Lipid Metabolism and Types

Lipid Metabolism

• Lipids are a class of hydrophobic compounds that are soluble in non-polar organic solvents.
• Lipids are important energy source for the body.
• Due to their lack of solubility, the body's lipids are transported in plasma-bound albumin or in combination with proteins (lipoproteins).
• Imbalances in lipid metabolism can lead to major conditions such as atherosclerosis and obesity.

Lipid Types

• Lipids can be divided into: fatty acids, glycerol esters of fatty acids, phosphoglycerides, sphingolipids, and steroids.
• Fatty acids have the general formula R-COOH.
• Glycerol esters of fatty acids include mono-, di-, and triglycerides.
• Phosphoglycerides, also known as phosphatides, are phosphatidic acid derivatives.
• Sphingolipids are sphingosine derivatives.
• Steroids have a characteristic steroid nucleus structure.

Lipid Organization

• Lipids may be organized as storage lipids (neutral) or membrane lipids (polar).
• Storage lipids include triacylglycerols composed of glycerol and fatty acids.
• Membrane lipids include: Glycerophospholipids, Sphingolipids and Galactolipids.
• Glycophospholipids are composed of glycerol, fatty acids, PO4, and alcohol.
• Sphingolipids are composed of sphingosine, fatty acids, PO4, and choline.
• Galactolipids (sulfolipids) are composed of glycerol, fatty acids, and Mono- or disaccharide (SO4).
• Archaebacterial ether lipids composed of glycerol, PO4, and diphytanyl with an ether linkage.

Fatty Acid Metabolism

• Fatty acids are formed from a hydrophobic hydrocarbon chain and a carboxyl group (-COOH).
• At physiological pH, the carboxyl group is ionized and becomes -COO-
• The anionic group makes fatty acids amphipathic, having both hydrophobic and hydrophilic portions.
• Free fatty acids are insoluble in water and are transported in the circulation linked to albumin.

Fatty Acid Classification

• Fatty acids can be classified into two categories: saturated and unsaturated.
• Saturated fatty acids include butyric acid (C4), capric acid (C10), palmitic acid (C16), and stearic acid (C18).
• Unsaturated fatty acids have one or more double bonds.
• One-double-bond fatty acids are monounsaturated; more double bonds are polyunsaturated.
• Natural forms of unsaturated fatty acids are isomers cis
• Oleic acid is an unsaturated fatty acid designated as Δ189 or ω9.
• Linoleic acid is an unsaturated fatty acid designated as Δ189,12 or ω6.
• Linolenic acid is an unsaturated fatty acid designated as Δ189,12,15 or ω3.
• Arachidonic acid is an unsaturated fatty acid designated as Δ205,8,11,14 or ω6.

Fatty Acid Degradation

• Triglyceride deposits are found in adipose tissue.
• Triglyceride deposits are mobilized when glycogen reserves are depleted and the body requires energy in increased quantities.
• Released fatty acids leave adipocytes.
• Albumin-bound fatty acids leave transported to tissues, especially to muscle tissues, and diffuse into cells for degradation.
• Free fatty acids cannot be used as an energy source by erythrocytes (lacking mitochondria) or the brain (due to the impermeable blood-brain barrier).

Saturated Fatty Acid Catabolism

• The major pathway of catabolism of saturated fatty acids is called β-oxidation.
• β-oxidation is mitochondrial.
• β-oxidation involves the removal of 2-carbon atom fragments at the acyl-CoA carboxyl terminus.
• ẞ-oxidation produces acetyl-CoA, NADH and FADH2.

Fatty Acid Degradation Stages

• Fatty acid degradation involves three stages.
• Stage one: Fatty acid activation in the cytoplasm - requires HSCoA and ATP.
• Fatty acids must first be converted to an active intermediate before they can be catabolized.
• This is the only step in the complete degradation of a fatty acid that requires energy from ATP.
• Stage two: Acyl-CoA transport from cytoplasm to mitochondria.
• Stage three: Beta Oxidation

Cat I Regulation

• Malonyl-CoA inhibits carnitine-acyl-transferase I (CAT I).
• CAT I is inhibited to prevents the entry of activated acids into mitochondria.
• Malonyl-CoA is a precursor (starting product) in the synthesis of fatty acids, which occurs in the cytosol.
• Inhibiting CAT I prevents the transfer of newly formed fatty acid into mitochondria and degradation.
• Genetic deficiency of CAT I affects the liver, causing a decline in synthesizing glucose during post-period (severe hypoglycemia, coma).

Cat II & Carnitine

• CAT II deficiency is mainly found in the cardiac and skeletal muscle.
• Cats II deficiency resulting in muscle weakness and myoglobinemia after prolonged exercise.
• Carnitine comes from food (especially meat products) or can be synthesized from amino acids lysine and methionine (liver and kidney).
• Deficiency of carnitine results in low tissue capacity to use fatty acids as fuel.

Beta (β) Oxidation Steps

• A saturated acyl Co A is degraded by a recurring sequence of four reactions:
• Oxidation by flavin adenine dinucleotide (FAD)
• Hydration
• Oxidation by NAD+
• Thiolysis by Co ASH
• This fatty acyl chain is shortened by two carbon atoms as a result of these reactions.
• FADH2, NADH, and acetyl Co A are generated.
• Oxidation is on the β carbon and the chain is broken between the α (2)- and β (3)-carbon atoms, hence the name – β oxidation.
• Beta oxidation of palmitic acid (C16) results in 129 ATP

Odd Chain Fatty Acids

• Fatty acids with an odd number of carbon atoms are oxidized by the pathway of β-oxidation.
• Producing acetyl-CoA until a three-carbon (propionyl-CoA) residue remains
• This compound is converted to Succinyl-CoA, a constituent of the citric acid cycle.
• The propionyl residue from an odd-chain fatty acid is the only part of a fatty acid that is glucogenic.

Unsaturated Fatty Acids

• In the oxidation of unsaturated fatty acids, most of the reactions are the same as those for saturated fatty acids.
• Only two additional enzymes isomerase and a reductase is needed to degrade a wide range of unsaturated fatty acids.
• Energy yield is less by the oxidation of unsaturated fatty acids since they are less reduced.
• Per double bonds 2 ATP are less formed, since the first step of dehydrogenation to introduce double bond is not required.

Fatty Acid Biosynthesis

• Synthesis of fatty acids take place in the cytosol.
• Fatty acid biosynthesis involves two distinct stages:
• Step of synthesis of palmitic acid
• The step of modifying palmitic acid to produce higher or unsaturated fatty acids (except for linoleic and linolenic acids).
• The modification step consists of elongation, desaturation, and hydroxylation processes.

Palmitic Acid Synthesis

• Occurs in the cytosol.
• Is a process in which palmitic acid results from the head-tail binding of the 2-C units provided by acetyl-CoA
• The process needs:
• Acetyl-CoA-repeating unit
• Malonil-CoA - Synthesis of this product is the limiting stage of process speed
• NADPH -reducing equivalents
• NADPH is obtained via the pentose phosphate pathway.
• Isocitrate-dehydrogenase catalysed reaction, malate conversion in pyruvate-catalyzed malic enzyme process
• Enzymatic system

Cytosolic Acetyl-CoA

• Mitochondrial acetyl-CoA can be produced by:
• oxidation of pyruvate
• catabolism of fatty acids
• catabolism of ketone bodies
• catabolizing some amino acids
• Its transfer from mitochondria to cytosol is done through CITRATE.

Malonyl-CoA Synthesis

• It is the key step in the synthesis of palmitic acid
• The enzyme catalysing the process is acetyl-CoA carboxylase, it requires biotin, ATP and CO2.

Acetyl-CoA Carboxylase Regulation

• Allosteric: + Citrate; -palmitate CoA
• Covalent: phosphorylated form – inactive
• Induction/repression- dietary intake of excess calories determines the synthesis of acetyl-CoA carboxylase

Palmitic Acid Synthase

• The synthesis of palmitic acid is carried out by a multienzymatic complex called fatty acid synthase.
• This complex is a dimer consisting of two subunits, each monomer having 7 domains with different enzymatic activity plus a domain linking the rest * acyl *.
• The ACP family contains a 4 phosphopantetein (CoASH) molecule and a cysteine residue.
• Forms palmitic acid in reverse β-oxidation

Modification Stage

• The body synthesizes all the fatty acids it needs from palmitic acid.
• Except for essential fatty acids: LINOLEIC AND LINOLENIC
• For the synthesis of other fatty acids, palmitic acid undergoes elongation, desaturation and hydroxylation processes.

Synthesis vs Degradation

• Synthesis metabolic process occurs after a meal rich in carbohydrates.
• Degradation metabolic process occurs during starvation.
• Synthesis occurs in the cytosol
• Degradation occurs in the mitochondria
• Important synthesis tissue is the liver
• Important degradation tissue is the muscle and the liver
• Synthesis utilizes citrate for transport
• Mitochondria transports to cytosol during synthesis
• Degradation transport utilizes carnitine
• Cytosol is transported to the mitochondria during the degradation process
• NADPH is used during synthesis (reduction)
• NAD + and FAD are used during degradation (oxidation)
• Citrate is used as an activator and Acyl-CoA is used as an inhibitor during synthesis
• Malonyl-CoA is used as an inhibitor during degradation
• Acetyl-CoA is the product that is obtained during synthesis
• Palmitic Acid is the product that is obtained during degradation
• Condensation, reduction, dehydration are cyclical stages during synthesis
• Dehydrogenation and hydration are cyclical during degradation