Lipids and Their Functions in Biology

Lipids: Introduction

• Lipids are a diverse group of hydrophobic molecules
• They are important for energy storage and cell structure
• Lipids are compartmentalized (e.g., in adipocytes or lipoprotein particles) due to their insolubility in aqueous solutions
• Lipid imbalances can lead to medical issues like atherosclerosis, diabetes, and obesity

Degradation of Triacylglycerols

• Triacylglycerols (TGs) consist of fatty acids esterified to glycerol
• TGs are stored in white adipose tissue (WAT) as a major energy reserve
• Lipolysis (breakdown of TGs) is necessary to mobilize stored fat

Fasting Stage: Lipolysis

• Glucagon activates lipolysis, which is essential in times of starvation.
• Glucagon activates trimeric G-protein
• This activates adenylate cyclase
• This leads to cAMP production
• cAMP activates protein kinase A (PKA)
• HSL is activated by PKA phosphorylation
• Lipases are crucial enzymes in the process
• Triacylglycerols are degraded to produce free fatty acids (FFAs) and glycerol
• Degradation is a major pathway when glucose is not readily available

Utilization of Fatty Acids

• Fatty acids are taken up by cells and used for energy production in mitochondria
• Breakdown of fatty acids produces acetyl-CoA, NADH, and FADH2
• These products are used in the tricarboxylic acid cycle and oxidative phosphorylation

Uptake and Activation of Fatty Acids

• Fatty acids must be converted to their activated form (acyl-CoA)
• This is catalyzed by fatty acyl-CoA synthetases (FACS) using ATP

Transport of Acyl Groups into Mitochondria

• Short- and medium-chain fatty acids (FCAs) can enter mitochondria through simple passive diffusion
• Long-chain fatty acids (LCFAs) require carnitine for transport in order to enter the mitochondria

β-Oxidation

• Fatty acyl-CoAs are broken down in a cyclical process known as β-oxidation
• Four reactions in a cycle degrade the fatty acyl chain in two-carbon segments, generating acetyl-CoA
• Each cycle generates one molecule of FADH2 and NADH, as well as one molecule of acetyl-CoA

Synthesis of Ketone Bodies

• Ketone body synthesis occurs when there's a high rate of fatty acid oxidation in the liver.
• This process produces acetoacetate, β-hydroxybutyrate, and acetone
• These compounds are used as an alternative energy source by many tissues when glucose availability is limited (e.g., during prolonged fasting or starvation)

Utilization of Ketone Bodies

• Ketone bodies are transported in blood and used by extrahepatic tissues as a source of energy.
• Important source of energy when glucose levels are insufficient
• The brain can use ketone bodies

Regulation of Ketogenesis

• Ketosis only occurs with elevated levels of circulating free fatty acids (FFAs) from adipose tissue lipolysis.
• Regulation is influenced by CPT-I, malonyl-CoA, and the mitochondrial NAD+/NADH ratio
• Factors affecting the rate of ketone body synthesis

Synthesis of Fatty Acids in the Cytosol

• Fatty acid synthesis primarily takes place in the cytosol
• Acetyl-CoA, transported from mitochondria as citrate, is the essential substrate for this process.
• Acetyl-CoA carboxylase is the key rate-limiting step in fatty acid synthesis.
• The synthesis involves the stepwise addition of two-carbon units to a growing fatty acyl chain, requiring NADPH

Fatty Acid Elongation and Desaturation

• Fatty acids can be further elongated or desaturated in the endoplasmic reticulum (ER)
• Elongation involves the addition of two-carbon units at the carboxyl end of a fatty acid chain
• Desaturation is the introduction of double bonds into the fatty acid chain, increasing its fluidity

Synthesis and Storage of Triacylglycerols (TGs)

• Lipoprotein lipase (LPL) is needed for the uptake of fatty acids by adipocytes.
• Glycerol is necessary for TG synthesis
• The synthesis takes place in the smooth endoplasmic reticulum (SER), with acyl-CoA being the source of the acyl groups