Fasting, the absence of food intake, initiates a profound metabolic shift as the body transitions from relying on external calories to internal energy stores. The liver sits at the center of this transition, functioning as the primary metabolic regulator to maintain energy homeostasis. Its most significant task is ensuring a stable supply of glucose, particularly for the brain and red blood cells, which depend almost entirely on this sugar for fuel.
Phase One: Depleting Glycogen Stores
The liver’s immediate response to fasting is to tap into its readily available glucose reserve, a complex carbohydrate called glycogen. This process, known as glycogenolysis, begins hours after the last meal, typically within the first 8 to 12 hours of fasting. The liver breaks down its stored glycogen into glucose molecules, which are then released directly into the bloodstream.
This initial phase quickly stabilizes blood sugar levels using the most accessible internal fuel source. Liver glycogen stores are finite, usually amounting to about 100 grams in an adult, making this phase relatively short-lived. Once these reserves are depleted, the liver must pivot its strategy to manufacturing a new supply of glucose.
Phase Two: Manufacturing New Glucose
As liver glycogen stores dwindle, the body enters a phase where it must create new glucose from non-carbohydrate sources, a process termed gluconeogenesis. This pathway becomes the main source of glucose production, ramping up significantly after the initial 12 to 24 hours of fasting. The liver takes in precursor molecules from other tissues to construct new glucose molecules.
The starting materials are diverse, including lactate recycled from red blood cells and exercising muscle tissue. Glycerol, a byproduct released when fat is broken down in adipose tissue, also travels to the liver for conversion into glucose. Most significantly, glucogenic amino acids, mobilized from the breakdown of muscle protein, are utilized to provide the necessary carbon skeletons for glucose synthesis.
The Shift to Fat Fuel: Producing Ketone Bodies
While the liver continues to produce a baseline of glucose through gluconeogenesis, it orchestrates a massive shift toward using fat as the primary fuel source for the body. This is accomplished through the production and release of ketone bodies, which serve as an alternative energy source to spare the limited glucose supply. Fasting causes fat cells to release large amounts of fatty acids into the bloodstream, which the liver takes up.
Inside the liver’s mitochondria, these fatty acids undergo beta-oxidation, breaking them down into two-carbon units of acetyl-CoA. When the liver is flooded with acetyl-CoA from this high rate of fat breakdown, it accumulates faster than it can be processed by the normal energy cycle. The liver diverts this excess acetyl-CoA into a different pathway called ketogenesis.
This process creates three primary ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone. The liver releases acetoacetate and beta-hydroxybutyrate into the circulation, where they are transported to tissues outside the liver, such as the brain, heart, and muscle. These organs convert the ketones back into acetyl-CoA to power their energy needs. By supplying ketones, the liver reduces the overall demand for glucose, ensuring the brain has a sustainable fuel source during prolonged fasting.
Managing Nitrogenous Waste
The liver’s metabolic activity during fasting is not solely focused on energy production; it also manages waste. The reliance on amino acids for gluconeogenesis, particularly in the early stages of prolonged fasting, results in the liberation of excess nitrogen. This nitrogen takes the form of ammonia, a compound highly toxic to the central nervous system.
The liver handles this threat through the urea cycle. Within the liver cells, ammonia is rapidly combined with carbon dioxide in an energy-intensive process to synthesize urea. This conversion renders the toxic ammonia into a harmless, water-soluble compound.
The newly formed urea is released from the liver into the bloodstream and travels to the kidneys for filtration. The kidneys excrete the urea in the urine, effectively removing the excess nitrogenous waste generated from protein breakdown.