Lipolysis

Lipid Basics

• Triacylglycerol (TG): Also known as Triglyceride

  • Comprises 95% of lipid consumed in the diet.

  • Functions as adipose storage.

  • Structure consists of a glycerol "backbone" attached to three fatty acids.

• Other types of lipids include:

  • Phospholipids

  • Sterols

Lipids in Food

• Fats and Oils:

  • Common oils include:

  • Sunflower oil

  • Safflower oil

  • Corn oil

  • Oleic oil

  • Coconut oil

  • Palm oil

  • Common fats include:

  • Butter

  • Lard

  • Tallow

  • Cholesterol is primarily found in animal foods.

• Types of Triglycerides:

  • Simple TG: All three fatty acids (FAs) are identical.

  • Mixed TG: The fatty acids are different.

Prevalent Fatty Acids in Western Diets

• Saturated Fatty Acids (SFA):

  • Examples include:

  • Palmitic acid (16:0)

  • Stearic acid (18:0)

• Unsaturated Fatty Acids (UFA):

  • Examples include:

  • Oleic acid (18:1)

  • Linoleic acid (18:2)

• Most fatty acids range from 14 to 26 carbon atoms and are typically present in even numbers.

Fatty Acids (FAs)

• Structure: Fatty acids consist of carbon atoms bonded to hydrogens.

• Each carbon forms four bonds, influencing solubility and other properties.

• Polar Carboxyl End:

  • Water soluble (COOH).

• Nonpolar Methyl End:

  • Water insoluble (CH3).

  • Identified as omega end (ω) opposite to the alpha end (α).

Fatty Acid Chain Length

• Fatty Acid Chain Classification by Length:

  • Short chains: 2-4 carbons.

  • Medium chains: 6-12 carbons.

  • Long chains: 14-26 carbons.

  • Example: Linoleic acid (18:2)

Fatty Acid Saturation

• Types of Fatty Acids Based on Saturation:

  • Saturated: No double bonds between carbons.

  • Monounsaturated: Contains one double bond.

  • Polyunsaturated: Contains multiple double bonds.

• Factors influenced by fatty acid saturation and length:

  • Water solubility

  • Polarity

  • Melting point

Fatty Acid Structures

• Saturated Fatty Acid (SFA):

  • Structure can be represented as:

``` H H H H H H H H H H H H H H H H H
H-C--C--C--C--C--C--C--C--C--C--C--C--C--C--C--C--C-C-OH
H H H H H H H H H H H H H H H H H

- **Monounsaturated Fatty Acid (MUFA)**:
  - Structure represented as:

H H H H H H H H
H H H H H H H O H-C--C--C--C--C--C--C--C--C=C--C--C--C--C--C--C--C--C-OH
H H H H H H H H H H H H H H H H H

- **Polyunsaturated Fatty Acid (PUFA)**:
  - Structure represented as:

H H H H H H H H H H H H H O H-C--C--C--C--C--C=C--C--C=C--C--C--C--C--C--C--C--C-OH
H H H H H H H H H H H H H H H H H
```

Lipogenesis

• Definition: The metabolic process of synthesizing fatty acids from acetyl CoA.

• Location:

  • Primarily in the liver (the major lipogenic organ)

  • Also occurs in adipose tissue, mammary glands, lungs, brain, and kidneys.

• Acetyl CoA is derived from:

  • Carbohydrates (CHO)

  • Fats

  • Ketogenic amino acids

  • Alcohol

• Pathway:

  • Excess carbohydrates convert first to glycogen (limited storage capacity: 400-500g).

  • Excess dietary proteins are not stored but used for synthesizing fat.

Key Features of Lipogenesis

• Not the Reverse of Lipolysis:

  • Lipogenesis takes place in the cytoplasm while lipolysis occurs in the mitochondria.

• Transfer of acetyl CoA from mitochondria to the cytoplasm occurs as citrate:

  • Citrate lyase converts citrate to oxaloacetate (OAA) and acetyl CoA.

  • Acetyl CoA is now available as a precursor for fatty acid synthesis.

Pyruvate Carboxylation Steps

1. Pyruvate undergoes carboxylation with ATP, resulting in an intermediate that produces acetyl CoA.

2. The malate, converted from OAA, also has a vital role in transferring carbons into the mitochondrial matrix.

Fatty Acid Synthesis

• Begins from the methyl end towards the carboxylic acid end.

• Primary Fatty Acid: Palmitate (16C) is synthesized first.

• Can undergo elongation to 18 or 20 carbon chains.

• Can undergo desaturation, unable to exceed the 9th carbon.

• All synthesis occurs in the cytosol using specific enzymes.

Enzymes Involved in Fatty Acid Synthesis

• Key Enzyme: Acetyl CoA carboxylase.

• Formation of a complex called fatty acid synthase (FAS).

• Components of FAS include:

  • Condensing enzyme (CE)

  • Acyl carrier protein (ACP)

• Both components have free –SH groups for attachment of acetyl CoA and malonyl CoA.

Regulation of Fatty Acid Synthesis (FAS)

• Enhancements: Induced by insulin, cytosolic citrate, and high carbohydrate diets.

• Inhibitors: Long-chain acyl-CoA, cAMP, glucagon, and elevated plasma free fatty acids (FFA).

Fatty Acid Synthesis Intermediates

• Intermediates are linked to ACP.

• The synthesis follows a four-step cycle:

  • Condensation: Joining of acetyl CoA to malonyl CoA.

  • Reduction: Utilizes NADPH.

  • Dehydration: Removal of water.

  • Another Reduction: Concludes formation of a new fatty acid chain.

Malonyl CoA Formation

• Synthesized when acetyl CoA is carboxylated by acetyl CoA carboxylase.

• Irreversible Reaction: Rate-limiting step in fatty acid biosynthesis.

  • Regulation by allosteric factors such as insulin and citrate (positive) and malonyl CoA, long-chain acyl-CoA, and glucagon (negative).

Fatty Acid Elongation

• Occurs in endoplasmic reticulum or mitochondria.

• Malonyl CoA contributes two-carbon units.

• Reducing power from NADPH.

• Catalyzed by fatty acid elongase enzymes.

Fatty Acid Desaturation

• Enzymes: Notably, Delta-5, -6, and -9 desaturases.

• Humans cannot desaturate beyond the 9th carbon.

• Linoleic (18:2 w-6) and linolenic acid (18:3 w-3) are essential dietary fatty acids.

Cis vs. Trans Fatty Acids

• Cis FAs: Hydrogens are on the same side of the double bond, causing kinks that maintain fluidity.

• Trans FAs: Hydrogens on opposite sides, leading to straighter chains and less membrane fluidity.

Trans Fatty Acids Influence

• Can affect lipid enzymatic operations, reduce prostaglandins, and impair desaturation and chain elongation necessary for metabolic functions.

Essential Fatty Acids (EFA)

• Function: Key in growth, reproduction, cell membrane formation, brain development, and eicosanoid production (e.g., thromboxanes, leukotrienes, prostaglandins).

• Deficiency Results In:

  • Anatomical and physiological anomalies

  • Poor dermal integrity

  • Decreased epidermal water barrier

  • Cell hyperproliferation

Dietary Lipid Requirements

• Approximately 2-3% of fat in the diet meets minimum EFA requirements, with optimal intake for linolenic acid being 800-1100 mg/day.

Sources of Essential Fatty Acids

• Linoleic Acid: Sourced from PUFA-rich vegetable oils (sunflower, corn, safflower).

• Linolenic Acid: Found in canola, linseed, soybean, and marine oils.

Formation of Triglycerides (Triacylglycerol)

• Fatty acids are joined via esterification to form triglycerides.

• Also exist as monoglycerides and diglycerides, utilizing ester linkages (-C-O-C-).

Phospholipids Structure

• Contain a glycerol backbone, two fatty acids, and a phosphatidic acid unit substitutes for the third fatty acid.

• Distinct hydrophilic and hydrophobic sides facilitate their function in cell membranes and transport of lipids.

• Lecithin is a liver-made phospholipid.

Common Types of Phospholipids

• Examples include:

  • Phosphatidylcholine

  • Phosphatidylethanolamine

  • Phosphatidylserine

  • Phosphatidylinositol

Plasmogens and Sphingolipids

• Plasmogens replace one fatty acid with a long-chain ether group.

• Sphingolipids contain sphingosine instead of glycerol.

Sterols Function

• Include a variety of steroid hormones, cholesterol, and vitamin D.

• Steroid Hormones: Examples include estrogen, androgens, DHEA, and adrenocorticoid hormones.

Cholesterol Synthesis

• Approximately 700 mg are synthesized daily in the liver.

• Originates from the condensation of acetyl CoA.

• Process includes:

  • Formation of HMG-CoA from acetyl CoA and isoprene units catalyzed by HMG-CoA reductase.

Molecular Control Mechanisms of Fat Metabolism

• Governed by nuclear hormone receptors like PPARs (Peroxisome proliferator-activated receptors):

  • Key Players: PPARα, PPARδ, PPARλ.

Digestion of Lipids

• Enzymes Involved:

  • Lingual lipase

  • Gastric lipase

  • Intestinal mucosal-secreted lipase

• Phases of Digestion:

  • Intraluminal phase

  • Mucosal phase

  • Secretory phase.

Intraluminal Phase

• Occurs in the upper jejunum and relies on emulsification processes via bile salts.

• Mixes pancreatic secretions with chyme forming micelles for fat absorption.

Mucosal Phase

• Absorption of free fatty acids and monoglycerides takes place, with shorter-chain fatty acids entering the portal vein, and longer chain fatty acids being re-synthesized into triglycerides and absorbed as chylomicrons.

Secretory Phase

• Chylomicrons are released from mucosal cells, entering lymphatic circulation.

• Short-chain fatty acids exit to the portal vein.

Transport of Lipids

• Integral lipoproteins include triglycerides, cholesterol esters, phospholipids, and proteins.

• Types of Lipoproteins:

  • Chylomicrons

  • Very Low-Density Lipoproteins (VLDL)

  • Low-Density Lipoproteins (LDL)

  • High-Density Lipoproteins (HDL)

Metabolism of Different Lipoproteins

• Lipoprotein metabolism involves chylomicrons, VLDL, LDL, and HDL with distinct functions in lipid transport and cholesterol management.

Control of Fatty Acid Oxidation

• Entry of fatty acids into mitochondria is inhibited by malonyl-CoA.

Ketogenesis

• Involves production of ketone bodies when lipolysis exceeds triglyceride formation, seen in conditions with low insulin levels or insufficient carbohydrate intake.

Summary of Ketone Bodies

• Main sources of ketone production derived from fatty acid oxidation, amino acids, and alcohol oxidation, with the key ketones including acetoacetate, acetone, and β-hydroxybutyrate.

Role of Ketones

• Provide energy for cells excluding certain types (e.g., red blood cells), with varying levels observable under different metabolic states (fasting, low-carbohydrate diets, diabetic conditions).