Study Notes on Carb & Lipid Metabolism: Fatty Acid Metabolism & Cholesterol Synthesis
Unit 4: Carb & Lipid Metabolism
Overview of Course Material
Focus on Fatty Acid Metabolism and Cholesterol Synthesis.
Instructor: Elizabeth Hull, PhD
Learning Objectives
Lipolysis
Distinction in Lipolysis:
Fasting: Mediated by Hormone-Sensitive Lipase (HSL) in adipose tissue.
Fed State: Mediated by Lipoprotein Lipase (LPL) in the capillaries.
Metabolic pathways of free fatty acids (FA) produced are poorly regulated.
β-Oxidation
Activation Process:
Free FA activated to FA-CoA, costing 2 ATP.
Carnitine Shuttle: Transports FA-CoA into mitochondria.
Oxidation process includes:
Introduction of double bond.
Addition of water to create hydroxyl group.
Conversion to carbonyl group prior to cleavage into acetyl-CoA.
Energy Yield: Knowing the number of β-oxidation cycles from palmitate is essential.
Ketone Body Formation
Process in Liver:
Formation in mitochondria, exclusive to liver.
Ketone bodies identified as acetoacetate and 3-hydroxybutyrate.
Understand acetone formation and peripheral tissue utilization.
Transport Shift:
MCT (monocarboxylate transporter) shift in brain during fasting.
De novo Lipogenesis
Definition: Utilizing newly synthesized palmitate; repackaging FA with glycerol.
Transport Mechanism:
TAG made in liver is transported via VLDL, while TAG made in adipose is stored.
Citrate-Pyruvate Shuttle
Important for providing NADPH and carbon sources from glucose for palmitate synthesis.
Connecting Pathways:
Understanding FA synthase function in reverse mechanism to β-oxidation.
Regulation of Metabolic Pathways
Lipolysis regulation by HSL; FA synthesis regulation through carnitine shuttle and multiple levels affecting Acetyl-CoA carboxylase.
Mass action governs ketone body production following FA accumulation in liver.
Cholesterol Biosynthetic Pathway
Rate-Limiting Step: HMG-CoA reductase is critical.
Locations and regulations around ketone and cholesterol synthesis differ.
Listing cholesterol uses and its intermediates, including bile salt synthesis.
Overview of Lipid Metabolism
Role of Lipids: Major energy source with essential functions and associated health risks such as atherosclerosis, diabetes, and obesity.
Recommended Macronutrient Distribution:
AMDR: 20–35% of total calories from fat.
Energy-Related Pathways
Lipolysis:
Hydrolyzing TAG from lipoproteins to release glycerol and free fatty acids.
β-Oxidation:
Breakdown of fatty acids to acetyl-CoA for TCA cycle energy.
Ketogenesis:
Producing ketone bodies for energy during fasting.
De novo Lipogenesis:
Synthesizing TAGs from Acetyl-CoA.
Cholesterol Metabolism:
Unique as it does not serve for energy.
Lipolysis
Mechanism of TAG Breakdown
Fasting vs. Fed State: Sources of Free FA determined by metabolic state.
Fasting State
HSL action in adipose tissue releases FA and glycerol.
Hormonal activation through epinephrine, not glucagon.
Fed State
Source: Circulating dietary lipoproteins; LPL digests these TAGs into free FAs.
Goal of Lipolysis
Hydrolyze TAGs into usable substrates during fasting.
Regulation of Lipolysis
Active when insulin is low; stimulated during exercise and fasting.
β-Oxidation Overview
Goals and Phases
Converts FA-CoA to acetyl-CoA for TCA cycle.
Active: Post-absorptive phase and fasting state.
Pathway steps include:
Enter mitochondria via carnitine shuttle.
Cleave FA-CoA to yield acetyl-CoA.
Carnitine Shuttle Mechanism
CPT-1 exchanges CoA for Carnitine.
Transport complex moves FA-Carnitine to the mitochondrial matrix.
CPT-2 re-exchanges Carnitine for CoA.
Steps of β-Oxidation
Cycle yields 1 acetyl-CoA, 1 FADH2, and 1 NADH per cycle.
Total cycles required: (where n = number of carbons).
Energy Yield from Palmitate
Complete oxidation yields 129 ATP from palmitate compared to glucose's 30-32 ATP.
Regulation of β-Oxidation
Regulation by Availability and Hormones
Substrate availability influences the on/off regulation during fasting/fed states.
HSL serves as the rate-limiting step and regulates through several hormones:
Epinephrine activates HSL while insulin counteracts.
Glucagon does not impact directly due to receptor absence in adipose tissue.
Ketogenesis
Goals and Mechanism
Produce ketones (acetoacetate and 3-hydroxybutyrate) as energy during fasting.
Rate-limiting step: HMG-CoA synthase combines acetyl-CoAs.
Regulation
High levels of FA result in increased acetyl-CoA leading to reduced pyruvate processing and stimulating ketogenesis.
Efficacy relies on metabolic conditions such as OAA levels.
De Novo Lipogenesis
Mechanism Overview
Goal: Store energy as TAGs; active in the FED state.
Transport: TAGs from the liver (via VLDL) and adipose stores.
Leveraging citrate for regulatory mechanisms and production of malonyl-CoA.
Steps Involved in FA Synthesis
Start with acetyl-CoA.
Elongate chain using malonyl-CoA.
Each addition requires NADPH sourced from HMP shunt and malic enzyme.
Regulation of De Novo Lipogenesis
Achieved through the activity levels of Acetyl-CoA carboxylase, competing hormonal signals, and feedback mechanisms.
Cholesterol Synthesis
Overview
Active primarily in the FED state for membrane incorporation and hormone synthesis.
Rate-limiting enzyme: HMG-CoA reductase.
Synthesis Steps
Acetyl-CoA to mevalonate process.
Further conversion of intermediates to complete cholesterol synthesis.
Requires energy investment (ATP) and reducing equivalents (NADPH).
Uses of Cholesterol
Membrane integrity.
Precursor for steroid hormones.
Involved in signaling pathways and crucial for lipoprotein metabolism.
Key Concepts Summarized
Pathways of lipolysis, β-oxidation, ketogenesis, and de novo lipogenesis form metabolic crossroads impacting energy homeostasis.
Fundamental regulatory mechanisms indicate body response to feeding and fasting states, affecting lipid metabolism and energy utilization.
Knowledge Checks and Clinical Connection
Review knowledge check answers and their implications on metabolic disorders and symptomatology like hypoglycemia, ketogenic states, hypertriglyceridemia etc.