Liver Kupffer cells | macrophages.com Home » macrophage-images Liver Kupffer cells Kupffer cells are the major macrophage population of the body that has direct contact with the blood. They are found in the vascular sinuses, attached to the outer surface of endothelial cells and together with those cells and fat-forming Ito cells, they form a major non-parenchymal component of the liver. In this low power view, we see a liver lobule, with the portal triad in the centre of the view. Note that the stellate F4/80-positive Kupffer cells are more concentrated towards the portal vein. The Kupffer cells would be exposed to toxic components, including bacterial endotoxns, arriving in the portal blood. Kupffer cells | definition of Kupffer cells by Medical dictionary Kupffer cells | definition of Kupffer cells by Medical dictionary Related to Kupffer cells: Space of Disse Kupf·fer cells (kūp'fĕr), [koo͡p′fərz] Etymology: Karl W.

von Kupffer, German anatomist, 1829-1902 immobile macrophages that line liver sinusoids. Kupffer cells filter bacteria and other foreign proteins from the blood and initiate immune responses. Kupf·fer cells (kup'fĕr selz) Phagocytic cells of the mononuclear phagocyte series found on the luminal surface of the hepatic sinusoids. Kupffer cells Fixed MACROPHAGE cells that line the fine blood sinuses (capillaries) of the liver and act as scavengers to remove senescent red blood cells, bacteria and other foreign material. (Karl Wilhelm von Kupffer, 1829–1902, German anatomist) Kupffer, Karl W. von, German anatomist, 1829-1902. Kupffer cell sarcoma Kupffer cells - phagocytic cells of the mononuclear phagocyte series found on the luminal surface of the hepatic sinusoids.

Synonym(s): stellate cells of liver Liver – Anatomy and Function of the Human Liver Sinusoids and Bile Canaliculi Full Liver Description [Continued from above] . . . of growing as quickly as a cancerous tumor to restore its normal size and function. Anatomy of the Liver Gross Anatomy The liver is a roughly triangular organ that extends across the entire abdominal cavity just inferior to the diaphragm. Most of the liver’s mass is located on the right side of the body where it descends inferiorly toward the right kidney . The liver is made of very soft, pinkish-brown tissues encapsulated by a connective tissue capsule. This capsule is further covered and reinforced by the peritoneum of the abdominal cavity, which protects the liver and holds it in place within the abdomen. The peritoneum connects the liver in 4 locations: the coronary ligament, the left and right triangular ligaments, and the falciform ligament. These connections are not true ligaments in the anatomical sense; rather, they are condensed regions of peritoneal membrane that support the liver. The wide coronary ligament connects the central superior portion of the liver to the diaphragm.

Located on the lateral borders of the left and right lobes, respectively, the left and right triangular ligaments connect the superior ends of the liver to the diaphragm. The falciform ligament runs inferiorly from the diaphragm across the anterior edge of the liver to its inferior border. At the inferior end of the liver, the falciform ligament forms the round ligament (ligamentum teres) of the liver and connects the liver to the umbilicus. The round ligament is a remnant of the umbilical vein that carries blood into the body during fetal development. The liver consists of 4 distinct lobes – the left, right, caudate, and quadrate lobes. The left and right lobes are the largest lobes and are separated by the falciform ligament. The right lobe is about 5 to 6 times larger than the tapered left lobe. The small caudate lobe extends from the posterior side of the right lobe and wraps around the inferior vena cava. The small quadrate lobe is inferior to the caudate lobe and extends from the posterior side of the right lobe and wraps around the gallbladder.

Bile Ducts The tubes that carry bile through the liver and gallbladder are known as bile ducts and form a branched structure known as the biliary tree. Bile produced by liver cells drains into microscopic canals known as bile canaliculi. The countless bile canaliculi join together into many larger bile ducts found throughout the liver. These bile ducts next join to form the larger left and right hepatic ducts , which carry bile from the left and right lobes of the liver. Those two hepatic ducts join to form the common hepatic duct that drains all bile away from the liver. The common hepatic duct finally joins with the cystic duct from the gallbladder to form the common bile duct , carrying bile to the duodenum of the small intestine. Most of the bile produced by the liver is pushed back up the cystic duct by peristalsis to arrive in the gallbladder for storage, until it is needed for digestion. Blood Vessels The blood supply of the liver is unique among all organs of the body due to the hepatic portal vein system.

Blood traveling to the spleen , stomach , pancreas , gallbladder, and intestines passes through capillaries in these organs and is collected into the hepatic portal vein . The hepatic portal vein then delivers this blood to the tissues of the liver where the contents of the blood are divided up into smaller vessels and processed before being passed on to the rest of the body. Blood leaving the tissues of the liver collects into the hepatic veins that lead to the vena cava and return to the heart . The liver also has its own system of arteries and arterioles that provide oxygenated blood to its tissues just like any other organ. Lobules The internal structure of the liver is made of around 100,000 small hexagonal functional units known as lobules. Each lobule consists of a central vein surrounded by 6 hepatic portal veins and 6 hepatic arteries. These blood vessels are connected by many capillary-like tubes called sinusoids , which extend from the portal veins and arteries to meet the central vein like spokes on a wheel. Each sinusoid passes through liver tissue containing 2 main cell types: Kupffer cells and hepatocytes.

Kupffer cells are a type of macrophage that capture and break down old, worn out red blood cells passing through the sinusoids. Hepatocytes are cuboidal epithelial cells that line the sinusoids and make up the majority of cells in the liver. Hepatocytes perform most of the liver’s functions – metabolism, storage, digestion, and bile production. Tiny bile collection vessels known as bile canaliculi run parallel to the sinusoids on the other side of the hepatocytes and drain into the bile ducts of the liver. Physiology of the Liver Digestion The liver plays an active role in the process of digestion through the production of bile. Bile is a mixture of water, bile salts, cholesterol, and the pigment bilirubin. Hepatocytes in the liver produce bile, which then passes through the bile ducts to be stored in the gallbladder. When food containing fats reaches the duodenum , the cells of the duodenum release the hormone cholecystokinin to stimulate the gallbladder to release bile. Bile travels through the bile ducts and is released into the duodenum where it emulsifies large masses of fat.

The emulsification of fats by bile turns the large clumps of fat into smaller pieces that have more surface area and are therefore easier for the body to digest. Bilirubin present in bile is a product of the liver’s digestion of worn out red blood cells. Kupffer cells in the liver catch and destroy old, worn out red blood cells and pass their components on to hepatocytes. Hepatocytes metabolize hemoglobin, the red oxygen-carrying pigment of red blood cells, into the components heme and globin. Globin protein is further broken down and used as an energy source for the body. The iron-containing heme group cannot be recycled by the body and is converted into the pigment bilirubin and added to bile to be excreted from the body. Bilirubin gives bile its distinctive greenish color. Intestinal bacteria further convert bilirubin into the brown pigment stercobilin, which gives feces their brown color. Metabolism The hepatocytes of the liver are tasked with many of the important metabolic jobs that support the cells of the body.

Because all of the blood leaving the digestive system passes through the hepatic portal vein, the liver is responsible for metabolizing carbohydrate, lipids, and proteins into biologically useful materials. Our digestive system breaks down carbohydrates into the monosaccharide glucose, which cells use as a primary energy source. Blood entering the liver through the hepatic portal vein is extremely rich in glucose from digested food. Hepatocytes absorb much of this glucose and store it as the macromolecule glycogen, a branched polysaccharide that allows the hepatocytes to pack away large amounts of glucose and quickly release glucose between meals. The absorption and release of glucose by the hepatocytes helps to maintain homeostasis and protects the rest of the body from dangerous spikes and drops in the blood glucose level. (See more about glucose in the body .) Fatty acids in the blood passing through the liver are absorbed by hepatocytes and metabolized to produce energy in the form of ATP. Glycerol, another lipid component, is converted into glucose by hepatocytes through the process of gluconeogenesis. Hepatocytes can also produce lipids like cholesterol, phospholipids, and lipoproteins that are used by other cells throughout the body.

Much of the cholesterol produced by hepatocytes gets excreted from the body as a component of bile. Dietary proteins are broken down into their component amino acids by the digestive system before being passed on to the hepatic portal vein. Amino acids entering the liver require metabolic processing before they can be used as an energy source. Hepatocytes first remove the amine groups of the amino acids and convert them into ammonia and eventually urea. Urea is less toxic than ammonia and can be excreted in urine as a waste product of digestion. The remaining parts of the amino acids can be broken down into ATP or converted into new glucose molecules through the process of gluconeogenesis. Detoxification As blood from the digestive organs passes through the hepatic portal circulation, the hepatocytes of the liver monitor the contents of the blood and remove many potentially toxic substances before they can reach the rest of the body. Enzymes in hepatocytes metabolize many of these toxins such as alcohol and drugs into their inactive metabolites. And in order to keep hormone levels within homeostatic limits, the liver also metabolizes and removes from circulation hormones produced by the body’s own glands.

Storage The liver provides storage of many essential nutrients, vitamins, and minerals obtained from blood passing through the hepatic portal system. Glucose is transported into hepatocytes under the influence of the hormone insulin and stored as the polysaccharide glycogen. Hepatocytes also absorb and store fatty acids from digested triglycerides. The storage of these nutrients allows the liver to maintain the homeostasis of blood glucose. Our liver also stores vitamins and minerals - such as vitamins A, D, E, K, and B12, and the minerals iron and copper - in order to provide a constant supply of these essential substances to the tissues of the body. Production The liver is responsible for the production of several vital protein components of blood plasma: prothrombin, fibrinogen, and albumins. Prothrombin and fibrinogen proteins are coagulation factors involved in the formation of blood clots. Albumins are proteins that maintain the isotonic environment of the blood so that cells of the body do not gain or lose water in the presence of body fluids. Immunity The liver functions as an organ of the immune system through the function of the Kupffer cells that line the sinusoids.

Kupffer cells are a type of fixed macrophage that form part of the mononuclear phagocyte system along with macrophages in the spleen and lymph nodes . Kupffer cells play an important role by capturing and digesting bacteria, fungi, parasites, worn-out blood cells, and cellular debris. The large volume of blood passing through the hepatic portal system and the liver allows Kupffer cells to clean large volumes of blood very quickly. Prepared by Tim Taylor, Anatomy and Physiology Instructor Role of Kupffer cells in host defense and liver disease. - PubMed - NCBI Role of Kupffer cells in host defense and liver disease. 1Department of Medicine II, University of Munich, Klinikum Grosshadern, Munich, Germany. manfred.bilzer@med.uni-muenchen.de Abstract Kupffer cells (KC) constitute 80-90% of the tissue macrophages present in the body. They reside within the lumen of the liver sinusoids, and are therefore constantly exposed to gut-derived bacteria, microbial debris and bacterial endotoxins, known to activate macrophages.

Upon activation KC release various products, including cytokines, prostanoides, nitric oxide and reactive oxygen species. These factors regulate the phenotype of KC themselves, and the phenotypes of neighboring cells, such as hepatocytes, stellate cells, endothelial cells and other immune cells that traffic through the liver. Therefore, KC are intimately involved in the liver's response to infection, toxins, ischemia, resection and other stresses. This review summarizes established basic concepts of KC function as well as their role in the pathogenesis of various liver diseases. PMID: Endotoxin and Kupffer Cell Activation in Alcoholic Liver Disease Endotoxin and Kupffer Cell Activation in Alcoholic Liver Disease Michael D. Wheeler, Ph.D. Michael D. Wheeler, Ph.D., is an assistant professor in the Center for Alcohol Studies at the University of North Carolina, Chapel Hill. One central component in the complex network of processes leading to the development of alcoholic liver disease is the activation of immune cells residing in the liver (i.e., Kupffer cells) by a substance called endotoxin, which is released by bacteria living in the intestine. Alcohol consumption can lead to increased endotoxin levels in the blood and liver.

When activated, Kupffer cells produce signaling molecules (i.e., cytokines) that promote inflammatory reactions as well as molecules called reactive oxygen species (ROS), which can damage liver cells. Endotoxin activates Kupffer cells by interacting with a complex of protein molecules that are located on the outside of the Kupffer cell or which extend into the cell. Binding of endotoxin alters the activities of the proteins in this complex so that they trigger a cascade of biochemical signals in the Kupffer cell, resulting in cytokine and ROS production and, ultimately, liver damage. Because alcohol can enhance endotoxin release and, therefore, Kupffer cell activation, novel approaches to inhibit these processes might help prevent or ameliorate alcoholic liver disease. Key words: alcoholic liver disorder; chronic AODE (alcohol and other drug effects); endotoxins; Kupffer cell; cell growth and differentiation; biological activation; cell signaling; cytokines; intestinal cell; epithelium; membrane permeability; treatment method Alcoholic liver disease progresses through several stages of tissue damage and liver dysfunction.

One of the early stages, alcohol–induced steatohepatitis, is characterized by the accumulation of fat molecules in the liver tissue, accompanied by the migration into the liver of cells associated with inflammation processes. These inflammation–promoting cells are attracted to the liver largely because of the activities of a type of immune cell called Kupffer cells, which reside there.1 (1 In addition to the Kupffer cells, the primary liver cells [i.e., hepatocytes] also produce and release the molecules that attract inflammation–producing cells to the liver.) To investigate and clarify the contribution of Kupffer cells to the development of alcohol–induced liver injury, researchers studied rats in which they could induce liver disease by continuously administering alcohol. If the animals were first treated with a chemical (i.e., gadolinium chloride) that specifically destroyed their Kupffer cells, they did not develop alcohol–induced liver injury (Adachi et al. 1994). This key finding supports the idea that Kupffer cells play an important role in alcohol’s detrimental effects on liver function.

Alcohol activates Kupffer cells primarily through the action of a substance called endotoxin, which is released by certain bacteria normally present in the intestine of humans and other animals. This article describes the interaction between endotoxin and Kupffer cells, particularly the mechanisms by which endotoxin activates signaling pathways within the Kupffer cells, and how these mechanisms contribute to liver injury. The article concludes by discussing how these findings could be translated into new approaches to treating alcoholic liver disease. What Are Kupffer Cells? Kupffer cells belong to a class of immune cells called macrophages, which are found throughout most tissues. Macrophages take various actions to eliminate foreign materials (e.g., bacteria or bacterial products) from the body. For example, macrophages can ingest and destroy foreign materials or secrete immune molecules as well as molecules that regulate the functions of other cells involved in the immune response. These regulatory molecules are called cytokines. Kupffer cells are macrophages that reside in the liver. Their main role—removing bacteria and foreign proteins from the blood—is essential to the liver’s primary function, which is cleansing the blood of foreign materials and toxic substances.

When no foreign materials are present, Kupffer cells are in a resting state. They can be activated by numerous molecules, including bacterial endotoxins (described in the next section). When activated, Kupffer cells secrete a variety of cytokines, including a molecule called tumor necrosis factor alpha (TNF–α) and several types of interleukins. All of these molecules can act as inflammatory cytokines—that is, they induce an inflammatory response necessary to remove the offending toxic or foreign molecules and initiate the healing process. (For more information on cytokines and their role in alcoholic liver disease, see the article by Neuman in this issue.) Macrophages, including Kupffer cells, and related cells appear to increase their production of cytokines in patients with alcoholic liver disease. Clinical observations have revealed that the precursor cells of macrophages (i.e., monocytes) from patients with alcohol–induced hepatitis produced greater amounts of cytokines, particularly TNF–α, than did monocytes from control patients (McClain and Cohen 1989). Moreover, patients with alcoholic liver disease had higher levels of TNF–α in their blood (Bird et al. 1990).

These data have been confirmed in animals chronically exposed to alcohol (Honchel et al. 1992). Such observations suggest that TNF–α is a critical factor in alcoholic liver disease, a hypothesis that has been confirmed in animal models using rodents (Iimuro et al. 1996; Yin et al. 1999). Results of other animal studies also have supported the role of TNF–α in alcoholic liver disease. For example, researchers have analyzed cells from a mouse strain that lacks a protein with which TNF–α interacts (i.e., a TNF–α receptor). Several TNF–α receptors exist, the primary one being TNF R1. Researchers found that mice in which TNF R1 was inactivated (i.e., TNF R1 knockout mice), thereby preventing TNF–α from exerting its effects, were resistant to alcohol–induced liver disease (Yin et al. 1999). In addition to producing cytokines, activated Kupffer cells are the major source of reactive oxygen species (ROS) in the liver.

ROS are oxygen–containing molecules that are highly reactive with other complex molecules in the cells (e.g., proteins, fat molecules [i.e., lipids], and DNA). ROS such as superoxide, hydrogen peroxide, and hydroxyl radicals have been implicated in the development of liver damage. Excessive levels of ROS within a cell and/or the lack of molecules that can eliminate ROS (i.e., antioxidants) leads to a state called oxidative stress that is detrimental to the cell. (For more information on how ROS and oxidative stress contribute to the development of alcoholic liver disease, see the article in this issue by Wu and Cedarbaum.) One important ROS is superoxide, which in activated Kupffer cells is generated by the enzyme NADPH oxidase. Several experiments using a variety of antioxidants and inhibitors of ROS–producing enzymes have explored the relationship of superoxide generation and oxidative stress to alcohol–induced liver injury. For example, studies in which rats received chronic alcohol administration have shown that preventing superoxide production by inhibiting NADPH oxidase activity could reduce the alcohol–induced liver injury (Kono et al. 2001).

Similarly, antioxidant compounds and extracts such as green tea and cocoa—which generally reduce ROS production and, consequently, oxidative stress—also provided substantial protection against alcoholic liver disease in rats (Arteel et al. 2002; McKim et al. 2002). Interestingly, in most studies using antioxidants, the alcohol–induced production of TNF–α also was reduced, suggesting that oxidative stress promotes TNF–α production. What Is Endotoxin? One substance that can effectively activate Kupffer cells is bacterial endotoxin. This molecule, also known as lipopolysaccharide, is a component of the cell walls of some of the bacteria that normally inhabit the intestine. When the bacteria die, the endotoxin is released into the intestine, from which some of it can cross the intestinal wall and enter the bloodstream. Higher–than–normal amounts of endotoxin entering the bloodstream or tissues can cause fever, chills, shock, and various other symptoms and can often lead to more severe conditions, such as endotoxemia or adult respiratory distress syndrome (ARDS). Several lines of research have shown that gut–derived endotoxin plays a critical role in alcoholic liver disease.

For example, studies have found that patients with alcoholic liver disease have elevated levels of endotoxin circulating in the blood (Fukui et al. 1991). Furthermore, in experiments with rodents, researchers have found that eliminating all bacteria and, consequently, all the endotoxin from the intestine (e.g., by using antibiotics) completely prevented alcohol–induced liver injury (Adachi et al. 1995). Similarly, by lowering the number of intestinal bacteria through other means (e.g., administration of lactobacillus bacteria, which are present in yogurt), investigators could curb the rise in endotoxin levels in alcohol–treated animals (Nanji et al. 1994). As endotoxin crosses the intestinal barrier and enters the bloodstream, it interacts with the Kupffer cells in the liver, thereby activating them. Thus, it was hypothesized that Kupffer cell activation by endotoxin derived from intestinal bacteria causes those cells to generate superoxide and TNF–α, both of which can lead to tissue damage in the liver (see figure 1). Experiments on isolated cells grown in culture (i.e., in vitro experiments) as well as other experimental approaches have confirmed this hypothesis.

For example, endotoxin did not induce the production of superoxide or TNF–α in isolated Kupffer cells that contained excess amounts of an antioxidant capable of eliminating superoxide (i.e., the enzyme superoxide dismutase) (Wheeler et al. 2000). This finding supports the connection between endotoxin, Kupffer cells, and superoxide production. Figure 1 Model of the association between endotoxin release, Kupffer cell activation, and liver injury. Following chronic alcohol ingestion, endotoxin released from certain intestinal bacteria moves from the gut into the bloodstream and into the liver. There the endotoxin activates Kupffer cells—a type of immune cell (i.e., macrophages) residing in the liver—by interacting with a molecule called CD14 located on the surface of those cells. This interaction causes the production of the regulatory nuclear factor kappa B (NFκB), which in turn leads to the generation of significant amounts of cytotoxic factors, namely superoxide radicals (O2) and various signaling molecules (i.e., cytokines), most prominently TNF–α.

TNF–α has been shown to be an essential factor in the injury to primary liver cells (i.e., hepatocytes) associated with alcoholic liver disease. Mechanisms and Consequences of Kupffer Cell Activation by Endotoxin The idea that gut–derived endotoxin is central to the activation of Kupffer cells in alcoholic liver disease gave rise to further questions about endotoxin’s specific role in the process: How does endotoxin leak from the gut into the bloodstream? How does endotoxin activate the Kupffer cells? What are the consequences of Kupffer cell activation? Answers to these questions have become clearer in recent years thanks to several research advances, especially the development of new genetic mouse models and the landmark discovery of a molecule located on the Kupffer cells that can bind to and interact with endotoxin (i.e., the LPS receptor). Eventually these emerging answers may contribute significantly to new therapies for alcoholic liver disease. Changes in Gut Permeability Lead to Increased Endotoxin Levels in the Blood Several mechanisms may underlie the significant increase in endotoxin levels in the bloodstream following chronic alcohol use.

According to one hypothesis, chronic alcohol use leads to higher endotoxin levels in the blood because it prevents Kupffer cells from effectively clearing these molecules from the circulation (Rivera et al. 1998). In addition, increased absorption of endotoxin from the intestine may play a role in alcohol–induced liver disease (Nolan 1975; Adachi et al. 1994). Researchers found that, in rats, acute ingestion of high alcohol concentrations facilitated the absorption of endotoxin from the animals’ small intestine by increasing intestinal permeability—that is, the degree to which the cell wall allows the passage of various molecules, including endotoxin, into the blood (Tamai et al. 2000). Other studies have shown that high alcohol concentrations can directly damage the cells lining the interior of the intestine (i.e., the intestinal epithelium), thereby impairing the ability of the epithelium to serve as a barrier preventing access of unwanted substances from the intestine to the bloodstream (Ma et al. 1999). The exact mechanism by which alcohol disrupts this protective barrier to endotoxin still is unknown, however.

Interestingly, females have higher levels of endotoxin in the blood after chronic alcohol exposure than do males (Kono et al. 2000a), suggesting that females may be more susceptible than males to alcohol–induced increases in gut permeability to endotoxin. These variations may be related to differences between male and female hormone systems, because researchers have demonstrated that gut permeability is significantly increased in animals treated with the female hormones estradiol and progesterone (Konno et al. 2002). Whether this mechanism explains the long–standing observation that women are more susceptible than men to alcohol–induced liver damage, however, has yet to be determined. How Endotoxin Activates Kupffer Cells Researchers have identified a protein called CD14, which is located on the surface of Kupffer cells, as the receptor to which endotoxin binds (Wright et al. 1990). CD14 must be present for endotoxin to activate Kupffer cells. This activation involves the transmission of some kind of signal from the Kupffer cell’s exterior to the interior, where it triggers the numerous biochemical reactions through which an activated Kupffer cell performs its functions.

CD14 is located exclusively on the outside of each Kupffer cell and does not reach through the membrane surrounding the cells into the cell’s interior. Therefore, researchers have postulated that endotoxin also must interact with another receptor which transmits a signal into and within the Kupffer cell. Indeed, investigators recently identified several molecules called Toll–like receptors (TLR)2 that serve as coreceptors for endotoxin, with different TLR proteins interacting with endotoxin from different bacteria (Beutler and Rietschel 2003). (2 These receptors derive their name from the fact that their structure is similar to that of a protein called Toll previously identified in fruit flies.) The receptor most relevant to endotoxin–induced alcoholic liver disease is TLR4.3 (3 By convention, the human protein is written as TLR4, the corresponding mouse protein is written as Tlr4, and the gene encoding the mouse protein is written as tlr4.) Subsequent analyses have established the relationships between endotoxin, CD14, and TLR4 (see figure 2).

CD14, together with another protein called LPS–binding protein (LBP), serves as a structural receptor for endotoxin—that is, it binds to the endotoxin and physically attaches it to the Kupffer cell. The endotoxin can then interact with TLR4, and this interaction generates a signal that is transmitted by TLR4 to the cell’s interior. Figure 2 How endotoxin activates Kupffer cells in the liver. Endotoxin, also called lipopolysaccharide (LPS), in association with soluble LPS–binding protein (LBP), interacts with a receptor complex consisting of the proteins CD14 and TLR4. This interaction initiates a variety of signaling cascades in the cell. One of these cascades, which involves interleukin–1 receptor–associated kinase (IRAK) and the associated proteins MyD88 and TRAF, acts on a regulatory molecule called nuclear factor kappa B (NFκB), which is inactive in the cell if it is associated with the inhibitory molecule IκBα. In response to the signals initiated by endotoxin binding, IκBα is released from NFκB, leading to activation of NFκB.

This activation, in turn, results in a number of different responses, such as the generation of superoxide through the NADPH oxidase complex and the production of cytokines. NOTE: MyD88 = myeloid differentiation factor 88; TRAF = tumor necrosis factor receptor–associated factor. Animal experiments have confirmed the importance of TLR4 in endotoxin–mediated liver damage. For nearly 25 years, researchers have known that animals from the C3H/HeJ strain of mice do not suffer adverse effects after being treated with endotoxin (Glode et al. 1976). Recent studies have shown that these mice carry a mutation in the tlr4 gene which alters an important amino acid in the part of the Tlr4 protein that is located on the inside of the Kupffer cell (Qureshi et al. 1999; Poltorak et al. 1998). As a result, the altered protein cannot send signals into the Kupffer cells that initiate the cells’ usual response to endotoxin; thus these mice are resistant to endotoxin’s effects.

Researchers then hypothesized that if endotoxin is critical for the development of alcoholic liver disease, C3H/HeJ mice should be resistant to liver injury caused by chronic alcohol administration. Investigation of this hypothesis was made easier by two methodological advances: First, a method for administering alcohol directly into animals’ stomachs (i.e., intragastric infusion) (see the article by Nanji and French in this issue), was modified for use with mice, which are more commonly used in research. Second, using genetic engineering, investigators developed new mouse strains that carried specific foreign genes (i.e., transgenic mice) or lacked certain genes (i.e., knockout mice) in order to analyze the consequences of these alterations. Together, these advances enabled researchers to create mouse strains that either produce higher–than–normal amounts of certain components of the CD14/LBP/Tlr4 complex or lack them, and then to study the effects of these changes when the animals were chronically exposed to alcohol. These developments led to an explosion of studies that significantly expanded researchers’ understanding of the role of endotoxin in alcoholic liver disease.

For example, investigators demonstrated that C3H/HeJ mice, which were resistant to endotoxin’s effects, showed no signs of alcohol–induced liver injury following 4 weeks of chronic alcohol feeding (Uesugi et al. 2001a). In contrast, mice without the tlr4 mutation normally develop severe alcoholic hepatitis after consuming the same amount of alcohol. Other studies using animals in which the genes for CD14 were removed or which lacked LBP demonstrated that signaling processes mediated by the LPS receptor were critical to the development of liver disease associated with chronic alcohol administration (Yin et al. 2001a). Consequences of Kupffer Cell Activation by Endotoxin As mentioned earlier, one consequence of Kupffer cell activation is the production of ROS, particularly superoxide, which in large amounts can lead to oxidative stress. Results of several studies suggest that the oxidative stress associated with chronic alcohol consumption is largely attributable to endotoxin–induced activation of Kupffer cells (Kono et al. 2000a; Yin et al. 2001b).

This hypothesis expanded the current assumption that alcohol–associated oxidative stress results primarily from the degradation of alcohol in the liver by an enzyme system called cytochrome P450 2E1. (For more information on this enzyme system and its role in the production of ROS, see the article by Wu and Cedarbaum in this issue.) Evidence for the Kupffer cell–centered hypothesis of oxidative stress comes from research with mice that lack a critical component of the NADPH oxidase complex (Jackson et al. 1995), the enzyme responsible for generating superoxide in activated Kupffer cells. After 4 weeks of chronic alcohol administration, these mice did not show signs of liver damage or an increase in the production of ROS (Kono et al. 2000b). This finding—combined with the previously mentioned research showing that malfunctioning or absent Kupffer cell receptors appear to protect against liver damage normally associated with alcohol consumption—establishes a link between endotoxin, Kupffer cell activation, and alcohol–induced oxidative stress.

Endotoxin–Induced Intracellular Signaling Pathways in Kupffer Cells As a result of endotoxin’s binding to CD14 and TLR4, Kupffer cells initiate various internal signaling processes. How endotoxin triggers these signaling pathways has been the subject of increasing research attention, given the importance of endotoxin and Kupffer cells in the development of alcohol–induced liver injury and other liver diseases. As discussed earlier, endotoxin activates Kupffer cells through interaction with the receptor complex consisting of LBP, CD14, and TLR4. When endotoxin binds to this complex of molecules, TLR4 activates a molecule called interleukin–1 receptor–associated kinase (IRAK–1). The term “kinase” means that this enzyme can add phosphate groups to other molecules, such as enzymes, in the cells. Adding phosphate groups to various enzymes, or removing them, is important for activating or deactivating those enzymes and thereby conveying signals from the cell surface into and within all cells.

For example, IRAK–1 sets off a series of signals leading to the activation of an important regulatory molecule called nuclear factor kappa B (NFκB) (Beutler and Rietschel 2003), which is crucial for regulating the activities of many genes and the cellular processes governed by those genes. Numerous other signaling pathways in Kupffer cells also are activated by endotoxin (see figure 2). IRAK–1 is rapidly activated and then again inactivated or degraded in response to endotoxin’s activation of macrophages, including Kupffer cells (Li et al. 2000). This finding indicates both that IRAK–1 is essential for endotoxin–mediated signaling and that IRAK–1 may regulate the cellular response to endotoxin. More–over, changes in IRAK–1 activity may serve to regulate the cascade of signals that has been triggered by endotoxin. Thus, altered IRAK–1 expression and activity may decrease signaling events mediated by TLR4 as well as the production of cytokines (i.e., a negative feedback mechanism).

When it became evident that endotoxin alters IRAK–1 activity, researchers postulated that acute alcohol exposure would lead to changes in IRAK–1 as well. Consistent with this hypothesis, Yamashina and colleagues (2000) found that in mice, alcohol administration rapidly suppressed the production and activity of IRAK–1 in the liver. In addition, IRAK–1 production was strongly correlated with the degree to which liver cells responded to endotoxin levels after acute alcohol administration. Changes in IRAK–1 activity may be central to the phenomena of tolerance and sensitization. Tolerance means that the cells become less sensitive than normal to a stimulus (i.e., are hypo–responsive), whereas sensitization means that the cells become more sensitive than normal (i.e., are hyper–responsive). Scientists have known for some time that in addition to causing Kupffer cells to be activated by endotoxin, alcohol alters the degree to which these cells respond to endotoxin. Alcohol can cause both tolerance and sensitization to endotoxin, depending upon conditions: Acute alcohol administration typically induces tolerance, whereas chronic alcohol administration sensitizes or “primes” the liver to the toxic effects of endotoxin (Mathurin et al.

2000). Compelling evidence indicates that changes in the levels and activity of IRAK–1 and CD14 may underlie these observations (Yamashina et al. 2000; Wheeler and Thurman 2003). As the previous sentence implies, levels of CD14 on Kupffer cells are variable rather than constant. Normally Kupffer cells have relatively few CD14 molecules on their surface (Antal–Szalmas 2000). However, numerous stimuli, including endotoxin, can lead to an increase in CD14 levels (Yamamoto et al. 1998). In humans, Kupffer cells in the normal liver have a low number of CD14 molecules, but this number increases in different inflammatory liver diseases. In rodents, CD14 levels in the liver also rise in many liver diseases, including alcoholic and cholestatic4 liver injury.

(4 Cholestatic liver disease is a type of liver disease [i.e., hepatitis] that leads to an interruption of the flow of bile from the liver to parts of the intestine.) Additional animal models have demonstrated that the levels of CD14 on macrophages vary with different stages of alcohol–induced damage (Kono et al. 2000a; Kishore et al. 2002). Finally, studies in mice have demonstrated that after acute alcohol exposure, the levels of CD14 mRNA—the intermediary molecule required for production of the CD14 protein from the genetic information encoded in the DNA—increase rapidly in the liver (Wheeler and Thurman 2003). The physiological significance of these changes in the levels and activities of CD14 and IRAK–1 in Kupffer cells is not entirely clear, but these modifications could determine the liver’s sensitivity to the toxic effects of endotoxin. In addition, emerging data suggest that changes in the levels of TLR4 and other related proteins may be associated with various diseases.

Potential Targets for the Treatment of Alcoholic Liver Disease One of the main purposes of investigating the role of endotoxin–induced signaling events in alcoholic liver disease is to develop therapeutic approaches that can interrupt these processes, thereby preventing or at least ameliorating the resulting liver disease. One relatively unspecific approach has been to use a variety of antioxidant compounds and extracts to reduce the amount of ROS produced by activated Kupffer cells. This approach has been successful in experimental models. Most antioxidant compounds and dietary extracts, however, cannot target the production or accumulation of specific ROS. Therefore, we cannot definitively determine whether using antioxidants is effective against ROS generated by endotoxin–induced superoxide or against other mechanisms of oxidative stress associated with chronic alcohol abuse. Another successful experimental approach has been the use of genetically engineered viruses that produce excessive amounts of (i.e., overexpress) specific enzymes and signaling molecules. For example, treating animals with a virus that overexpressed an enzyme which helps to convert superoxide into harmless products (i.e., cytosolic Cu/Zn superoxide dismutase) almost completely prevented alcohol–induced liver injury and reduced alcohol–induced TNF–α production in the animals (Wheeler et al. 2001).

Similar results were obtained using a genetically engineered virus to overexpress a molecule that can suppress the activation of NFκB (Uesugi et al. 2001b). Whether such virus–mediated gene transfer will be of clinical use, however, has yet to be determined. As researchers rapidly learn more about the role of TLR4 and other TLR molecules in signal transmission in macrophages, it becomes more likely that additional important therapeutic targets will be identified. For example, inhibitors that specifically interfere with signal transmission by TLR4 should be ideal candidates for potential therapy of alcoholic liver disease. With the convincing demonstration of the role of endotoxin in pathology associated with chronic alcohol exposure and further discoveries related to TLR activity, the next few years could yield exciting advances in liver disease research. To date, there has been no effective therapy for alcoholic liver disease. Now, however, researchers and clinicians are hopeful that these approaches will result in novel and effective therapies for this debilitating disease. References Adachi, Y.; Bradford, B.U.; Gao, W.; et al. Inactivation of Kupffer cells prevents early alcohol–induced liver injury. Hepatology 20:453–460, 1994.

Adachi, Y.; Moore, L.E.; Bradford, B.U.; et al. Antibiotics prevent liver injury following chronic exposure of rats to ethanol. In: Wisse, E.; Knook, D.L.; and Wake, K.; eds. Cells of the Hepatic Sinusoid. Leiden, The Netherlands: Kupffer Cell Foundation, 1995. pp. 72–74. Antal–Szalmas, P. Evaluation of CD14 in host defence. European Journal of Clinical Investigation 30:167–179, 2000. Arteel, G.E.; Uesugi, T.; Bevan, L.N.; et al. Green tea extract protects against early alcohol–induced liver injury in rats. Biological Chemistry 383:663–670, 2002. Beutler, B., and Rietschel, E.T. Innate immune sensing and its roots: The story of endotoxin. Nature Reviews Immunology 3:169–176, 2003.

Bird, G.L.; Sheron, N.; Goka, A.K.; et al. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Annals of Internal Medicine 112:917–920, 1990. Fukui, H.; Brauner, B.; Bode, J.C.; and Bode, C. Plasma endotoxin concentrations in patients with alcoholic and non–alcoholic liver disease: Reevaluation with an improved chromogenic assay. Journal of Hepatology 12:162–169, 1991. Glode, L.M.; Scher, I.; Osborne, B.; and Rosenstreich, D.L. Cellular mechanism of endotoxin unresponsiveness in C3H/HeJ mice. Journal of Immunology 116:454–461, 1976. Honchel, R.; Ray, M.B.; Marsano, L.; et al. Tumor necrosis factor in alcohol enhanced endotoxin liver injury. Alcoholism: Clinical and Experimental Research 16:665–669, 1992.

Iimuro, Y.; Gallucci, R.M.; Luster, M.I.; et al. Antibodies to tumor necrosis factor–a attenuate hepatic necrosis and inflammation due to chronic exposure to ethanol in the rat. Hepatology 26:1530–1537, 1996. Jackson, S.H.; Gallin, J.I.; and Holland, S.M. The p47phox mouse knock–out model of chronic granulomatous disease. Journal of Experimental Medicine 182:751–758, 1995. Kishore, R.; Hill, J.R.; McMullen, M.R.; et al. ERK1/2 and Egr–1 contribute to increased TNF–alpha production in rat Kupffer cells after chronic ethanol feeding. American Journal of Physiology: Gastrointestinal and Liver Physiology 282:G6–G15, 2002. Konno, A.; Enomoto, N.; Takei, Y.; et al. Oral contraceptives worsen endotoxin–induced liver injury in rats.

Alcoholism: Clinical and Experimental Research 26:70S–74S, 2002. Kono, H.; Wheeler, M.D.; Rusyn, I.; et al. Gender differences in early alcohol–induced liver injury: Role of CD14, NFκB, and TNFα. American Journal of Physiology: Gastrointestinal and Liver Physiology 278:G652–G661, 2000a. Kono, H.; Rusyn, I.; Yin, M.; et al. NADPH oxidase–derived free radicals are key oxidants in alcohol–induced liver disease. Journal of Clinical Investigation 106(7):867–872, 2000b. Kono, H.; Rusyn, I.; Uesugi, T.; et al. Diphenyl–eneiodonium sulfate, an NADPH oxidase inhibitor, prevents early alcohol–induced liver injury in the rat. American Journal of Physiology: Gastrointestinal and Liver Physiology 280:G1005–G1012, 2001.

Li, L.; Coursat, S.; Hu, J.; and McCall, C.E. Characterization of IRAK in normal and endotoxin tolerant cells. Journal of Biological Chemistry 275:2410–2414, 2000. Ma, T.Y.; Nguyen, D.; Bui, V.; et al. Ethanol modulation of intestinal epithelial tight junction barrier. American Journal of Physiology: Gastrointestinal and Liver Physiology 276: G965–G974. 1999. Mathurin, P.; Deng, Q.G.; Keshavarzian, A.; et al. Exacerbation of alcoholic liver injury by enteral endotoxin in rats. Hepatology 32:1008–1017, 2000. McClain, C.J., and Cohen, D.A. Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology 9:349–351, 1989. McKim, S.E.; Konno, A.; Gabele, E.; et al.

Cocoa extract protects against early alcohol–induced liver injury in the rat. Archives of Biochemistry and Biophysics 406:40–46, 2002. Nanji, A.A.; Khettry, U.; and Sadrzadeh, S.M. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver disease. Proceedings of the Society for Experimental Biology and Medicine 205:243–247, 1994. Nolan, J.P. The role of endotoxin in liver injury. Gastroenterology 69:1346–1356, 1975. Poltorak, A.; He, X.; Smirnova, I.; et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene. Science 282:2085–2088, 1998. Qureshi, S.T.; Gros, P.; and Malo, D.

The Lps locus: Genetic regulation of host responses to bacterial lipopolysaccharide. Inflammation Research 48: 613–620, 1999. Rivera, C.A.; Bradford, B.U.; Gao, W.; et al. Role of endotoxin in the hypermetabolic state following acute ethanol exposure. American Journal of Physiology: Gastrointestinal and Liver Physiology 275:G1252–G1258, 1998. Tamai, H.; Kato, S.; Horie, Y.; et al. Effect of acute ethanol administration on the intestinal absorption of endotoxin in rats. Alcoholism: Clinical and Experimental Research 24:390–394, 2000. Uesugi, T.; Froh, M.; Arteel, G.E.; et al. Toll–like receptor 4 is involved in the mechanism of early alcohol–induced liver injury in mice. Hepatology 34:101–108, 2001a. Uesugi, T.; Froh, M.; Arteel, G.E.; et al.

Delivery of IkappaB superrepressor gene with adenovirus reduces early alcohol–induced liver injury in rats. Hepatology 34:1149–1157, 2001b. Wheeler, M.D., and Thurman, R.G. Up–regulation of CD14 in liver caused by acute ethanol involves oxidant–dependent AP–1 pathway. Journal of Biological Chemistry 278:8435–8441, 2003. Wheeler, M.D.; Froh, M.; Yamashima, S.; et al. Adenovirus can transduce Kupffer cells: Role of oxidants in NFκB activation and TNFα production. Journal of Leukocyte Biology 69:622–630, 2000. Wheeler, M.D.; Kono, H.; Yin, M.; et al. Delivery of the Cu/Zn–superoxide dismutase gene with adenovirus reduces early alcohol–induced liver injury in rats. Gastroenterology 120:1241–1250, 2001.

Wright, S.D.; Ramos, R.A.; Tobias, P.S.; et al. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249:1431–1433, 1990. Yamamoto, S.; Tamura, Y.; Higuchi, Y.; et al. Roles of CD14 in LPS signaling and scavenging: Analysis of CD14 transgenic and non–transgenic mice and rats in response to LPS. Progress in Clinical and Biological Research 397:89–96, 1998. Yamashina, S.; Wheeler, M.D.; Rusyn, I.; et al. Tolerance and sensitization to endotoxin in Kupffer cells caused by acute ethanol involve interleukin–1 receptor–associated kinase. Biochemical and Biophysical Research Communications 277:686–690, 2000. Yin, M.; Wheeler, M.D.; Kono, H.; et al. Essential role of tumor necrosis factor alpha in alcohol–induced liver injury.

Gastroenterology 117:942–952, 1999. Yin, M.; Bradford, B.U.; Wheeler, M.D.; et al. Reduced early alcohol–induced liver injury in CD14–deficient mice. Journal of Immunology 166:4737–4742, 2001a. Yin, M.; Gabele, E.; Wheeler, M.D.; et al. Alcohol–induced free radicals in mice: Direct toxicants or signaling molecules? Hepatology 34:935–942, 2001b. Prepared: October 2004 What are Kupffer Cells? (with pictures) Hobbies What are Kupffer Cells? Last Modified Date: 12 December 2016 Copyright Protected: 10 hilariously insightful foreign words Kupffer cells are a specialized form of immune cells that exist only within the liver.

They are one of several kinds of macrophages , a type of white blood cell , that help the body maintain health by destroying bacteria, old blood cells and other foreign substances that occur in the blood stream because of illness, injury or body malfunction or simply through natural aging of the various body cells. These cells develop within the bone marrow , then migrate to the liver, where they complete their development into cells specially designed to protect the liver. These specialized cells are considered part of the reticuloendothelial system , a part of the immune system . This subdivision of the overall human immune system consists not only of the Kupffer cells, but also of immune cells located in the reticular connective tissue. Reticular connective tissue is specialized tissue that supports the lymph nodes, the spleen and the red bone marrow. It also helps support adipose tissue , or fat cells. All of these elements contribute to the complex network of cells and organs that constitute the human immune system. Originally discovered in 1876 by Karl Wilhelm von Kupffer, these cells originally were believed to originate within the liver and to constitute part of the lining of the liver's blood vessels .

Additional research and observation led another scientist, Tadeusz Browicz, to realize that they were macrophages that originated not in the liver, but in the bone marrow. He made this discovery in 1898, and because of his role in their discovery and function, they are sometimes also called Browicz-Kupffer cells. Since then, scientists have discovered many of their functions, including their role in recycling dead blood cells and helping the liver respond to toxic substances in the blood stream. As part of their normal immune function, Kupffer cells also help repair injury to the liver. They have a role in the development of cirrhosis of the liver, a serious disease characterized by scarring and excess fibrous tissue in the organ, most often caused by excessive alcohol consumption. Some triggers, including carcinogenic agents, can cause the cells to initiate production of collagen , a connective tissue, within the liver. Too much of this tissue, as well as excessive scarring in the liver, eventually renders the liver unable to perform its normal function. It also makes it impossible for the liver to regenerate itself as it does under normal circumstances.

Ad Kupffer cell - Biology-Online Dictionary A specialized stellate macrophage cell that is located fixedly within the liver sinusoids Supplement Kupffer cells are the specialized macrophages located in the liver , particularly at the lining of liver sinusoids. They are part of the mononuclear phagocyte system . Their name is derived from Karl Wilhelm von Kupffer, a German anatomist who was the first to describe them in 1876.1 Initially, he referred to these cells as sternzellen because of the star-shape of the cells. He described the cells as specialized endothelial cells of the liver capable of phagocytosis. Tadeusz Browicz, a Polish pathologist, was able to correctly identify them as macrophages residing in the liver.2 The Kupffer cells originate from bone marrow stem cells and migrate to the liver via the bloodstream as monocytes . In the liver sinusoidal walls, they differentiate into Kupffer cells.3 The Kupffer cells can be found lying next to endothelial cells or in the endothelial lining and may extend into the space of Disse .

They contain peroxidases in the endoplasmic reticulum , which make them different from hepatic endothelial cells since the latter lack peroxidase. 4 The Kupffer cells are the most abundant resident macrophages. They are the body's largest population (about 80%) of fixed macrophages of the mononuclear phagocyte system . The function of Kupffer cells is to break down red blood cells through phagocytosis , liberating the globin chains and the heme component for further metabolic processing and re-use. Kupffer cells also play an essential role in innate immunity. They are involved in phagocytosing blood-borne bacteria passing through the liver from the gut. They are also capable of producing cytokines , chemokines , and ROS. Therefore, they are capable of recruiting monocytes into the liver , as well as participate in the development of alcoholic liver damage (via ROS production). Variant(s): Kupffer cell | anatomy | Britannica.com Kupffer cell white blood cell Kupffer cell, any of the stellate (star-shaped) cells in the linings of the liver sinusoids. The sinusoids are microscopic blood channels.

The Kupffer cells are phagocytic, i.e., capable of ingestion of other cells and of foreign particles. They also store hemosiderin so that it is available for the production of hemoglobin , the oxygen-transporting component of the red blood cell . Hemosiderin is an iron-containing pigment that is formed from the hemoglobin of red blood cells that have disintegrated. Learn More in these related articles: in human digestive system: Microscopic anatomy ...which fingerlike projections (microvilli) of the hepatocytes extend, allowing direct accessibility of the hepatocyte to the bloodstream in the sinusoids. The other major cell of the liver, the Kupffer cell, adheres to the wall of the sinusoid and projects into its lumen. It functions as a phagocyte (a cell that engulfs and destroys foreign material or other cells). Small spaces (Disse... in liver ...bile ducts and blood vessels. Hepatic cells make up about 60 percent of the tissue and perform more metabolic functions than any other group of cells in the body.

A second group of cells, called Kupffer cells, line the smallest channels of the liver’s vascular system and play a role in blood formation, antibody production, and ingestion of foreign particles and cellular debris. in sinusoid ...marrow. The sinusoids form from branches of the portal vein in the liver and from arterioles (minute arteries) in other organs. The walls of the sinusoids are lined with phagocytic cells, called Kupffer cells, that digest old red blood cells and clear the bloodstream of toxins. 3 References found in Britannica Articles Assorted References Corrections? Updates? Help us improve this article! Contact our editors with your feedback. MEDIA FOR: You have successfully emailed this. Error when sending the email. Try again later. Edit Mode Submit Tips For Editing We welcome suggested improvements to any of our articles. You can make it easier for us to review and, hopefully, publish your contribution by keeping a few points in mind. Encyclopædia Britannica articles are written in a neutral objective tone for a general audience. You may find it helpful to search within the site to see how similar or related subjects are covered. Any text you add should be original, not copied from other sources.

At the bottom of the article, feel free to list any sources that support your changes, so that we can fully understand their context. (Internet URLs are the best.) Your contribution may be further edited by our staff, and its publication is subject to our final approval. Unfortunately, our editorial approach may not be able to accommodate all contributions. Submit Thank You for Your Contribution! Our editors will review what you've submitted, and if it meets our criteria, we'll add it to the article. Please note that our editors may make some formatting changes or correct spelling or grammatical errors, and may also contact you if any clarifications are needed. Uh Oh There was a problem with your submission. Please try again later. Close Date Published: July 20, 1998 URL: Access Date: January 19, 2017 Share Iron Absorption Iron Absorption In general, the digestive system is set up to maximize absorption; there is no regulation in the amount of substances absorbed into the body. A notable exception is iron, in which daily dietary absorption is regulated so that it matches daily iron loss. The reason that absorption must be carefully regulated is that the body does not possess a physiological mechanism for regularly eliminating iron from the body.

Iron is a necessary component of various enzymes, but its major role is in oxygen-binding as a component of hemoglobin in red blood cells. Iron deficiency leads to anemia, a decrease in the oxygen carrying capacity of blood. However, too much iron in the body can be extremely toxic to tissues because it promotes the formation of free radicals. The majority of the body's iron is found in hemoglobin of developing and mature red blood cells. Of the remaining iron, a significant portion is stored in the liver, both in the hepatocytes, and in the Kupffer cells (also known as reticuloendothelial cells), a type of macrophage found in the liver. Kupffer cells play an important role in recycling body iron. They ingest aged red blood cells, liberating iron for reuse by breaking down hemoglobin. The small amount of iron that is lost each day (about 1-2 mg) is matched by dietary absorption of iron. The important players in the dietary absorption of iron are diagrammed in the figure. (Note that this is a simplified scheme; not all the details are included).

Iron is brought into the cell through an active transport process involving the protein DMT-1 (divalent metal transporter-1), which is expressed on the apical surface of enterocytes in the initial part of the duodenum. DMT-1 is not specific to iron, and can transport other metal ions such as zinc, copper, cobalt, manganese, cadmium or lead. Enterocytes also absorb heme iron through a mechanism that has not yet been characterized. Once inside the enterocyte, there are two fates for iron: It may leave the enterocyte and enter the body via the basolateral transporter known as ferroportin. It can be bound to ferritin, an intracellular iron-binding protein. For the most part, iron bound to ferritin in the enterocyte will remain there. This iron will be lost from the body when the enterocyte dies and is sloughed off from the tip of the villus. Iron that enters the internal environment of the body from the basolateral surface of the enterocyte is rapidly bound to transferrin, an iron-binding protein of the blood.

Transferrin delivers iron to red blood cell precursors, that take up iron bound to transferrin via receptor-mediated endocytosis. Normally, the capacity of transferrin to bind iron in the plasma greatly exceeds the amount of circulating iron. The transferrin saturation (percent of transferrin occupied by iron) is measured to determine if an individual has an excessive load of iron in the body. The normal transferrin saturation is in the range of 20-45%. Iron absorption by the enterocyte is programmed to match the body's needs. There are two major signals that affect iron absorption. 1. One signal reflects the need for iron due to erythropoiesis (red blood cell generation). The hormone erythropoietin (produced by the kidneys) stimulates red blood cell production, but it is NOT the signal regulating iron absorption. Rather, once erythropoiesis is stimulated, another signal is generated that promotes increased iron absorption. 2. A second signal depends upon the amount of iron in body stores. Iron absorption is stimulated if the level in body stores is low. These signals (and others) regulate iron absorption in the proximal duodenum, where iron is absorbed.

An important player in this regulation is the recently discovered hormone hepcidin. Hepcidin is produced by hepatocytes when iron stores are full. Inflammation can also stimulate hepcidin production. The figure shows the model for how hepcidin acts on duodenal enterocytes to decrease the amount of iron absorbed into the body. Experiments have shown that hepcidin binds to the basolateral iron transporter ferroportin. This causes ferroportin to be internalized and degraded. As a result, more iron remains within the enterocyte. This stimulates ferritin synthesis, so that the iron that enters the enterocyte gets bound to ferritin. This iron is mostly lost from the body when the enterocyte dies. Hemochromatosis arises when there is an excess of iron in the body. Excessive iron forms deposits in tissues, promoting free-radical formation and damage to cells. Particular tissues that are affected are the joints, liver, pancreas, heart and pituitary gland. The most prevalent form of hereditary hemochromatosis is caused by a mutation in a gene known as HFE.

The mutation in HFE that causes hemochromatosis is quite common in the Caucasian population, however, only some homozygotes will develop hemochromatosis later in life (after middle age). Women with mutations in HFE are to some degree protected from developing iron overload because of regular blood loss through menstrual bleeding. A very rare, severe juvenile form of hemochromatosis is due to a homozygous deletion of the gene for hepcidin. The exact function of the HFE protein is still being determined, but it is thought that HFE functions in the process of sensing body iron levels and regulating hepcidin secretion. Genetic experiments in mice have shown that HFE function is required in hepatocytes to trigger normal levels of hepcidin secretion in response to increased iron in the body. Individuals with hereditary hemochromatosis have deficient secretion of hepcidin, and so iron absorption by duodenal enterocytes continues even when body iron stores are full. Hemochromatosis is treated by reducing the load of iron in the body. This is effectively accomplished by periodic phlebotomy (blood withdrawal).

Half a liter of blood contains approximately 200-250 mg of iron. Quick Quiz

Question: Where in the body are the Kupffer Cells found?
Answer: Liver