The liver

Abstract

The liver is a critical hub for numerous physiological processes. These include macronutrient metabolism, blood volume regulation, immune system support, endocrine control of growth signaling pathways, lipid and cholesterol homeostasis, and the breakdown of xenobiotic compounds, including many current drugs. Processing, partitioning, and metabolism of macronutrients provide the energy needed to drive the aforementioned processes and are therefore among the liver's most critical functions. Moreover, the liver's capacities to store glucose in the form of glycogen, with feeding, and assemble glucose via the gluconeogenic pathway, in response to fasting, are critical. The liver oxidizes lipids, but can also package excess lipid for secretion to and storage in other tissues, such as adipose. Finally, the liver is a major handler of protein and amino acid metabolism as it is responsible for the majority of proteins secreted in the blood (whether based on mass or range of unique proteins), the processing of amino acids for energy, and disposal of nitrogenous waste from protein degradation in the form of urea metabolism. Over the course of evolution this array of hepatic functions has been consolidated in a single organ, the liver, which is conserved in all vertebrates. Developmentally, this organ arises as a result of a complex differentiation program that is initiated by exogenous signal gradients, cellular localization cues, and an intricate hierarchy of transcription factors. These processes that are fully developed in the mature liver are imperative for life. Liver failure from any number of sources (e.g. viral infection, overnutrition, or oncologic burden) is a global health problem. The goal of this primer is to concisely summarize hepatic functions with respect to macronutrient metabolism. Introducing concepts critical to liver development, organization, and physiology sets the stage for these functions and serves to orient the reader. It is important to emphasize that insight into hepatic pathologies and potential therapeutic avenues to treat these conditions requires an understanding of the development and physiology of specialized hepatic functions.

Figure 1. Organization of the liver

(A) Geometric representation of a hepatic lobule. Appearing roughly hexagonal in shape, the vertices represent the portal triad area. Each triad contains branches of the hepatic artery, portal vein, and bile duct. Oxygenated blood from the hepatic artery mixes with nutrient-rich blood from the portal circulation drained from the gut. Upon mixing, this blood equilibrates and fl ows across the lobule through a sinusoidal network before draining in to branches of the central vein. This organization leads to formation of a number of gradients including oxygen, hormones, nutrients, and waste products. This gradient formation and the consequential organization of relevant metabolic processes has been dubbed ‘metabolic zonation’. These zones are depicted as roughly equal, but can shift in size and location based on a number of factors (e.g. hepatocellular damage or altered blood flow). (B) A schematic representation of a sinusoid within the liver and the corresponding zonation of several metabolic processes across the sinusoid. A number of cell types exist within the sinusoid including hepatocytes, biliary epithelial cells (cholangiocytes), endothelial cells, Kupffer cells, and stellate cells. As previously mentioned blood flows through the sinusoid leading to a number of gradients along the length of this vessel. Liver endothelial cells do not form tight junctions, but instead have sieve plate networks between them. This creates a minimal barrier between the circulating blood and hepatocytes. Hepatocytes perform a majority of the hepatic metabolic functions. The gradients depicted below the scheme pertain to both essential molecules (oxygen) and metabolic processes along the sinusoid. These processes are critical to both liver and whole body metabolic homeostasis. Therefore, it is important to note the flexibility of these gradients as they are often modified during times of variable nutrient availability, such as the fasting or fed states.

Figure 2. The liver in the fasted and fed state

(A) In the fasting state the liver is in a net hepatic glucose output mode due to the low insulin to glucagon ratio. Glucose is derived from both glycogen and gluconeogenesis. Gluconeogenic substrates are provided in the form of amino acids (gut and muscle), lactate (muscle), pyruvate (muscle), and glycerol (adipose tissue). Fatty acids from adipose tissue lipolysis are also directed to several pathways, such as beta-oxidation and the TCA cycle. These processes support gluconeogenesis through production of ATP and reducing equivalents. Ketone bodies may also be produced from lipid oxidation and act as an additional energy shuttle between the liver and other organs. Amino acids can also enter the TCA cycle as anaplerotic substrates and be utilized for synthesis of proteins. Nitrogen released as a result of deamination during amino acid metabolism are disposed of during ureagenesis. Urea is released from the liver and excreted by the kidneys. (B) During feeding, water soluble nutrients enter the portal venous circulation from the intestine. At the liver, the insulin to glucagon ratio is elevated leading to net hepatic glucose uptake. Glucose may undergo glycolysis, as a means of ATP production, or may be stored as glycogen. Amino acids may be oxidized for energy production or utilized as anaplerotic substrates for the TCA cycle. Once again, these amino acids, as in the fasted state, may be used for synthesis of local or secreted proteins. Ingested fats are assembled to form triglycerides from fatty acids and glycerol. These triglycerides are packaged into chylomicrons, which then enter the lymphatic system. Chylomicrons drain from the lymphatics to the circulation and, upon reaching the liver, are unloaded of remaining fatty acids and glycerol. Fatty acids can be used for restoration of energy state, repletion of TCA cycle intermediates, or re-esterified to triglycerides. Triglycerides can be loaded on to very low density lipoproteins, which shuttle lipid to other tissues including muscle and adipose depots.