Glycogenesis and Glycogenolysis

Glucose Metabolism

• Glycogenesis is the creation of glycogen, a polysaccharide and the only stored carbohydrate in humans.
• When glucose isn't needed immediately, multiple glucose molecules combine to form glycogen.
• Insulin stimulates glycogenesis in hepatocytes and skeletal muscle cells and is considered a storage hormone.
• The body stores approximately 500g of glycogen, with 75% in skeletal muscle.
• Both hepatocytes and skeletal muscle store glycogen, but the majority is in skeletal muscle.

Glycogenolysis

• Glycogenolysis is the breakdown of glycogen into glucose, which is released into the blood.
• Glycogen stored in muscle converts to glucose-6-phosphate, entering glycolysis because skeletal muscle lacks the enzyme to cleave the final phosphate.
• Glucagon and epinephrine stimulate glycogenolysis, increasing blood sugar and energy availability during stress.
• Glycogen stored in skeletal muscle is exclusively for use by skeletal muscle as glucose 6-phosphate, not being used by other tissues.

Gluconeogenesis

• Gluconeogenesis is the formation of glucose from non-carbohydrate sources like glycerol, lactic acid, and most amino acids.
• This occurs in the liver and is stimulated by cortisol and glucagon, hormones associated with stress and increased blood sugar.
• Carbon, hydrogen, and oxygen are the essential ingredients for creating carbohydrates.

Lipid Transport

• Lipids, being mostly nonpolar and hydrophobic, combine with proteins to form lipoproteins for transport, making them more water-soluble.
• Lipoproteins are spherical, with an outer shell of proteins, phospholipids, and cholesterol surrounding fats with hydrophobic tails and hydrophilic heads.
• Apoproteins are the proteins in the outer shell of lipoproteins, each having specific functions as transport vehicles.
• Lipoproteins are categorized and named according to density (ratio of lipids to proteins); high density means more proteins.
• Examples of lipoproteins are chylomicrons, very low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs).

Chylomicrons

• Chylomicrons are formed in small intestine mucosal epithelial cells.
• Their function is to transport dietary fats.
• They enter villi, and eventually lacteals, and are carried by lymph into venous blood.
• They transport dietary lipids to skeletal muscle, cardiac muscle, adipose tissue, and the liver.

Very Low-Density Lipoproteins (VLDLs)

• VLDLs are formed in the liver (hepatocytes).
• They transport triglycerides to adipocytes.
• They become LDLs once triglycerides are removed.
• The liver creates fat and uses VLDLs to transport them to adipose tissue for endogenous fats.

Low-Density Lipoproteins (LDLs)

• LDLs are known as "bad cholesterol".
• They carry 75% of total cholesterol in the blood.
• LDLs deliver cholesterol to body cells for cell membrane repair and synthesis of steroid hormones.
• In excess, LDLs deposit cholesterol around smooth muscle in arteries, forming fatty plaques and increasing the risk of coronary artery disease.
• LDL levels are more genetically influenced than lifestyle-dependent.
• LDLs main function is to transport cholesterol as cholesterol carriers.

High-Density Lipoproteins (HDLs)

• HDLs are known as "good cholesterol".
• They remove excess cholesterol from body cells and blood.
• HDLs are cholesterol scavengers.
• They deliver cholesterol to the liver for elimination (removed in bile salts).
• HDLs prevent cholesterol accumulation in the blood, so high HDL levels are associated with a decreased risk of coronary artery disease.

Cholesterol

• There are two sources of cholesterol in the body: cholesterol present in foods and endogenous cholesterol made in the liver.
• Endogenous cholesterol has a bigger impact on total blood cholesterol.
• Trans fats and saturated fats have the biggest impact on circulating cholesterol.

Health Applications

• Indicators of potential cardiovascular problems are total cholesterol above 200 milligrams/deciLiter and a high LDL:HDL ratio.
• These values indicate high cholesterol levels in circulation, with most cholesterol going into tissues and staying instead of returning to the liver.
• Excess cholesterol can accumulate as plaques in blood vessels, causing hypertension, heart attacks, and strokes.

Lipid Catabolism: Lipolysis

• Lipolysis is the breakdown of lipids into pieces that can be converted to pyruvate or channeled directly into the citric acid cycle to generate ATP.
• If the demand for energy is low, triglycerides are stored in adipocytes.
• Triglycerides consist of glycerol and 3 fatty acids, both of which can generate ATP.
• Breakdown must occur for muscle, liver, and adipose tissue to oxidize fatty acids for ATP.
• Lipolysis is enhanced by epinephrine, norepinephrine, cortisol, and thyroid hormones while insulin inhibits it.

Glycerol

• Glycerol is converted to glyceraldehyde 3-phosphate (a glycolysis intermediate) and eventually pyruvate, yielding 2 ATP.

Fatty Acids

• Fatty acids are catabolized to acetyl-CoA through beta-oxidation in the mitochondrial matrix.
• Beta-oxidation involves chopping 2 carbons off at a time and turning it into acetyl-CoA.
• Both pyruvate (from glycerol) and acetyl-CoA (from fatty acids) can enter the Citric Acid Cycle.
• For each step in beta-oxidation, the cell gains 13 ATP.
• Excessive beta oxidation, with a lack of glucose, results in the formation of ketones in the liver.
• Heart, brain, and RBCs can use ketone bodies to generate ATP since they cannot use beta oxidation.
• Excessive ketones can lead to ketosis and/or ketoacidosis, of which the latter damages tissue.

Benefits and Drawbacks of Lipid Catabolism

• Beta-oxidation is very efficient.
• Excess lipids can be easily stored as triglycerides.
• However, lipid catabolism cannot provide large amounts of ATP quickly and is difficult for water-soluble enzymes to access insoluble droplets.
• Well suited for chronic energy demands during stress or starvation.

Lipid Anabolism: Lipogenesis

• Lipogenesis occurs in liver cells and adipose cells, which synthesize lipids.
• Lipogenesis begins with acetyl-CoA.
• Almost any organic substrate (lipids, amino acids, carbohydrates) can be converted to acetyl-CoA.
• Occurs when more calories are consumed than needed for ATP production.
• Excess dietary carbs, proteins, and fats are ALL converted to triglycerides.
• Essential fatty acids cannot be synthesized and must be obtained from the diet.

Metabolism of Proteins

• Amino acids are either oxidized to produce ATP or used to synthesize new proteins.
• Excess dietary amino acids are not excreted but converted into glucose (gluconeogenesis) or triglycerides (lipogenesis).

Protein Catabolism

• Protein from worn-out cells is recycled and can be converted to other amino acids to make new proteins or enter the CAC.
• Before entering the CAC, the amine group must be removed through deamination, which occurs in hepatocytes.
• Produces ammonia, which the liver converts to urea and is excreted in urine.
• Amino acids enter the Krebs cycle for oxidation at various points.

Protein Anabolism

• Protein synthesis is carried out using ribosomes (translation) using free amino acids.
• Amino acids can be essential (cannot be synthesized in the body, must be acquired from the diet) or nonessential.
• There are 9 essential amino acids in humans that must be present in the diet because they cannot be synthesized.
• 11 nonessential amino acids can be synthesized by body cells using amination and transamination.
• Transamination is the transfer of an amine group from one amino acid to a ketoacid to form a new amino acid.

Metabolic Adaptations

• There are two general patterns of metabolic activity: the absorptive state and the postabsorptive state.
• During the absorptive state, ingested nutrients are entering the bloodstream.
• During the postabsorptive state, the absorption of nutrients from the GI tract is complete.
• During the absorptive state glucose is readily available for ATP production and the effects of insulin dominate.
• During the postabsorptive state the absorption of nutrients from GI tract complete.

Absorptive State

• This is the time following a meal, when nutrient absorption is occurring, typically for about 4 hours.
• Insulin is the primary regulating hormone.
• Insulin stimulates glucose uptake and glycogenesis, amino acid uptake and protein synthesis, and triglyceride synthesis.
• Glycolysis and aerobic metabolism provide the ATP needed to power cellular activities as well as the synthesis of lipids and proteins.
• The liver, fat and muscle also store of excess fuel molecules.

Postabsorptive State

• This state occurs about 4 hours after the last meal, when absorption in the small intestine is nearly complete, and blood glucose levels start to fall.
• The main purpose is to maintain blood sugar.
• Metabolic activity is focused on mobilizing energy reserves and maintaining blood glucose.
• This is coordinated by glucagon, epinephrine, and glucocorticoids.

Hormonal Influence

• Glucocorticoids stimulate the mobilization of lipid and protein reserves, enhanced by growth hormone.
• Glucagon stimulates glycogenolysis and gluconeogenesis, primarily in the liver.
• Epinephrine stimulates glycogenolysis in skeletal and cardiac muscle, and lipolysis in adipocytes.

Metabolic Processes

• Production of glucose is increased by the breakdown of liver glycogen, lipolysis, and gluconeogenesis using lactic acid, glycerol and/or amino acids.
• Blood glucose is conserved by the oxidation of fatty acids, lactic acid, amino acids, ketone bodies, and the breakdown of muscle glycogen.
• Blood lipid levels decrease, triggering the release of fatty acids by adipocytes.
• Blood amino acid levels decrease, triggering amino acid release by skeletal muscles and other tissues.
• Blood glucose levels decrease and glucose is released by the liver.
• The catabolism of lipids and amino acids in the liver produces acetyl-CoA
• Acetyl-CoA leads to the formation of ketone bodies, which diffuse into the blood and are used by other cells as energy source.

Fasting and Starvation

• Fasting means going without food for many hours or a few days.
• Starvation implies weeks or months of food deprivation or inadequate food intake.
• During these times, nervous tissue and RBC's continue to use glucose for ATP production.
• The most dramatic metabolic change that occurs is the increase in formation of ketone bodies by hepatocytes from excess fatty acid metabolism, which can be used as an alternative fuel source.