Glucose Metabolism & Atherosclerosis

• After absorption, fructose and galactose are converted to glucose in the liver.
• Glucose (C6H12O6) serves as the final common pathway for carbohydrate transport into cells.

Transport of Glucose

• Glucose needs active co-transport or facilitated diffusion with a carrier protein to cross cell membranes.
• Insulin facilitates glucose transport.

Phosphorylation of Glucose

• Glucose is phosphorylated upon cell entry, forming glucose-6-phosphate.
• Glucose-6-phosphate can be used immediately for energy or stored as glycogen in the liver and muscles.

Glycogenesis

• Glycogenesis is the formation of glycogen (starch).

Glycogenolysis

• Glycogenolysis is the breakdown of glycogen into glucose in the liver to make glucose available.
• Phosphorylase splits glycogen branches through phosphorylation.
• Epinephrine and glucagon activate phosphorylase.

Glycolytic Pathway

• One gram-mole of glucose releases 686,000 calories of energy; 12,000 calories are needed to form 1 gram-mole of ATP.
• Enzymes oxidize glucose gradually, capturing energy as ATP.
• Energy is released in packets, resulting in 38 moles of ATP per mole of glucose.

Glycolysis

• Glycolysis (glucose lysing) is an important process for glucose energy release, involving 10 steps.
• Glycolysis end products are then oxidized to produce ATP.
• Glycolysis takes place in the cytoplasm.
• Glucose (6 C) splits into two pyruvic acid molecules (3 C).

Glycolysis ATP Yield

• Glycolysis yields 2 pyruvic acid molecules + 2 ATP molecules + 4 H per glucose molecule.
• ATP formation efficiency is 43%.
• Two pyruvic acid molecules combine with Coenzyme A to form Acetyl-CoA, which yields up to 6 ATP molecules later.

Citric Acid Cycle (Krebs Cycle)

• Reactions take place in the mitochondrial matrix.
• The reaction starts with Acetyl CoA combining with oxaloacetic acid to form citric acid.
• The reaction both begins and ends with oxaloacetic acid production.
• Twenty-four hydrogen atoms are released per glucose molecule (4 during glycolysis, 4 forming acetyl-CoA, 16 in the Krebs cycle).

Citric Acid Cycle Details

• Twenty of the hydrogen atoms combine with NAD+ via dehydrogenase.
• Water is added; carbon dioxide and hydrogen atoms are released during subsequent stages.
• Two ATP molecules are produced.

Net Reaction in Citric Acid Cycle Per Glucose Molecule

• 2 Acetyl-CoA + 6 H2O + 2 ADP → 4 CO2 + 16 H + 2 CoA + 2 ATP

Oxidative Phosphorylation

• Oxygen is required.
• NADH splits into NAD+, H+, and e- via hydrogen oxidation in the mitochondria.
• Electrons enter the Electron Transport Chain.
• Energy released is captured as a proton gradient, used to make ATP, called chemiosmosis.
• Oxidative phosphorylation = Electron Transport Chain + chemiosmosis

Summary of ATP Formation

• Glycolysis: 4 ATP made, 2 ATP used = 2 ATP net.
• Citric Acid Cycle: 2 ATP.
• Electron Transport: 34 ATP.
• Total: 38 ATP.
• 456,000 calories are stored as ATP out of 686,000 available from glucose, resulting in 66% efficiency.
• Feedback control mechanisms can initiate or stop ATP formation.

Anaerobic Glycolysis

• Anaerobic glycolysis is inefficient for energy use.
• Pyruvic acid + NADH + H+ -> lactic acid
• Elevated lactic acid indicates that cells are not using oxygen properly.
• Lactic acid can convert back when oxygen is available again to either glucose or energy.

Glucose Storage

• Glycogen stores are filled first.
• Excess is stored in fat.

Gluconeogenesis

• When glucose runs out, it can be synthesized from fats (glycerol) and proteins (amino acids).
• Low blood glucose concentration is the trigger.
• Low blood glucose triggers the adenohypophysis to release corticotropin. Which then stimulates the adrenal cortex to release cortisol.
• Cortisol causes cells to break proteins into amino acids that are ideal for the liver to convert to glucose.
• Gluconeogenesis is catabolic metabolism.

Lipid Metabolism

• Lipids are cellular fuels with the highest energy content and efficient for energy storage.
• Lipids include triglycerides, phospholipids, and cholesterol.

Fatty Acids

• Fatty acids are simple, long-chain hydrocarbon carboxylic acids with a –COOH (carboxylic group).
• Generalized formula: CH3(CH2)14COOH.
• Palmitic acid: CH3(CH2)14COOH.

Triglycerides

• Contain three long-chain fatty acid molecules bound with one glycerol molecule.
• Glycerol is a triple alcohol: 3 –OHs.

Absorption of Fats

• Dietary triglycerides are broken down to monoglycerides and fatty acids in the intestines.
• Intestinal epithelial cells break fats down and repackage them as triglycerides called chylomicrons.
• Chylomicrons are absorbed into the lymphatic system.
• Plasma appears turbid one hour after a high-fat meal.

Uptake of Fats Into Cells

• Lipoprotein lipase in capillary endothelium of fat and liver cells hydrolyzes triglycerides into fatty acids and glycerol.
• Fatty acids diffuse into cells, resynthesize into triglycerides, and are stored.

Transport Through Body

• Fat cells hydrolyze triglycerides to fatty acids and glycerol when lipids are needed.
• Fatty acids and glycerol enter the blood and combine with albumin, becoming free fatty acids.

Fat Deposits

• Adipose tissue constitutes fat deposits, or simple tissue fat.
• Fats are also stored in the liver.
• Fat cells of adipose tissue are 80-95% full of triglycerides.
• Fat is responsive to factors and not benign.

Use of Triglycerides for Energy

• Up to 50% of calories in the typical American diet come from fats.
• Triglycerides hydrolyze to fatty acids and glycerol.
• Glycerol is changed to glycerol-3-phosphate and then enters the glycolytic pathway.
• Fatty acids enter mitochondria and are oxidized.

Beta-Oxidation

• Fatty acids convert to Acetyl-CoA, called beta-oxidation.
• Acetyl-CoA enters the citric acid cycle.
• Tremendous amounts of ATP are formed from beta-oxidation of fatty acids.
• Complete oxidation of one molecule of stearic acid produces a net gain of 146 ATP.

Ketosis

• Fats will be oxidized to fuel the body when carbs are unavailable.
• High concentrations of B-hydroxybutyric acid, acetoacetic acid, and acetone are metabolites.
• Ketone bodies are caused by starvation, diabetes mellitus, or a high-fat/low-carb diet.

Regulation of Fat Utilization

• Epinephrine and norepinephrine activate triglyceride lipase, increasing FFA by as much as 8X.
• Corticotropin release from anterior pituitary enhances fatty acid use.
• Glucocorticoid release from adrenal cortex enhances fatty acid use.
• Decreased secretion of insulin enhances fatty acid use.

Phospholipids

• Phospholipids contain a fatty acid molecule, a phosphoric acid radical, and a nitrogenous base.
• Three types of phospholipids are lecithins, cephalins, and sphingomyelins.

Uses of Phospholipids

• Phospholipids are important in cell membranes and are constituents of lipoproteins.
• Thromboplastin aids in clotting.
• Sphingomyelin is found in myelin sheaths surrounding nerve cells.
• Phospholipids act as phosphate radical donors.

Uses of Cholesterol

• Cholesterol forms cholic acid in the liver, aiding fat digestion (bile).
• Cholesterol is converted to adrenocortical hormones, estrogen, progesterone, and testosterone.
• Cholesterol forms the corneum of the skin, making it waterproof.

Atherosclerosis

• Atherosclerosis is a disease of large arteries where fatty lesions (atheromatous plaques) are deposited.
• Arteriosclerosis causes thick, stiff vessels of all sizes.
• Lesions are primarily cholesterol.
• Connective tissue grows in the plaques, stiffening vessel walls (sclerotic).
• Plaques can occlude the vessel over time or rupture easily.

Factors Leading to Atherosclerosis

• Familial factors
• Physical inactivity and obesity
• Diabetes mellitus
• Hypertension
• Hyperlipidemia
• Smoking

Prevention of Atherosclerosis

• Eat a low-fat diet.
• Don’t smoke.
• Exercise.
• Control blood pressure and blood glucose.
• Eat oat bran to bind bile acids in the gut.
• Statins inhibit HMG-CoA reductase for cholesterol synthesis.

Protein Metabolism

• Proteins make up 3/4 of body solids.
• Proteins are made up of about 20 amino acids linked by peptide linkages and hydrogen bonding.
• Functions of proteins include structure, enzymes, oxygen transport, nucleoproteins, muscle contraction, and cellular functions.

Regulatory Protein

• Transmits signals from a chemical signal to another part of the cell.
• G Protein Coupled Receptor passes a message through the cell membrane for cell communication.
• A ligand is the chemical substance binding to this receptor.
• The internal receptor binds to a G protein, leading to downstream second-messenger events and cell communication.

Transport of Amino Acids

• Proteins are digested into AAs in the gastrointestinal tract in 2-3 hours.
• Amino acids enter cells via active transport or facilitated diffusion.
• Amino acids are lost in urine if their concentrations exceed the renal threshold for reabsorption.

Storage of Amino Acids

• Amino acids incorporate into new proteins almost immediately after entering the cell.
• When blood levels are low, amino acids are transported out to restore the supply.
• A reversible balance of amino acids and various proteins exists.
• Cancer cells are prolific users of amino acids, potentially depleting proteins in other cells.

Major Plasma Proteins

• Albumin maintains colloid osmotic pressure.
• Globulins function as enzymes and are crucial for the immune system.
• Fibrinogen is key for coagulation.

Dietary Amino Acids

• 10 essential AAs cannot be synthesized and must be ingested.
• 10 nonessential AAs are synthesized but still needed for protein synthesis.

Use of Proteins for Energy

• Protein use for energy occurs in the liver.
• Begins with deamination, removing an amino group (-NH2) from an amino acid.
• Aminotransferases are enzymes responsible for deamination.

Urea

• Ammonia, created through deamination of AAs, is removed from the blood through conversion to urea.
• Ammonia is a neurotoxin.
• Urea is synthesized in the liver and excreted by the kidneys.

Oxidation of Deaminated Amino Acids

• The resulting keto acid from deaminated amino acids is degraded into a substance that can enter the citric acid cycle.
• This substance is oxidized, similarly to acetyl-CoA, to produce ATP.
• Ketogenesis refers to the conversion of amino acids into keto acids or fatty acids for energy.

Obligatory Degradation of Proteins

• Twenty to 30 g of protein is degraded to AAs and oxidized regardless of dietary intake.
• Eating less protein than this leads to starvation.
• Carbohydrates are protein sparers.

Hormonal Regulation of Protein Metabolism

• Growth hormone increases AA transport into cells, thus promoting protein synthesis.
• Insulin accelerates AA transport into cells.
• Glucocorticoids increase the breakdown of extrahepatic proteins, increasing available AAs.
• Testosterone increases protein deposition in muscle tissues.
• Thyroxine increases the rate of metabolism, either catabolism or anabolism.