Fatty Acid Oxidation (Beta-Oxidation)

Fatty Acid Oxidation (Beta-Oxidation)

• Fatty acid oxidation (beta-oxidation) breaks down fatty acids to generate energy.
• This metabolic pathway primarily occurs in the mitochondria of cells.
• It is prevalent in tissues like the liver, muscle, and adipose tissue.
• Fatty acids need activation before oxidation, occurring in the cytoplasm.
• Activation involves attaching a coenzyme A (CoA) molecule to the fatty acid, to form acyl-CoA, using ATP in the process.
• Acyl-CoA molecules are transported into the mitochondria for beta-oxidation using the carnitine shuttle system.
• Within the mitochondria, fatty acids undergo enzymatic reactions called beta-oxidation.
• Each beta-oxidation cycle cleaves a two-carbon unit from the fatty acid chain, producing acetyl-CoA, NADH, and FADH2.
• Acetyl-CoA, NADH, and FADH2 enter the citric acid cycle (Krebs cycle) to generate ATP through oxidative phosphorylation.
• Acetyl-CoA from fatty acid oxidation enters the citric acid cycle for further oxidation, creating more NADH and FADH2.
• Electron carriers donate electrons to the electron transport chain, producing ATP.
• Regulation occurs via hormonal signals (glucagon and insulin), substrate availability, and cellular energy needs.
• Enzymes in beta-oxidation are hormonally and allosterically controlled.
• Impairments in fatty acid oxidation cause FAODs (fatty acid oxidation disorders) due to defects in enzymes/transport proteins.
• FAODs can cause hypoglycemia, muscle weakness, and cardiomyopathy.

Ketone Bodies

• Ketone bodies are water-soluble molecules the liver produces from fatty acids during prolonged fasting, low carbohydrate intake, or untreated diabetes mellitus.
• The 3 primary ketone bodies are acetoacetate, beta-hydroxybutyrate, and acetone.
• Ketogenesis occurs in the liver mitochondria and converts acetyl-CoA from fatty acid oxidation into ketone bodies.
• Upregulation occurs with low insulin and high glucagon, signaling a need for alternative fuel sources.
• Ketone bodies transport from the liver to extrahepatic tissues like muscle and brain, before conversion back into acetyl-CoA via ketolysis.
• Acetyl-CoA from ketone bodies enters the citric acid cycle to produce ATP.
• Hormonal and metabolic factors tightly regulate ketone body production.
• Insulin inhibits ketogenesis, while glucagon and cortisol stimulate it.
• Fatty acid availability impacts the rate of ketone body production.
• Ketone bodies serve as an alternative fuel source, especially for the brain when glucose is scarce.
• They cross the blood-brain barrier and oxidize by neurons to generate ATP, preserving glucose for essential functions.
• Ketosis is a physiological state defined by high ketone bodies in the blood during fasting or low-carb diets.
• Uncontrolled ketogenesis can lead to ketoacidosis, a life-threatening condition with high ketone levels, metabolic acidosis, and dehydration, seen in untreated type 1 diabetes.
• Understanding ketone body metabolism is critical for managing conditions like diabetes mellitus.
• Abnormal carbohydrate and lipid metabolism can lead to dysregulated ketone production and metabolic complications.

Lipid Profile and Disorders

• A lipid profile measures various lipids and lipid-associated parameters, including total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol.
• Total cholesterol represents the sum of all cholesterol in circulating lipoproteins.
• High total cholesterol levels are linked to increased atherosclerosis and cardiovascular disease risk.
• Triglycerides are fats in the blood from dietary intake and liver synthesis.
• High triglyceride levels (hypertriglyceridemia) are linked to obesity, insulin resistance, metabolic syndrome, and cardiovascular disease risk.
• HDL cholesterol ("good" cholesterol) removes excess cholesterol from the bloodstream and transports it to the liver for excretion.
• High HDL cholesterol levels reduce cardiovascular disease risk.
• LDL cholesterol ("bad" cholesterol) is a major cholesterol carrier in the blood.
• Elevated LDL cholesterol contributes to atherosclerosis development and increases heart disease and stroke risk.
• Lipid profile disorders include: Hyperlipidemia, Dyslipidemia, Familial Hypercholesterolemia, and Hypertriglyceridemia.
• Hyperlipidemia is elevated lipids in the blood, including cholesterol and triglycerides, and is a significant cardiovascular disease risk factor.
• Dyslipidemia is imbalanced lipid levels like high LDL, low HDL, or high triglycerides, associated with metabolic disorders like obesity, diabetes, and metabolic syndrome.
• Familial Hypercholesterolemia is a genetic disorder causing high LDL cholesterol from birth, leading to premature atherosclerosis and increased cardiovascular risk.
• Hypertriglyceridemia is elevated triglyceride levels from genetic factors, diet, obesity, insulin resistance, or medical conditions.
• Managing lipid profile disorders involves lifestyle changes (diet, exercise), pharmacotherapy (lipid-lowering medications), and treating underlying metabolic conditions to lower cardiovascular risk and improve overall health.