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Liver Metabolism: Gluconeogenesis, Glycogen Synthesis, and Fuel Utilization

Learn about the important processes in liver metabolism, including gluconeogenesis, glycogen synthesis, and the utilization of different fuels such as glucose, amino acids, and lipids. Understand how the liver plays a central role in distributing nutrients to various tissues and the generation of ATP for energy.

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Liver Metabolism: Gluconeogenesis, Glycogen Synthesis, and Fuel Utilization

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  1. Gluconeogenesis Glycogen synthesis Piruvate GLUCOSE Glycogen Glycolysis Glycogenolysis DEFINITIONS • Glycolysis: The catabolic pathway by which a molecule of glucose is broken down into two molecules of pyruvate. • Gluconeogenesis: The biosynthesis of a carbohydrate from simpler, non carbohydrate precursors such as oxalacetate or pyruvate. • Glycogen synthesis:The synthesis of glycogen from glucose. • Glycogenolysis:The controlledbreakdown of glycogen and release of glucose.

  2. 13-15% from Proteins (100 g) 40% from Carbohydrates (300 g) Diet of 3000 kilocalories/day 40% from Fats (130 g) 7% from Ethanol (30g) Nature of fuels provided to the liver by the intestine

  3. Different FUELS Monomeric subunits Different Nutrients Absorption Digestion Blood Carbohydrates Sugars Liver Blood Proteins Aminoacids Liver Liver Adipose Tissue Blood Lipids Triacylglycerols Lymphatic System Nature of fuels provided to the liver by the intestine • The liver plays a central processing and distributing role in metabolism and furnishes all the organs and tissues with an appropriate mix of nutrients via the blood stream. Tissues Glucose Acetoacetate Storage lipids Creatine Metabolites Digestion

  4. CARBOHYDRATES • Glucose, fructose, galactose and manose, all absorbed from the small intestine, and are converted in glucose-6-phosphate. Liver Glycogen Glucose-6-phosphate is 1.-converted in glucose and exported 2.-converted into glycogen 3.-oxidized for energy production via glycolisis. 4.-degraded into acetyl-CoA, which serves as precursor for the synthesis of lipids. 5.-substrate of the pentose phosphate pathway, yielding ribose-5 phosphate, a precursor in nucleotide synthesis.

  5. AMINO ACIDS Amino acids act as precursors for protein synthesis in hepatocytes. 1.-The liver constantly renews its own proteins, and is also the site of biosynthesis of most of the plasma proteins of the blood. 2.-Amino acids may pass from the liver via the blood to other organs. 3.-certain amino acids are precursors in the biosynthesis of; -nucleotides -hormones -other nitrogen compounds 4.-Amino acids not needed as a biosynthetic precursors are degraded to yield acetyl-CoA and citric acid cycle intermediates which can be converted in -glucose and glycogen -can be oxidize for ATP energy

  6. AMINO ACIDS The liver also metabolizes amino acids that arrives intermittently from other tissues. During a period between meals, especially if prolonged, some muscle proteins is degraded into amino acids. These amino acids donate their amino groups to pyruvate, the product of glycolysis, ti yield alanine, which is transported to the liver and deaminated. The resulting pyruvate is converted by hepatocytes into BLOOD GLUCOSE, and the ammonia is converted into urea for excretion.

  7. LIPIDS Fatty acids are; 1.-converted into liver lipids. 2.-major oxidative fuel in the liver Excess acetyl-CoA released on oxidation of fatty acids is; 3.-converted into ketone bodies Acetoacetate b-hidroxybutyrate, These are circulated in the blood to the other tissues. 4.- used in the biosynthesis of cholesterol 5.- Fatty acids are converted to the phospholipids and triacylglycerols of the plasma lipoproteins, which carry to adipose tissue for storage as triacylglycerols 6.- Some free fatty acids become bound to serum albumin and are carried in the blood to the heart and skeletal muscles.

  8. The standard free energy of ATP is 7.3 Kcal/mole or 30.5 Kj/mole • Under most conditions, the liver obtains its ATP • -In the largest fraction of through the oxidation of fatty acids • -In less fraction from the oxidation of pyruvate formed in glycolysis • from lactate brought from skeletal muscle and blood cells • Glycogen stored in the liver is used primarily to provide glucose to the blood for distribution to tissues that require it for energy metabolism. • However, some glucose 1-phosphate derived from glycogen is directed into the glycolytic pathway yielding some ATP for use by the liver. • The cost in energy for the storage of glucosyl units into glycogen is modest relative to the functions served. • Casting of glucose into its polymeric form allows a relative large amount to be stored in hepatocytes without • -Lost by diffusion • -The osmotic consequences of store a monosacaride. ATP and GLYCOGEN

  9. Muscle uses ATP for mechanical work • Metabolism in skeletal muscle is specialized to generate ATP as the immediate source of energy. • In resting muscle, the primary fuels are free fatty acids from adipose tissue and ketone bodies from the liver. Acetyl-CoA ATP In Muscle

  10. Muscle uses ATP for mechanical work • Moderately active muscles uses blood glucose in addition to fatty acids and ketone bodies. Blood Glucose In Muscle Piruvate

  11. Muscle uses ATP for mechanical work • In maximal active muscles, the demand for ATP is so great that the blood flow cannot provide O2 and fuels fast enough to produce the necessary ATP by aerobic respiration alone. Under these conditions, stored muscle glycogen is broken down to lactate by fermentation. • Lactic acid fermentation thus provides extra ATP energy quickly

  12. The use of blood glucose and muscle glycogen as fuels for muscular activity is greatly enhanced by the secretion of epinephrine, which stimulates the formation of blood glucose from glycogenin the liver and the breakdown of glycogen in muscle tissue. • Skeletal muscle does not contain glucose-6-phosphatase and can not convert glucose-6-phosphate to free glucose for export to other tissues. • Consequently, muscle glycogen is completely dedicated to providing energy in the muscle, via glycolysis. ATP Muscle Pyruvate Glycogen Glucose-6-phosphate Ephinephrine Liver Free Glucose Export to other tissues Muscle uses ATP for mechanical work

  13. Glucose Glucose-6-P Fructose-6-P Fructose-1,6-bisP 1,3-Bisphosphoglycerate 3- phosphoglycerate 2- phosphoglycerate phosphoenolpyruvate pyruvate Glycolysis Liver enzime Glucose-6-phosphatase Glyceraldehyde 3-P Dihydroxyacetone phosphate

  14. Muscle uses ATP for mechanical work • The minute-by-minute adjustment that keep the blood glucose level near 4.5 mM involve the combined actions of insulin, glucagon and epinephrine, especially in liver, muscle and adipose tissue. • Insulin signals these tissues that the blood glucose concentration is higher than necessary. • Glucagon carries the message that blood glucose is too low. • Epinephrine is released into the blood to prepare the muscles, lungs and heart for a burst of activity.

  15. Muscle uses ATP for mechanical work

  16. Muscle uses ATP for mechanical work

  17. GLUT 2 • Hepatocyte membranes are equipped with hexose transporters that facilitate the movement of the sugars into and out of the cells. • The main transporter of glucose in the hepatocyte is called GLUT 2. • Its expression is limited to sinusoidal membranes, and is not present in apical and bile canalicular membranes. • GLUT 2 of hepatocytes is not translocated to intracellular membranous vesicles, but remains associated with the plasma membranes. • GLUT 2 is insensible to insulin • The transporter in hepatocytes is symmetrical, the Km values for glucose entry and glucose exit are both about 20 mM.

  18. Hormones Hormones GLUT 2 • Thus the movement of glucose into and out of hepatocytes is controlled by hormonal regulation of enzymes involved in glycolysis, glycogen synthesis, and gluconeogenesis, and not by hormonal regulation of the glucose transporter (GLUT 2) per se. OUT IN - + GLUT 2 [GLUCOSE] [GLUCOSE] GLUT 2 GLUT 2 [GLUCOSE] [GLUCOSE] GLUT 2 - + OUT IN

  19. GLUT 2 • GLUT 2 occurs in isolated hepatocytes, basolateral membranes of intestinal cells, and in pancreatic islet cells. • GLUT 2 has been reported to be up-regulated by glucose and counteracted by insulin. • In diabetic rats after sequential transient hypoglycemia followed by hyperglycemia, the GLUT 2 mRNA and protein expression is up-regulated • GLUT 2 is more highly expressed in the periportal cells of the liver, also a characteristic of the gluconeogenic enzymes. • This type of regulation would support the argument that up-regulation of GLUT 2 was more critical in glucose export from the liver to maintain glucose homeostasis than in import. • During times when the liver is importing glucose, basal levels of GLUT 2 expression are sufficient to support oxidation. • Glucose transport out of the lumen of the ER is also required to have a net glucose output

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