Liver Development Proteins

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 Liver Development Proteins Background

Liver architecture and cell composition

The adult liver has a unique structure of repeating hexagonal units termed lobules. Lobules are contiguous throughout the liver’s three-dimensional architecture. The middle of each lobule contains a central vein, whereas each of the six corners consists of the portal triad. The portal triad consists of three main vessels: the bile duct, hepatic artery, and portal vein. The hepatic artery supplies oxygen-rich blood while the portal vein supplies blood low in oxygen, but rich in nutrients and metabolic byproducts from the gastrointestinal tract. Blood enters the liver and flows along sinusoids towards the central veins, and eventually re-enters the circulation through the vena cava. Bile flows in the opposite direction of blood flow, towards the portal triad where they are transported via bile ducts to the gall bladder for storage before release into the small intestine.

The adult liver is comprised of numerous cell types. Hepatocytes account for 60-70% of the normal liver parenchyma. Hepatocytes are highly proliferative in the fetal liver. In the adult liver, hepatocytes are generally quiescent although they are capable of regeneration in response to hepatocyte loss. Hepatocytes contain a high percentage of endoplasmic reticulum as well as over one thousand mitochondria per cell, providing this cell with great synthetic potential. The majority of the liver function can be attributed to the hepatocyte. Hepatocytes are polarized epithelial cells. The apical portion bridges the canalicular lining where bile flow and secretion occurs. The basolateral sides of the hepatocyte are involved in nutrients, toxins, and metabolic byproducts exchange. Sinusiodal endothelial cells (SECs) which make up about 20% of the cellular content of the liver. These cells form the blood hepatocyte barrier and are important for the exchange of materials between blood and the space of Disse. Biliary Epithelial Cells (BECs) are bile duct epithelial cells, which share a common lineage with hepatocytes. Kupffer cells derive from bone marrow and are resident macrophages of the liver. Kupffer cells account for about 50% of the macrophages in adult mammals. Kupffer cells reside primarily in the sinusoids nearer the portal vein. They are phagocytic for bacteria, damaged and aged red blood cells, as well as macromolecules from the circulation. Kupffer cells can also present antigens and produce a variety of cytokines and chemokines. Pit cells are resident natural killer cells of the liver and anchored to the sinusoidal endothelium by pseudopodia. Hepatic stellate cells (HSC) are the major sites of vitamin A storage in adults. Stellate cells are important in chronic injury that leads to liver fibrosis, which will be discussed in the next section.


Liver development and liver disease

Cells in the mature liver must function in a coordinated manner for the liver to function properly. Proper liver function is essential for maintaining metabolic homeostasis in mammals. These functions include (a) the production of serum proteins, including clotting factors and transport proteins such as albumin and transferrin; (b) the removal and breakdown of serum proteins, red blood cells and microbes; (c) the production or removal of glucose during periods of fasting or eating, respectively; (d) the processing of fatty acids and triglycerides; (e) the maintenance of cholesterol homeostasis via synthesis or catabolism; (f) the synthesis and interconversion of non-essential amino acids; (g) the breakdown of toxic endogenous compounds such as ammonia; (h) the production and excretion of bile components; (i) the detoxification of xenobiotic agents; and (j) the storage of numerous substances. The processes require the coordinated regulation of numerous genes, and a number of transcription factors that control these genes have been identified. Transcription factors, including Foxa1/2, Hnf4 and Gata 4/6, are important regulators of early liver development.

With the liver carrying out so many crucial functions, it is perhaps not surprising that the full spectrum of chronic liver disease is a significant health problem worldwide. HBV and HCV, alcohol, and a variety of metabolic disorders contribute to this problem. The increasing prevalence of obesity and insulin resistance will lead to increasing number of individuals with non-alcoholic fatty liver disease (NAFLD), which is predicted to increase the frequency of steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Thus, while not considered to be a major health concern in the United States at this time, the burden of liver disease in the US healthcare enterprise is expected to grow.

NAFLD. More than 20% of Americans have NAFLD, and this is the leading cause of liver enzyme abnormalities in the United States. The development of NAFLD is determined by the interaction of genetic and environmental factors. NAFLD parallels the frequency of central adiposity, obesity, insulin resistance, metabolic syndrome and type 2 diabetes. Nonalcoholic steatohepatitis (NASH), a more serious form of NAFLD, can proceed to cirrhosis and hepatocellular carcinoma (HCC). It is predicted that one third of NAFLD cased progress to NASH, and why this happens is still not fully understood. A ‘two-hit’ hypothesis has been proposed for the pathogenesis of NASH. The first hit, steatosis, increases the sensitivity of the liver to the induction of inflammation by a second pathogenic hit that promotes oxidative stress and hence steatohepatitis. Certain proinflammatory cytokines, oxidative stress and possibly industrial toxins could all be the second hit to transform simple steatosis into NASH. The present optimal therapy for NASH is modest weight reduction. The complications of NASH, including cirrhosis and HCC, are expected to increase with the growing epidemic of diabetes and obesity.

Fibrosis and cirrhosis. Chronic liver diseases causing hepatic fibrosis and cirrhosis are among the most common digestive diseases in the United States. Cirrhosis can be defined as the end stage consequence of fibrosis. Fibrosis and cirrhosis are the consequences of a sustained wound healing response to chronic liver injury from viral, autoimmune, drug induced, cholestatic and metabolic diseases. Hepatic fibrosis and cirrhosis are a main cause of morbidity and mortality. HCV infection, in particular, affects more than 170 million individuals and causes 300,000 deaths annually worldwide due to cirrhosis and hepatocellular carcinoma. Up to 40% of patients with cirrhosis are asymptomatic and may remain so for more than a decade. The marked variability in progression of fibrosis has been attributed to age, gender, environmental factors and genetic factors.

HCC. HCC is the most common primary malignancy of the liver. It is the fifth most common cancer and is the third most common cause of cancer death globally. Although the incidence of HCC in Asia is starting to plateau or decrease, it is increasing in the United States and Europe. This disease carries a devastating prognosis, in that most cases remain undiagnosed until the disease has advanced to a metastatic stage, and the one-year cause-specific survival rates are less than 50%. The risk factors for HCC are well known and include hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol and hepatic metabolic syndrome. Numerous studies have identified the major oncogenic pathways that are known to be disregulated in HCC as well as several drugs used to block these pathways.