Transport and Metabolic Functions of the Liver

Metabolic Functions of the Liver

Hepatocytes contribute to metabolism of the major nutrients: carbohydrates, lipids, and proteins. Thus, the liver plays an important role in glucose metabolism by engaging in gluconeogenesis, the conversion of other sugars to glucose. The liver also stores glucose as glycogen at times of glucose excess (such as in the postprandial period) and then releases stored glucose into the bloodstream as it is needed. This process is referred to as the “glucose buffer function of the liver.” When hepatic function is impaired, glucose concentrations in blood may rise excessively after the ingestion of carbohydrate; conversely, between meals, hypoglycemia may be seen.

Hepatocytes also participate in lipid metabolism. They are a particularly rich source of metabolic enzymes responsible for fatty acid oxidation to supply energy for other body functions. Hepatocytes also convert products of carbohydrate metabolism to lipids that can be stored in adipose tissue and synthesize large quantities of lipoproteins, cholesterol, and phospholipids. In addition, hepatocytes convert a considerable portion of synthesized cholesterol to bile acids, which will be discussed in more detail later in this chapter.

The liver also plays a vital role in protein metabolism. The liver synthesizes the nonessential amino acids (see Chapter 30 ) that do not need to be supplied in the diet and interconverts and deaminates amino acids so that the products can enter biosynthetic pathways for the synthesis of carbohydrates. With the exception of immunoglobulins, the liver synthesizes almost all of the proteins present in plasma, especially albumin, which determines plasma oncotic pressure, as well as most of the important clotting factors. Patients suffering from liver disease may develop peripheral edema secondary to hypoalbuminemia and are also susceptible to bleeding disorders. Finally, the liver is the critical site for disposal of the ammonia generated from protein catabolism. This is accomplished by converting ammonia to urea, which is excreted by the kidneys. The details of this process will be discussed later in this chapter.

The Liver and Detoxification

The liver serves both as a gatekeeper, by limiting the entry of toxic substances into the bloodstream, and as a garbage disposal, by extracting potentially toxic metabolic products produced elsewhere in the body and converting them to chemical forms that can be excreted. The liver is able to fulfill these functions, in part, because of its unusual blood supply. Unlike all other organs, the majority of blood arriving at the liver is venous in nature and is supplied via the portal vein from the intestine ( Fig. 32.1 ). As such, the liver is strategically located to receive both absorbed nutrients and potentially harmful absorbed molecules such as drugs and bacterial toxins. Depending on the efficiency with which these molecules are extracted by hepatocytes and subjected to first-pass metabolism, little or none of the absorbed substance may make it into the systemic circulation. This is a major reason why not all pharmaceutical agents can achieve therapeutic concentrations in the bloodstream if administered orally.

The liver has two levels at which it removes and metabolizes/detoxifies substances originating from the portal circulation. The first of these is physical. Blood arriving in the liver percolates among cells of the macrophage lineage, known as Kupffer cells. These cells are phagocytic and remove particulate material from portal blood, including bacteria that may enter blood from the colon even under normal conditions. The second level of defense is biochemical. Hepatocytes are endowed with a broad array of enzymes that modify both endogenous and exogenous toxins so that the products are, in general, more water soluble and less susceptible to reuptake by the intestine. The metabolic reactions involved are broadly divided into two classes. Phase I reactions (oxidation, hydroxylation, and other reactions catalyzed by cytochrome P-450 enzymes) are followed by phase II reactions that conjugate the resulting products with another molecule, such as glucuronic acid, sulfate, amino acids, or glutathione, to promote their excretion. The products of these reactions are then excreted into bile or returned to the bloodstream to ultimately be excreted by the kidneys.

Role of the Liver in Excretion

The kidneys play an important role in the excretion of water-soluble catabolites, as discussed in the renal section. Only relatively small water-soluble catabolites can be excreted by the process of glomerular filtration. However, larger water-soluble catabolites and molecules bound to plasma proteins, including lipophilic metabolites and xenobiotics, steroid hormones, and heavy metals, cannot be filtered by the glomerulus. All of these substances are potentially harmful if allowed to accumulate, so a mechanism must exist for their excretion. The mechanism involves the liver, which excretes these substances in bile. Hepatocytes take up these substances with high affinity by virtue of an array of basolateral membrane transporters, and the substances are subsequently metabolized at the level of microsomes and in the cytosol ( Table 32.1 ). Ultimately, substances destined for excretion in bile are exported across the canalicular membrane of hepatocytes via a different array of transporters. The features of bile allow solubilization of even lipophilic substances, which can then be excreted into the intestine and ultimately leave the body in feces.