The liver is situated just below the diaphragm and the upper right side of the stomach. In human, it comprises about 2% of the total adult body weight and consists of four lobes (right, left, quadrate, and caudate lobe). At the microscopic and functional level, the liver is composed of lobules each of which ranges from 1 to 2.5 mm in diameter and contains a mass of cells (2
cells per milligram) (1
). The outline of the lobules in human liver are irregular, but in some of the lower animal species (for example, the pig), they are well-defined and have hexagonal shape (2
). The base of the lobule is clustered around the smallest hepatic vein (central vein). The remaining part of each lobule is imperfectly isolated from the surrounding lobules by a thin stratum of connective tissue in which a plexus of blood vessels and ducts is contained (1
). In some animals, as in the pig, the lobules are completely isolated from one another by the interlobular connective tissue (2
The liver consists of plural types of cells. The hepatocytes are in polyhedral shape. They vary in size from 12 to 25 μm in diameter and contain one or sometimes two distinct nuclei in each cell. The hepatocytes face, the perisinusoidal space called space of Disse. The neighboring hepatocytes are connected by tight junctions, gap junctions, and desmosomes. The sinusoids are made of endothelial cells, phagocytic Kupffer cells, stellate cells (Ito cells), and pit cells. The Kupffer cell is the macrophage attached to the sinusoidal endothelium and responsible for the removal of invading particles into the blood. Ito cells lie in the space of Disse and have a function of storage of retinoids, and with hepatic injury, they transform to myofibroblast-like cells and produce fibrous tissue. Pit cells are one of the natural killer cells types that are attached to the sinusoidal surface of the endothelium (1
The liver has an unusual blood supply system. Approximately 1,300 mL of blood flow into the liver every minute, representing about 25% of total cardiac output. About 80% of the liver blood is transported via
the portal vein carrying nutrients or digested food from the digestive tract. The other 20% come via
hepatic artery carrying oxygen-enriched blood from the heart. The hepatic artery and the portal vein branch into a network of small blood vessels that empty into the sinusoids where the venous and arterial blood mix (1
). The endothelial wall of the sinusoids is discontinuous (or fenestrated) with pores of about 100 nm in diameter, which brings blood substances or particles below 100 nm into direct contact with the liver cells beyond the endothelium. The sinusoids drain into the central veins which join to form the hepatic vein, from which blood leaves the liver, enters the inferior vena cava, and returns to the heart (1
The bile ducts begin at little passages in the liver cells that communicate with bile capillaries. These passages are merely little channels or spaces left between the contiguous surfaces of two or more hepatocytes. These channel-like bile ducts are always separated from the blood capillaries by at least half the width of a liver cell and open into the interlobular bile ducts which run in Glisson’s capsule accompanying with the portal vein and hepatic artery. The walls of the bile ducts consist of a connective tissue coat in which there are muscle cells arranged both circularly and longitudinally and an epithelial layer consisting of short columnar cells resting on a distinct basement membrane. The exterior coats of the large bile ducts is composed of strong fibrotic tissue with a certain amount of muscular tissue arranged for the most part in a circular manner around the duct. The interior mucous coat of the bile ducts is continuous with the lining membrane of the bile ducts and gallbladder and also with that of the duodenum. The bile juice enters the duodenum through papilla (1
The functions of the liver are numerous, working closely with nearly every system and process in the human body. The hepatic parenchymal cells have a broad range of synthetic and catabolic functions. The liver is the primary organ responsible for the metabolism of carbohydrates, lipids, proteins, and heme and for removal of toxins, hormones, and aged red blood cells. The liver is responsible for synthesizing most plasma proteins (with the exception of immunoglobulins), bile acids, cholesterol, and heparin and serves as the principal site for storage of iron, glycogen, lipids, and vitamins. The liver also plays an important role in the detoxification of many drugs and excretion of metabolic end products such as bilirubin, ammonia, and urea.
Because of its sophisticated and important function in regulating metabolism and maintaining homeostasis, the liver is a key organ for most metabolic pathways, and therefore, numerous inherited diseases have their origin in this organ. Candidate diseases include genetic disorders such as hemochromatosis, hemophilia A and B, alpha 1 antitrypsin deficiency, Wilson’s disease, Crigler–Najjar syndrome type I, ornithine transcarbamylase deficiency, type IIa familial hypercholesterolemia, and afibrinogenemia. Therefore, the medical significance and afferent and efferent pathways to the liver have made the liver an ideal target for gene therapy studies.
The primary barrier for nucleic acid delivery to liver cells is the plasma membrane. If DNA molecules are larger than 100 nm, the endothelium also serves as the barrier for intrahepatocyte delivery. As far as gene delivery to the liver is concerned, the true challenge is to deliver nucleic acids to most hepatocytes in the liver, if not all, without causing tissue damage.