Wk 5&6 Lecture 4: Fatty acid & Triacyglycedride Synthesis

Overview of Julian's Case Study

• Profile: A 10-year-old boy, weighing 22 kg, height of 125 cm.

• BMI: 26.9, which is above the normal range for children his age.

• Dietary Habits: Enjoys calorie-dense fast foods, contributing to his excess weight and resulting in schoolyard teasing.

• Physical Activity: Avoids physical games due to sensitivity about his weight and difficulties in sports.

• Health Implications: Represents a growing population at risk for obesity-related diseases.

Metabolic Insights

• Focus: Understanding metabolic processes associated with high blood glucose, insulin, obesity, and diabetes.

• Caloric Intake: Julian consumes excess calories (2,500+ kcal/day), leading to elevated blood glucose and insulin levels.

Insulin and Fat Synthesis

• Role of Insulin: An anabolic hormone promoting the synthesis of glycogen and fat.

• Consequences of Insulin: Elevated levels lead to increased fat storage and triglyceride synthesis in adipose tissue.

• Fat Synthesis Stages:

  • Stage 1: Acetyl CoA from pyruvate degradation is converted into citrate in the mitochondrial matrix, which is then transported to the cytoplasm.

  • Stage 2: Citrate is converted back into acetyl CoA and oxaloacetate in the cytoplasm via ATP citrate lyase, using ATP.

  • Stage 3: Acetyl CoA is used to form malonyl CoA, which is used by fatty acid synthase (FAS) to create fatty acids.

Metabolic Pathway Overview

• Transporting Acetyl CoA: Acetyl CoA cannot cross the mitochondrial membrane directly; it is converted to citrate for transport.

• Oxaloacetate Recycling: Oxaloacetate formed during citrate conversion can be recycled back into the mitochondrial processes.

• NADPH Production: Generated during the conversion of malate to pyruvate, used extensively for fatty acid synthesis.

Acetyl CoA Carboxylase (ACC) Regulation

• Function of ACC: Key enzyme in the first committed step of fatty acid synthesis, converting acetyl CoA into malonyl CoA.

• Regulatory Mechanisms:

  • AMPK: Activates or inhibits ACC based on energy levels (AMP and ATP balance).

  • Insulin Effects: Stimulates ACC activation.

  • Citrate Role: Binds to ACC to enhance its activity during high energy states.

Fatty Acid Synthase Mechanism

• Structure of FAS: Dimeric enzyme complex with three distinct domains to facilitate fatty acid chain assembly.

• Cycle Overview: Each cycle adds 2 carbon units to the fatty acid chain, requiring NADPH and involving condensation and reduction steps.

• Final Product: Synthesizes palmitate (C16 fatty acid) after seven cycles, requiring diverse enzymes and co-factors.

Triglyceride Synthesis in the Liver

• Formation: Utilizes fatty acyl CoA and glycerol 3-phosphate through phosphatidic acid as an intermediate to generate triglycerides.

• Liver Role: Central processing organ for excess carbohydrates converting them into lipids for storage.

• Successive Reactions: Include converting phosphatidic acid to diacylglycerol and finally to triglycerides through acyltransferases.

Fatty Acid Elongation and Desaturation

• Elongation Pathway: Extends the palmitate chain into longer fatty acids using malonyl CoA.

• Desaturation Mechanism: Introduces cis double bonds into fatty acids, specifically beyond F9, which requires dietary essential fatty acids.

NADPH Generation Paths

• Citrate Decarboxylation: Yields acetyl CoA and NADPH from citrate metabolism in the cytoplasm.

• Pentose Phosphate Pathway: Converts glucose into ribose-5-phosphate and produces NADPH, supporting biosynthetic processes.

Summary of Metabolic Effects in Julian's Diet

• Pathological Consequences: Excessive caloric intake leads to obesity, reinforcing insulin signaling pathways that further promote fat storage.

• Insulin's Dual Role: While essential for metabolic health, chronic high levels linked to overconsumption lead to adverse health outcomes for Julian, including increased risk for diabetes and cardiovascular disease.

Conclusion

• Broader Implications: Julian exemplifies the metabolic challenges faced by many children today, underlining the need for education on healthy eating and physical activity to combat obesity and its associated health risks.