Biochemistry of Lipid Metabolism

Lipid Metabolism

• Fats (triglycerides) are high-energy molecules, yielding 9.3 kcal of energy. Carbohydrates and proteins yield 4.1 kcal.
• Fats are the best heat producers compared to carbohydrates and proteins due to the long hydrocarbon chains in fats.
• Excess energy consumed is stored as fats.
• Fats are hydrophobic and inert, allowing storage for long periods.
• Fats are stored as triacylglycerols in fat cells (adipose tissue).
• Fats can be stored in large amounts, whereas carbohydrates are stored as glycogen with limited storage capacity.
• Proteins cannot be stored.

Lipid Metabolism: Digestion & Absorption

• Dietary lipids (CE, PL, TAG) initially remain unchanged in the mouth.
• In the stomach, some short- and medium-chain fatty acids are digested.
• Most CE, PL, and TAG digestion occurs in the small intestine.
• Bile salts emulsify lipids, aiding in their breakdown by pancreatic enzymes.
• Pancreatic lipase degrades dietary lipids into free fatty acids and 2-monoglycerols.
• Chylomicrons (lymph) transport reesterified products to the bloodstream.
• Products include free fatty acids, 2-monoacylglycerol, remaining fragments of TAGs.
• The emulsified forms of digestive products (fatty acids and glycerol) are water-soluble and absorbed in the intestines.

Lipid Metabolism: Transport

• Free fatty acids and glycerols enter the cell membranes of adipocytes. These then pass into the bloodstream.
• Albumin helps transport fatty acids and glycerols.

Lipid Metabolism: Triglyceride Synthesis (Glycerol Phosphate Production)

• Liver cells use glucose to produce glycerol phosphate.
• This glycerol phosphate is a precursor for triacylglycerol production.
• Adipose tissue cells use the same glycolysis pathway to produce glycerol phosphate, also for triacylglycerol creation.

Lipid Metabolism: Fatty Acid Synthesis

• A large proportion of fatty acids are obtained from the diet.
• Carbohydrates and proteins from the diet can also be converted into fatty acids.
• Fatty acid synthesis occurs in the liver and lactating mammary glands.
• Acetyl CoA acts as a precursor in palmitate synthesis.
• Palmitate is used to create other long-chain fatty acids through processes in the endoplasmic reticulum and mitochondria.
• Enzymes in the endoplasmic reticulum (ER) are responsible for adding cis double bonds to fatty acids.
• Humans have desaturases for carbon 4, 5, 6, and 9, but do not have desaturases for carbons 10 and beyond, thus are unable to produce some long-chain fatty acids.

Lipid Metabolism: Fatty Acid Breakdown (β-Oxidation)

• Fatty acids are used for energy by undergoing β-oxidation in the mitochondrial matrix.
• Erythrocytes and the brain cannot use fatty acids as fuel due to the lack of mitochondria and the impermeable blood-brain barrier, respectively.
• β-oxidation is a catabolic process, completely breaking down fatty acids into CO2 and H2O, producing ATP.
• The process involves sequential oxidation of carbons in the fatty acid, producing acetyl CoA.
• Acetyl CoA enters the TCA cycle for further oxidation.
• β-oxidation produces molecules for further oxidative phosphorylation to create ATP.
• Other products of β-oxidation are NADH and FADH2 which enter the electron transport chain to generate ATP.

Lipid Metabolism: Carnitine

• Carnitine is acquired from the diet (meat products) or synthesized in the liver and kidneys.
• Heart and skeletal muscle depend on carnitine for fatty acid transport and metabolism.
• 97% of body carnitine is found in skeletal muscle.
• Deficiencies in carnitine can prevent the usage of long-chain fatty acids for fuel. Liver disease, malnutrition, strict vegetarianism, or hemodialysis can lead to such deficiencies.

Lipid Metabolism: Ketogenesis

• Ketogenesis occurs in the liver and kidney mitochondria.
• When energy sources are limited like during starvation, the liver produces ketone bodies such as acetoacetate, D-β-hydroxybutyrate (3-hydroxybutyrate), and acetone.
• These ketone bodies diffuse into the bloodstream to reach peripheral tissues, where they are converted back into acetyl-CoA via ketolysis, and enter the TCA cycle.
• Ketone bodies provide alternative energy sources, especially for the brain, when glucose is scarce.
• Under normal conditions, blood ketone levels are low (0.5 mg/100 mL). During starvation or diabetes, levels can rise, producing ketonemia and ketonuria (presence of ketone bodies in urine.)
• Acetone breath can also be a possible output.
• The brain can use ketone bodies for energy during prolonged fasting (starvation.)

Lipid Metabolism: Diabetic Ketoacidosis

• Diabetic ketoacidosis (DKA) is a serious complication of diabetes.
• Insulin deficiency leads to elevated blood glucose levels, and thus increased gluconeogenesis in the liver.
• This promotes lipolysis, increasing fatty acid release and subsequent hepatic ketogenesis.
• Ketone bodies accumulate in the blood (ketonemia), leading to metabolic acidosis (ketoacidosis). This can lead to coma or death if untreated.
• Treatment includes insulin to restore normal glucose metabolism, reducing ketone production. Additional measures like sodium bicarbonate may be required for dehydration correction.
• Alcohol use can also elevate ketone body production.