: Bilirubin is the waste product of heme catabolism. Macrophages release the iron from the heme group, and the remaining compound is converted to biliverdin and then bilirubin. The bilirubin is transported bound to albumin to the liver. The liver conjugates the bilirubin with glucuronate and/or sulfate before being excreted in bile.  Detoxification and excretion of drugs, hormones and toxins: Drugs are primarily metabolized in the liver, and drug metabolism has 2 primary functions: A) The drug becomes more hydrophilic (facilitating excretion by the kidneys), and B) most drugs become less active or inactive when they are metabolized (although some become more active – levodopa to dopamine – or remain as active – diazepam to nordiazepam).The same is true for processing of the steroid hormones and thyroxin. The liver accomplishes metabolism of drugs and hormones by two general types of reaction: – Phase I reactions: These are biotransformations of the drug to make it more polar (and therefore more hydrophilic). The reactions take place at the smooth endoplasmic reticulum and most commonly are oxidations by the cytochrome P-450 (mixed function) oxidases, but also include reductions or hydrolyses.  – Phase II reactions: For some drugs all that occurs is Phase I, while others proceed directly to Phase II. The Phase II reactions make the drug or drug metabolite (product of Phase I) even more polar (more hydrophilic) by conjugation with compounds such as glucuronate, acetate, glutathione, glycine, sulfate or a methyl group. NOTE: Some drugs, when administered frequently/ regularly act to increase cytochrome P-450 activity. This will increase the rate of inactivation of the drug, requiring a higher dosage in the future to produce the same effect (This plays a role both in long-term drug administration for disease states, and in drug abuse). Also note that many drugs are absorbed in the small intestine and immediately enter the hepatic portal system. This means that they are exposed to inactivation before ever having a chance to circulate throughout the body (“first-pass metabolism”).  Storage of vitamins A, D (including processing) and B12: The liver has been shown to temporarily store several vitamins, Vitamin A being the most highly concentrated. This storage allows the liver to prevent a Vitamin A deficiency for as much as 10 months, a Vitamin D deficiency for up to 4 months, and a Vitamin B12 deficiency for over a year. Iron storage (Fe bound to apoferritin): Heme groups, primarily in hemoglobin account for much of the iron in the body, but the next most abundant location of iron is in the liver. The liver serves as a reservoir of iron by reversibly binding it to the liver protein apoferritin. The combination of iron + apoferritin is called ferritin, and this store helps assure availability of iron for functional red blood cell synthesis.  Synthesize and release somatomedins: Somatomedins are also referred to as Insulin-Like Growth Factors (IGF), and it is this group of polypeptide hormones that produce the direct effects for Human Growth Hormone (HGH) at many tissues. Somatomedins (Somatomedin-C, also called IGF-1, is the most abundant) act to increase chondrocyte and osteoblast cell activity and cell number, as well as promoting conversion of chondrocytes to osteogenic cells. Blood cleansing of bacteria: Blood which flows through intestinal capillaries accumulates nutrients, but it also accumulates intestinal bacteria (When cultured, intestinal venous blood entering the hepatic portal system will almost always show growth of bacteria). These bacteria are removed from the circulatory system (where they pose a threat of septicemia) by the phagocytic macrophages called Kupffer cells which line the hepatic venous sinuses.