Glycogenesis and Glycogenolysis

Glucose Metabolism

• Glycogenesis is the creation of glycogen, a polysaccharide that is the only stored carbohydrate in humans.
• If glucose is not needed, many glucose molecules combine to form glycogen.
• Insulin stimulates hepatocytes and skeletal muscle cells to synthesize glycogen, acting as a storage hormone.
• The body can store about 500g of glycogen, with 75% stored in skeletal muscle.
• Hepatocytes and skeletal muscles store glycogen, with the majority in skeletal muscle.

Glycogenolysis

• Glycogenolysis is the breakdown of glycogen into glucose for release.
• Glycogen stored in hepatocytes is broken into glucose and released into the blood.
• Glycogen stored in muscle is converted to glucose-6-phosphate and enters glycolysis because skeletal muscle lacks the enzyme to cleave the final phosphate.
• Glycogenolysis is stimulated by glucagon and epinephrine.
• Glucagon increases blood sugar, while epinephrine responds to stress by breaking down energy stores.
• Glycogen stored in skeletal muscle needs to be used by the skeletal muscle.

Gluconeogenesis

• Gluconeogenesis is the formation of glucose from noncarbohydrate sources, such as glycerol, lactic acid, and most amino acids.
• Gluconeogenesis occurs in the liver.
• Gluconeogenesis is stimulated by cortisol and glucagon.
• Carbon, hydrogen, and oxygen are the three ingredients to create carbohydrates.

Lipid Transport

• Lipids are transported by lipoproteins due to their nonpolar and hydrophobic nature.
• Lipoproteins are spherical, with an outer shell of proteins, phospholipids, and cholesterol surrounding fats, making them more water-soluble.
• Proteins in the outer shell are called apoproteins with specific functions, essentially acting as transport vehicles.

Lipoproteins

• Lipoproteins are categorized and named according to density (ratio of lipids to proteins), with high density indicating more proteins.
• Examples of lipoproteins include 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 and transport dietary fats.
• Chylomicrons enter villi, then lacteals, and are carried by lymph into venous blood.
• Chylomicrons transport dietary lipids to skeletal muscle, cardiac muscle, adipose tissue, and the liver.

Very Low-Density Lipoproteins (VLDLs)

• VLDLs are formed in hepatocytes, in the liver.
• VLDLs transport triglycerides to adipocytes.
• VLDLs become LDLs once triglycerides are removed.
• The liver synthesizes fats and uses VLDLs to transport them to adipose tissue.

Low-Density Lipoproteins (LDLs)

• LDLs are known as "bad cholesterol" and carry 75% of the total cholesterol in the blood.
• LDLs deliver cholesterol to body cells for cell membrane repair and synthesis of steroid hormones.
• Excess LDLs deposit cholesterol in and around smooth muscle in arteries, forming fatty plaques that increase the risk of coronary artery disease.
• Transports cholesterol

High-Density Lipoproteins (HDLs)

• HDLs are known as "good cholesterol".
• HDLs remove excess cholesterol from body cells and blood, acting as a cholesterol scavenger.
• HDLs deliver cholesterol to the liver for elimination in bile salts.
• High HDL levels are associated with a decreased risk of coronary artery disease.

Cholesterol Sources

• The body obtains cholesterol from two sources: in foods and endogenous cholesterol made in the liver.
• Trans fats and saturated fats have the biggest impact on circulating cholesterol levels.

Health Applications

• Indicators of potential cardiovascular problems: total cholesterol above 200 milligrams/deciLiter and high LDL:HDL ratio.
• High levels of cholesterol in circulation and cholesterol accumulation in tissues increase the risk of 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, both generating ATP.
• If energy demand is low, triglycerides are stored in adipocytes.
• Triglycerides consist of glycerol and 3 fatty acids, both of which can generate ATP.
• Lipolysis must occur for muscle, liver, and adipose tissue to oxidize fatty acids for ATP.
• Lipolysis is enhanced by epinephrine, norepinephrine, cortisol, and thyroid hormones.
• Insulin acts to inhibit lipolysis.
• Glycerol is converted to glyceraldehyde 3-phosphate (a glycolysis intermediate) and eventually pyruvate, yielding 2 ATP.
• 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.
• Beta-oxidation produces more ATP per carbon than glucose.

Ketone Formation

• 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. Brain and RBCs rely heavily on this since they cannot use beta oxidation.
• Excessive ketones lead to ketosis and/or ketoacidosis, of which the latter damages tissue.

Lipid Catabolism

• Lipid catabolism is useful as beta-oxidation is very efficient, and excess lipids can be easily stored as triglycerides.
• Lipid catabolism cannot provide large amounts of ATP quickly and is difficult for water-soluble enzymes to access the insoluble droplets.
• Lipid catabolism is well-suited for chronic energy demands during stress or starvation.

Lipid Anabolism: Lipogenesis

• Liver cells and adipose cells synthesize lipids, beginning with acetyl-CoA.
• Almost any organic substrate (lipids, amino acids, carbohydrates) can be converted to acetyl-CoA.
• Lipogenesis 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, like omega-3 and omega-6, 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 or enter the citric acid cycle.
• Before entering the cycle, the amine group must be removed through deamination in hepatocytes.
• Deamination produces ammonia, which the liver converts to urea for excretion in urine.

Protein Anabolism

• Protein synthesis is carried out using ribosomes (translation) with free amino acids.
• Amino acids are either essential (cannot be synthesized and must be acquired from the diet) or nonessential.
• The body lacks the enzymes to facilitate essential amino acids.

Essential vs Nonessential Amino Acids

• There are 9 essential amino acids in humans that must be present in the diet because they cannot be synthesized.
• The 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

• Two general patterns of metabolic activity: absorptive state and postabsorptive state.
• During the absorptive state, ingested nutrients enter the bloodstream.
• During the postabsorptive state, absorption of nutrients from the GI tract is complete.

Absorptive State

• The absorptive state occurs following a meal, typically continuing for about 4 hours, when nutrient absorption is occurring.
• Insulin is the primary regulating hormone during this state.
• Insulin stimulates glucose uptake and glycogenesis, amino acid uptake and protein synthesis, and triglyceride synthesis.
• Glycolysis and aerobic metabolism provide ATP for cellular activities and the synthesis of lipids and proteins.
• Storage of excess fuel molecules in hepatocytes, adipocytes, and skeletal muscle cells.

Postabsorptive State

• About 4 hours after the last meal, absorption in the small intestine is nearly complete during the postabsorptive state.
• Blood glucose levels start to fall, and the main purpose is to maintain blood sugar.
• Metabolic activity focuses on mobilizing energy reserves, coordinated several hormones: glucagon, epinephrine, glucocorticoids, and growth hormone.
• Glucocorticoids stimulate the mobilization of lipid and protein reserves.

Blood Glucose

• Production of glucose is increased by the breakdown of liver glycogen, lipolysis, and gluconeogenesis.
• 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, resulting in the release of fatty acids by adipocytes.
• Blood amino acid levels decrease, resulting in amino acid release by skeletal muscles and other tissues.
• Catabolism of lipids and amino acids in the liver produces acetyl-CoA, leading to the formation of ketone bodies that diffuse into the blood and are used by other cells as an energy source.

Fasting

• Fasting is going without food for many hours or a few days.

Starvation

• Starvation implies weeks or months of food deprivation or inadequate food intake.
• During these times, nervous tissue and RBCs continue to use glucose for ATP production.
• The most dramatic metabolic change during starvation is the increase in the formation of ketone bodies by hepatocytes from excess fatty acid metabolism, which can be used as an alternative fuel source.