Human Nutrition

Fiber Recommendations

Adults should aim for 25-40g of fiber daily, achievable through:

• Whole-grain products (1-2g fiber/serving)
• Vegetables (2-3g fiber/serving)
• Fruits (about 2g fiber/serving)
• Legumes (6-8g fiber/serving)
• Refer to the Canada Food Guide for serving specifics.

Lipids

Types

• Fatty acids
• Triglycerides (TG)
• Phospholipids
• Sterols

Functions

• Energy production (fatty acid oxidation)
• Energy storage (TG accumulation)
• Insulation and padding (TG in adipose tissue)
• Cell signaling (diacylglycerol, DAG)
• Structural support (cell membrane formation)
• Inflammatory responses (eicosanoids)
• Hormonal production (steroids)

Characteristics

• Generally insoluble in H2O, requiring specific processes for digestion, absorbance, and transport.
• Found in butter, margarine, nuts, oils, lard, cheddar cheese, hamburger, salmon, eggs, avocado, etc.
• Cholesterol is only present in animal foods.

Recommendations

• Health Canada advises a diet low in saturated fat, trans fat, and cholesterol.
• Lipids should constitute 20-35% of daily energy intake.

Fatty Acids

Structure

• Simplest lipids with methyl (non-polar) and carboxyl (polar) ends.
• Do not cyclize.

Classification

• Chain Size
  • Short-chain: 2-4 carbons
  • Medium-chain: 6-12 carbons
  • Long-chain: 14-26 carbons
• Saturation
  • Saturated: No double bonds (e.g., palmitic acid)
  • Unsaturated: Presence of double covalent bonds
    • Monounsaturated (MUFA): One double bond (e.g., oleic and palmitoleic acids)
    • Polyunsaturated (PUFA): Two or more double bonds (e.g., linoleic and arachidonic acids)

Numeric Representation

• Ex: 16:0 (palmitic acid), 16:1 (palmitoleic acid), 18:1 (oleic acid), 20:4 (arachidonic acid)
• First number: Number of carbons
• Second number: Number of double bonds

Double Bond Position

Delta (A) System

• Counts carbons from the carboxyl end.
• Linoleic acid: 18:2 \Delta^{9-12}

Omega (w) System

• Counts carbons from the methyl end.
• Identifies the position of the first carbon with a double bond.
• Linoleic acid: 18:2 w-6

Dietary Fats Composition

• Composed of a mix of polyunsaturated, monounsaturated, and saturated fatty acids in varied proportions.
• Butter: Mostly saturated, but contains MUFA and PUFA.
• Oils: Mostly unsaturated, with small amounts of saturated fatty acids.

Solubility and Melting Point

• Shorter fatty acids: More water-soluble than longer ones.
• Greater number of double bonds: Greater polarity and water solubility.
• Greater chain length and saturation: Higher melting point.
• Common unsaturated fatty acids are liquid at room temperature, except for oleic acid.

Naturally Occurring Fatty Acids (Examples)

Essential Fatty Acids

• Cannot be synthesized by the body; must be obtained through diet.
• Linoleic (18:2 \Delta9,12 w-6) and a-linolenic (18:3 \Delta9,12,15 w-3) acids.
• Humans lack \Delta2 and \Delta15 desaturases needed to incorporate double bonds at these positions.
• Only plants have these enzymes.
• Deficiency can cause retarded growth, dermatitis, kidney lesions, and early death.

Omega-3 and Omega-6 Fatty Acids

Importance

• Great nutritional interest due to opposing metabolic effects.

Omega-3

• Associated with:
  • Reduced blood pressure and blood clots
  • Reduced risks of heart disease and stroke
  • Improved defense against inflammatory diseases

Omega-6

• Evidence suggests a pro-inflammatory effect and potential harm.

Ideal Ratio

• Historically, an ideal ratio between w-6 and w-3 was thought to promote health benefits and avoid harmful effects.
• Currently, no scientific evidence supports recommendations based on ratios.

Current Consensus

• Increase intake of dietary w-3 fatty acids to maximize potential benefits.

Recommendations to Increase Omega-3

• Canadian Food Guide: Two servings of fish a week.
• Emphasize fatty fish like salmon, herring, and mackerel.
• Prepare fish by grilling, baking, or broiling instead of frying.
• Use dietary supplements (fish oil capsules) cautiously due to potential for excessive intake.
• Excessive intake of w-3 supplements can lead to bleeding, interfere with wound healing, raise LDL, and suppress immune function.

Saturated Fatty Acids

• Oils such as Coconut Oil, Palm Kernel Oil, and Palm Oil are solid or semi-solid at room temperature due to their high content of short-chain saturated fatty acids. They are considered solid fats for nutritional purposes.

Fats

• Shortening may be made from partially hydrogenated vegetable oil, which contains Trans fatty acids.

Trans Fatty Acids

Definition

• Unsaturated fatty acids with hydrogens next to the double bond on the opposite side of the carbon chain.
• Small fraction of naturally occurring fatty acids are trans (seed fats, leaves, milk, meat products).

Formation

• Created through hydrogenation, adding hydrogens to unsaturated fatty acids.
• Often partially hydrogenated, leaving some double bonds in trans configuration.

Advantages of Hydrogenation

• Protects against oxidation, prolonging shelf life.
• Alters texture: Makes liquid oils creamier and more spreadable (e.g., margarine).

Health Concerns

• Associated with increased heart disease.
  • Raises LDL (bad cholesterol)
  • Lowers HDL (good cholesterol)
  • Increases weight gain
  • Promotes visceral fat accumulation
  • Induces inflammation

Mitigation

• Push to eliminate trans fat from processed foods.
• Food labels required to specify trans fat content.

Triglycerides (TG)

Composition

• Three fatty acids esterified to one glycerol molecule.
• Most abundant lipids in human consumption.
• Found in salad dressing, butter, margarine, cooking oil, nuts, dairy products, bacon, beef, chicken skin.

Functions

• Energy storage in adipocytes within white adipose tissue (subcutaneous fat).
• Insulation.
• Mechanical support for internal organs (visceral adipose tissue located in the intra-abdominal area)
• Carriers of lipid-soluble vitamins (A, D, E, K).
• Contribute to taste of food.
• Signal satiety.

Characteristics

• Fatty acid composition varies, reflecting diet.
• Composition determines whether lipid is liquid or solid at room temperature.
  • More saturated fatty acids: likely solid.
  • More unsaturated or short-chain fatty acids: tend to be liquid.

Mobilization

• Stored TGs mobilized for energy during food restriction or increased energy expenditure.
• Requires lipolysis to cleave TGs into fatty acids (NEFAs) and glycerol.
• NEFAs, also called free fatty acids, bind to albumin for transport in circulation due to low water solubility.
• Albumin facilitates NEFA uptake by organs (skeletal muscles, heart, liver).
• Liver converts glycerol into glucose through gluconeogenesis.

Catabolism of TGs and Fatty Acids

• Hydrolysis of TGs yields glycerol and three fatty acids.
• Inside cells, fatty acids are activated by attachment of coenzyme A to form acyl-CoA, consuming 2 ATPs.
• Activated fatty acids undergo oxidation in mitochondria.

Transport

• Short-chain fatty acids (SCFAs) pass directly into the mitochondrial matrix.
• Long-chain fatty acids (LCFAs) require carnitine transport system.
  • Carnitine is synthesized from lysine and methionine.
  • Acyl-CoA joins carnitine at the outer mitochondrial membrane.
  • Carnitine:acyltransferase (CAT I) moves acyl-carnitine across the inner membrane.
  • CAT II splits acylcarnitine to form acyl-CoA and carnitine.

Beta-Oxidation

• Acyl-CoA undergoes β-oxidation, cleaving fatty acids in two-carbon units (acetyl-CoA).
• Acetyl-CoA enters Krebs cycle for further oxidation.

ATP Yield

• Complete β-oxidation of palmitate (16-carbon fatty acid) yields about 106 ATP molecules.
• Complete catabolism of glucose (6-carbon sugar) yields net 32 ATP molecules.
• Glucose: C6H{12}O6 + 6O2 + 32(ADP + Pi) \rightarrow 6CO2 + 32ATP + 38H_2O
• Palmitate: C{16}H{32}O2 + 23O2 + 106(ADP + Pi) \rightarrow 16CO2 + 106ATP + 122H_2O

Phospholipids

Structure

• Glycerol + two fatty acids + a phosphate group (PO_4)
• Amphiphilic (attract water- and fat-soluble substances).

Function

• Structural components for cellular membranes and lipoprotein shells.
• Double layer membranes selectively allow both fatty acids and water-soluble substances into the cell

Features

• Carbon 1 (alpha carbon) of glycerol backbone: esterified to saturated fatty acid.
• Carbon 2 (beta carbon): esterified to unsaturated fatty acid.
• Carbon 3: Attached to phosphate group.

Variants

• Phosphatidylcholine (lecithin)
• Phosphatidylethanolamine (cephalin)
• Phosphatidylserine
• Phosphatidylinositol
• These variants have choline, ethanolamine, serine, and inositol bound to the phosphate group, respectively.
• More polar than TGs and sterols and attract H2O.
• Commonly located on surface of chylomicrons, stabilizing them in aqueous solution.
• Serve as conduits for passage of H2O and fat-soluble material across membranes.
• Provide compounds (e.g., arachidonic acid) for eicosanoid synthesis.
• Involved in intracellular signaling and cell anchorage (e.g., phosphatidylinositol).
• Cells tightly regulate functional roles by keeping fatty acids, choline, etc., bound in phospholipids and freeing them only as needed.

Sterols

Structure

• Four-ring core structure (cyclopentanoperhydrophenanthrene) or steroid nucleus.

Cholesterol

• Most common sterol in animals.
• Precursor for other steroid molecules with major physiological functions.
• Most human enzyme systems are specific for cholesterol, not plant sterols.
• Plants have other sterols but not cholesterol.
• Major dietary sources: Meats, egg yolk, poultry, and dairy products.
• Sterols along with phospholipids comprise about 5% of dietary lipids.

Synthesis

• Liver cells make about 800-1500 mg of cholesterol daily.
• Used for bile production, important for dietary lipid digestion.
• Abundant in brain and nerve tissues, necessary for normal physiological function.

Health Implications

• Potentially harmful effects on arteries, promoting plaque formation and atherosclerosis.
• Control of circulating cholesterol levels prevents or treats cardiovascular diseases.

Catabolism

• Not an energy-producing nutrient.
• Catabolism and elimination through the biliary system.
• Removal of bile salts is a therapeutic approach for hypercholesterolemia.
  • Uses unabsorbable resins that bind bile salts in the intestinal lumen and prevent return to the liver.

Phytosterols

• Plant sterols are poorly absorbed.
• Structurally similar to cholesterol, inhibiting its absorption.
• A diet rich in phytosterols can exert a cholesterol-lowering effect.

Endogenous Cholesterol Synthesis

• Body can synthesize cholesterol (not needed in the diet).
• 90% of cholesterol is inside cells.
• Biochemical machinery for synthesis present in most cells, mainly liver and intestine.
• Acetyl-CoA is the precursor used to synthesize cholesterol.
• Glucose and fatty acids are main substrates catabolized to generate acetyl-CoA in the mitochondria; amino acids can also be used.

Pathway Phases

1. Conversion of Acetyl-CoA into mevalonate
2. Mevalonate into squalene
3. Squalene into cholesterol

Regulation

• Pathway activity is regulated by the amount of cholesterol present in the cell.
• Rate-limiting enzyme: Hydroxymethylglutaryl-CoA (HMG-CoA) reductase.
• HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate and is inhibited by cholesterol.
• Endogenous production is low and high with elevated and reduced dietary cholesterol supply, respectively.

Pharmacological Target

• HMG-CoA reductase is a common target for treating hypercholesterolemia to prevent atherosclerosis and myocardial infarction.
• Statins inhibit HMG-CoA reductase and lower endogenous cholesterol production.
• Prescribed when lifestyle modifications (diet and exercise) do not suffice.

Digestion and Absorption of Lipids

Overview

• Lipids need to be broken into smaller compounds for absorption.
• Requires specialized system to allow lipids to be accessed by digestive enzymes due to insolubility in H2O.

Oral Cavity

• Salivation and mastication allow lingual lipase to start TG hydrolysis.
• Cleaves FA esterified at the sn-3 position of the glycerol moiety.

Stomach

• Gastric lipase continues lipid digestion.
• Lingual and gastric lipases preferentially hydrolyze TGs containing short- and medium-chain fatty acids.
• Fat entering the duodenum is ~70% TGs with a mixture of partially hydrolyzed lipid products.

Intestine

• Most TGs are digested in the intestine, requiring bile salts and pancreatic lipase.

Bile

• Released by the gallbladder and has amphipathic properties (hydrophilic and hydrophobic ends).
• Causes emulsification of lipids.
• Pancreatic lipase can access and hydrolyze ester bonds at the sn-1 and sn-3 positions of the glycerol moiety.
• Detergent-like action of bile acids and peristaltic agitation turns fat into small droplets, increasing surface area for pancreatic lipases (emulsification).
• Bile salts also inhibit lipase activity by displacing the enzyme from its substrate at the surface of the lipid droplet

Colipase

• Binds lipase and reverses inhibition by bile salts.
• Ensures adhesion of lipase to the lipid droplet for effective lipolysis.

Products of TG Digestion

• Small fraction of TGs totally hydrolyzed to free glycerol.
• Products include 2-monoacyl-glycerols (2-MAGs) and free fatty acids.
• Other lipids (phospholipids and cholesterol esters) have ester bonds cleaved by phospholipases and cholesterol esterase, respectively.
• The product of the partial digestion of lipids primarily contains 2-MAGS, 1-MAGs, lysolecithin, cholesterol and free fatty acids
• These lipids and Bile salts form micelles.
• Micelles interact with microvilli at the brush border and allow the movement of lipids into the enterocytes

Lipid Absorption in Enterocytes

• Absorption of fatty acids occurs in the distal duodenum and jejunum through:
  1. Protein independent (diffusion model)
  2. Protein-dependent (mediated by fatty acid transport proteins, FATP 1-4, as well as by FAT/CD36)
• Processes do not require energy.
• Absorption of free cholesterol is also energy-independent, mediated by transporter proteins (e.g., Nieman-Pick C1 or NPC1L1).

Processing Inside Enterocytes

• LCFAs and cholesterol are diverted to the endoplasmic reticulum.
• LCFAs are converted again into TGs, and cholesterol into cholesterol esters.
• Enzymes acyl-COA:cholesterol acyltransferases 1 and 2 (ACAT1 and ACAT2) esterify cholesterol, but not plant sterols.

Chylomicron Assembly

• ER and Golgi apparatus assemble chylomicrons.
• Chylomicrons are rich in TG, also contain cholesterol esters, phospholipids and apolipoprotein B-48 (ApoB-48).
• Chylomicrons exit the enterocyte by exocytosis and enter the lymphatic system (lacteal vessel).

Bile Acid Reabsorption

• Bile acids, formed from cholesterol in the liver, are not absorbed with the contents of the mixed micelles.
• Absorbed from the terminal part of the ileum by an energy requiring process and re-enter the portal vein (The liver then reuses bile salts; the process by which bile salts are reabsorbed in the gut is known as the "enterohepatic circulation").
• Remaining unabsorbed (~1 g/day) is modified by bacteria in the intestine and excreted in the feces.
• Total of 2.5 to 4 g of bile acids is recycled about twice with each meal.
• About 18 g/day of cholesterol leaves in the form of bile salts and most of it (~17.5 g) is reabsorbed.
• Free cholesterol is also secreted in the bile (~1 g/day) and about half of this is reabsorbed.
• Net loss of cholesterol and bile acids is about 1 g/day, which is matched by input from diet and endogenous synthesis.

Pharmacological Intervention

• Block re-absorption of bile and promote its elimination through the feces.
• Forces the liver to convert more cholesterol into bile.
• Depletes body's cholesterol pool through an increase in bile production to compensate for accelerated excretion through the feces (if completely efficient, this treatment could lead to the loss of ~18 g of cholesterol each day).
• Powerful feedback control that regulates the activity of HMG-CoA reductase proportionally increases endogenous cholesterol production, minimizing the impact of impaired bile re-absorption on circulating cholesterol levels.

Coronary Artery Disease (CAD) and Dietary Fat

Diet-Heart Hypothesis

• Developed during the 50s and 60s.
• Based on the idea that dietary saturated fat elevated circulating cholesterol levels, leading to CAD.
• Indeed, there is evidence that lipid infiltration within the intima layer of arteries progressively increases as atherosclerosis advances
• The "diet-heart hypothesis" set the basis for the adoption of a low-fat diet as a general dietary recommendation for the population and for the development and wide prescription of cholesterol-lowering pharmacological agents.
• Data used to support the "diet-heart hypothesis" originated from correlational studies that have been heavily criticized due to fraudulent data analysis, and also by dismissing/ignoring randomized clinical trials that contradict the hypothesis that saturated fat and cholesterol cause CAD
• Data do not support the claim that elevated intake of saturated fat is the culprit for the increase in CAD in North America and other western societies.
• Heart disease deaths increased during the 19th century despite unchanged consumption of saturated fat during this period (the consumption of vegetable oils, particularly seed oils, that markedly increased in the last century).

Concerns

• Oils high in PUFAs are susceptible to oxidation, particularly when heated.
• Vegetable/seed oils release toxic chemicals during cooking.
• The use of oils rich in PUFAs for cooking should be used with caution (the alternative for cooking would be saturated fats that are less susceptible to oxidation).
• Reheating of the oil is not recommended (used-oil will contain a higher free-fatty acid content and consequently drastically decrease its original smoke point, which will result in higher emissions of volatiles at lower temperatures).

Lipid Transport in the Blood

Lipoproteins

• Lipids are transported in the bloodstream as constituents of lipoproteins due to their hydrophobic nature (Exception: NEFAs released by white adipose tissue, circulate bound to albumin).
• Beyond chylomicrons, four additional lipoproteins circulate in the blood:
  • Very-low-density lipoprotein (VLDL)
  • Intermediary-density lipoprotein (IDL)
  • Low-density lipoprotein (LDL)
  • High-density lipoprotein (HDL)
• Lipoproteins vary in lipid composition, density, size, and metabolic function.

Apoproteins (Apo)

• Apoproteins confer water solubility and regulate the activity of key enzymes in lipoprotein metabolism.
• They also mediate particle removal from the circulation by binding to specific receptors located on the cell surface in various organs and tissues.

Types of Apoproteins

• Chylomicrons contain ApoB-48 (origins from the intestine).
• VLDL and LDL are enriched with ApoB-100 (origins in the liver).
• Apo-E exists in three isoforms and is present in almost all lipoproteins.
  * Synthesized in the liver and functions as a receptor ligand, particularly the LDL receptor.
• HDL particles contain apoproteins A-I, A-II, A-IV, and C.
  * ApoA-I and A-IV are believed to be activators of lecithin-cholesterol acyl transferase (LCAT).
  * LCAT is an enzyme that esterifies cholesterol derived from the plasma membrane of cells or surfaces of other lipoproteins.
• Three isoforms of ApoC exist (CI, CII, and CIII), which are all synthesized by the liver.
  • Each isoform of ApoC seems to exert a distinct function, although ApoC-II is the best understood.
  • ApoCII is present in chylomicrons, VLDL, IDL, and HDL.
  • Important, along with ApoE, for the activation of LPL.

Chylomicrons

• Produced by enterocytes.
• Largest of the lipoproteins.
• Composition:
  • 90% TG
  • 5% cholesterol
  • 4% phospholipids
  • 1% protein
• Role:
  • Deliver dietary lipids to tissues other than the liver.
  • Skeletal muscle and adipose tissue take up most of it (~80%).
  • The remaining (20%) goes to the liver as chylomicron remnants.

VLDLs

• Produced by the liver.
• Similar to chylomicrons in the gut.
• Composition:
  • 65% TG
  • 13% cholesterol
  • 13% phospholipids
  • 10% protein
• Carbohydrate-rich diet increases de novo lipid synthesis in the liver and VLDL production.
• Role: Deliver endogenous rather than dietary TG to peripheral tissues.

Lipoprotein Lipase (LPL)

• Enzyme that hydrolyzes TG molecules present in lipoproteins passing through the capillary bed of tissues such as adipose, skeletal muscles, and heart
• Provides these tissues with NEFAs for esterification or energy metabolism.
• Requires Apo-CII for activation. Nascent chylomicrons and VLDL contain ApoB-48 and B-100, respectively, and they both acquire ApoC-II from HDL after interacting with this particle in the bloodstream.

LDLs

• Smaller, cholesterol-rich particle formed from VLDLs.
• Composition:
  • 10% TG
  • 45% cholesterol
  • 23% phospholipids
  • 20% protein
• Carry about 60% of total serum cholesterol.
• Role: Deliver cholesterol to tissues where it may be used for membrane construction, and steroid hormone production
• Interact with LDL-apoB-100 receptors on the membrane of hepatic and non-hepatic cells, Internalization by endocytosis and removal of the entire particle from the circulation (Once inside the cell, the LDL particle is degraded by lysosomal enzymes and the LDL receptor is released and returns to the surface of the cell).

Health Implications

• Elevated LDL is associated with atherosclerosis and is considered an important risk factor for the development of cardiovascular disease (