Lipid Metabolism Lecture 9

Lipid Metabolism Lecture 9

• Diet contains triglycerides, cholesterol, fatty acids, and phospholipids.
• Most triglycerides are digested by pancreatic lipase, which acts on emulsified lipids.
• Products of triglyceride digestion are 3 fatty acids and one glycerol molecule.
• Phospholipids are digested by phospholipases (A1, A2, C, and D) secreted by pancreas and intestines.
• Cholesterol esterase hydrolyzes cholesterol esters to free cholesterol and one fatty acid.
• Primary products of lipid digestion include free fatty acids, free cholesterol, and glycerol.
• These products, along with bile salts, form micelles (disk-shaped structures).

Mobilization of Fatty Acids from Adipocytes

• When energy supply from diet is limited, the body releases glucagon, epinephrine, or adrenocorticotropic hormone (ACTH).
• These hormones bind to adipocyte cell membranes and stimulate cyclic AMP (cAMP) synthesis.
• cAMP activates a protein kinase that phosphorylates and activates hormone-sensitive lipases.

Transport of Fatty Acids to Mitochondria

• Free fatty acids (FFAs) bind to albumin in the blood plasma and are transported to peripheral tissues.
• Glycerol is taken up by the liver and converted to glucose or pyruvate.
• Fatty acids must be activated by reaction with coenzyme A (CoA) at the expense of ATP, before entering mitochondria.
• The reaction is catalyzed by acyl-CoA synthetase (thiokinase) found in the cytosol and mitochondria.

Carnitine Shuttle

• Fatty acids enter mitochondria via a carrier protein called the carnitine shuttle.
• This shuttle carries the fatty acid from the cytosol to the mitochondria.

β-Oxidation of Fatty Acids

• β-oxidation is the successive oxidative removal of two carbons in the form of acetyl-CoA, starting from the carboxyl end of the fatty acid.
• It requires a set of enzymes and occurs in the mitochondria.
• The β-carbon is oxidized during the process.
• The cycle is repeated several times, depending on the length of the fatty acid chain. Palmitic acid (16 carbons) requires 7 cycles.

β-Oxidation Steps

• Acyl-CoA dehydrogenase converts acyl-CoA to acyl-trans-enoyl-CoA.
• Hydratase converts acyl-trans-enoyl-CoA to 3-hydroxyacyl CoA.
• Hydroxyacyl-CoA dehydrogenase converts 3-hydroxyacyl-CoA to 3-ketoacyl-CoA.
• Thiolase converts 3-ketoacyl-CoA to acetyl-CoA and a shorter acyl-CoA.

Complete Oxidation of Fatty Acids

• The complete oxidation of a fatty acid involves two stages: the formation of acetyl-CoA, and the oxidation of acetyl-CoA to CO2 and water via the citric acid cycle.
• For example, palmitoyl-CoA + 7 FAD + 7 NAD + 7 CoA → 8 acetyl-CoA + 7 FADH2 + 7 NADH2.

Energetics of Palmitic Acid Oxidation

• One palmitic acid molecule yields 131 ATPs, but 2 ATPs are used for activation.
• Therefore, the net ATP gain is 129.

Fatty Acid Synthesis

• Fatty acids can be synthesized de novo in the body, in the cytosol of liver, lactating mammary gland, adipose tissue, and renal cortex.
• Acetyl-CoA is converted to malonyl-CoA by acetyl-CoA carboxylase.
• Malonyl-CoA and acetyl-CoA are attached to acyl carrier protein (ACP).
• The process involves condensation, reduction, dehydration and reduction steps.
• The main sources of NADPH for fatty acid synthesis are the pentose phosphate shunt.

Regulation of Fatty Acid Synthesis

• High carbohydrate diets increase synthesis.
• Palmitoyl CoA inhibits synthesis.
• Fasting decreases fatty acid synthesis.
• Insulin stimulates synthesis.
• Malonyl CoA inhibits fatty acid oxidation by inhibiting the carnitine shuttle, preventing simultaneous fatty acid synthesis and oxidation.