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Page 46: Vitamin E and K Deficiency and Toxicity Symptoms

Vitamin E Deficiency

• Symptoms:

  • Skeletal muscle pain

  • Weakness

  • Hemolytic anemia

  • Degenerative neurological issues

  • Loss of coordination

• Causes of deficiency linked to:

  • Malabsorption due to pancreatic lipase deficiency

  • Hepatobiliary diseases

  • Genetic defects in lipoprotein metabolism

Vitamin E Toxicity

• Symptoms:

  • Hemolytic anemia

  • Impairment in nerve, muscle, and immune function

Vitamin E

Alpha-tocopherol(Variations in the presence of methyl or hydrogen at carbons 5,7 and 8)

Functions: quencher of free radicals, thus serves as anitoxidants, stabilize polyunsaturated lipids and minimize lipid preoxidation damage and deteriorative reaction that occur in cellular mechanisms of: aging, etherosclerosis, ethonol induced lvier injury and oxygen toxicity.

Recommended intake: 15 mg/day(men and women), upper limit: 1000mg/day, sources: sunflower, seeds, wheat, germ, almonds, vegetable oils and whole grain cereal.

Deficiency: rare, linked to malabsorption due to pancreatic lipase deficiency, heptobillary diseases and genetic defects in lipoprotein metabolism. Skeletal muscle pain, weakness, hemolytic anemia, degenerative neurological problems and loss of coordination of limbs.

Toxicity: hemolytic anemia, impairment of nerve, muscle and immune function.

Forms of Vitamin K

• Biologically Active Forms:

  • Naturally occurring forms: Phyloquinone, Menaquinone-7 (Vitamin K2, MK-7)

  • Synthetic: Menadione

Functions of Vitamin K

• Involvement in:

  • Red blood cell metabolism

  • Platelet function

  • Blood vessel mineralization

  • Maturation and activation of proteins involved in the injury cascade that forms blood clots (inactive vs. active osteocalcin)

Page 47: Vitamin D Deficiency and Toxicity Symptoms

Vitamin D Deficiency

• Symptoms:

  • Rickets in children

  • Osteomalacia (soft bones) and/or osteoporosis in adults

Vitamin D Toxicity

• Symptoms:

  • Hypercalcemia (high calcium levels)

  • Causes:

    • Weakness

    • Loss of appetite

    • Diarrhea

    • Mental confusion

    • Vomiting

    • Calcium deposits in soft tissues (kidneys, liver, heart)

Main Forms of Vitamin D

• Ergocalciferol (Vitamin D2)

• Cholecalciferol (Vitamin D3)

  • Found in plant foods(D2) and synthesized in skin with UVB exposure(D3)

• Comes from cholesterol, one of the four rings in D3 breaks, creating seco-steroids, caused by UVB light.

• Sun hits skin and converts into 7-dehydroxycholesterol —> previtamin D3 —> vitamn D3 —> Liver(25-hyrdroxylase+D3 = 25-OHD3) —> kidney(1alpha-hydroxylase) —> 1,25-OHD3(fully active, calcitriol) —> bone and intestine to regulate calcium(muscle contraction, nerve impulse control, etc.)

Vitamin D Recommended Intake

• Adults (19-70 years): 600 IU/day (15 µg/day)

• Adults (>70 years): 800 IU/day (20 µg/day)

• Upper limit: 4000 IU/day

• Actual results: 5000 IU/day minimum, especially in Canada because of lack of sun, and lack of sun penetration due to latitude. Absorption can be boosted when consuming vitamin D with a fat source(beef, avocado, etc.)

• Sunburns caused by polyunsaturated fat because UVA hits it in skin and creates free radicals(Which destroys cells)

• Dietary Sources:

  • Egg yolks, fatty fish (salmon, mackerel, sardines, tuna)

  • Fortified cow's milk and margarine, vitamin D-fortified yogurt and cheese, plant-based beverages (soy, orange juice)

Page 48: Vitamin A Deficiency and Toxicity Symptoms

Vitamin A Deficiency

• Symptoms:

  • Xerophthalmia (dry eye)

  • Impaired growth

  • Reduced immunity and reproductive function

Vitamin A Toxicity

• Symptoms:

  • Fatigue

  • Bone and joint pain

  • Spontaneous abortion

  • Birth defects

  • Nausea and diarrhea

  • Liver damage

  • Blurred vision

  • Hair loss and skin disorders

Active Forms of Vitamin A

• Retinol

• Retinal

• Retinoic acid

• Role in vision:

  • Involves conversion to opsin in photoreceptor cells, essential for light detection

Vitamin A Recommended Intake

• Men: 900 µg/day

• Women: 700 µg/day

• Upper limit: 3000 µg/day

• Dietary Sources:

  • Animal products (beef liver, dairy, chicken, egg yolk)

  • Plant-derived foods (spinach, carrots, mango, apricots)

  • 1 cup of carrots or sweet potatoes meets the RDA

Page 49: Vitamins Overview

Importance of Vitamins

• Vitamins are essential for regulating physiological processes in the body.

• Most vitamins are not synthesized endogenously and must be sourced from diet.

Water-Soluble Vitamins

• Include:

  • Vitamin C

  • B Vitamins:

    • Thiamin (B1)

    • Riboflavin (B2)

    • Niacin (B3)

    • Vitamin B6 (pyridoxine, pyridoxal, pyridoxamine)

    • Vitamin B12

    • Pantothenic acid

    • Biotin

    • Folate

Fat-Soluble Vitamins

• Comprise:

  • Vitamins A, D, E, and K

• Absorption occurs with dietary lipids, stored in fat tissues for later use.

Active Forms of Vitamin A and Functions

• Retinol(HEad and hydrocarbonic tail, making it hard to solubilize), retinal, and retinoic acid(Receptor inside the cell, moves within the cell and regulates expression of gene in nucleus) play crucial roles in vision.

• Role in Vision: Rod cell contains rhodopsin(opsin protein and retinal in cis-form(cis-retinal) bound together). Light hits eye and causes separation of opsin and cis-retinal(transforms into trans-retinal, then back into cis-retinal, then re-binds with opsin, this process leads to the creation of images)

• Recommended Dietary Allowance (RDA) for Vitamin A:

  • Men: 900 µg

  • Women: 700 µg

  • Upper limit: 3000 µg/day

• Dietary Sources: include animal and plant foods with specific contributions.

Page 50: PCSK9 and Lipid Metabolism

PCSK9 Overview

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) is secreted primarily by the liver.

• Binds to LDL receptors on hepatocytes, causing the degradation of these receptors in the lysosomes of hepatocytes, which impacts cholesterol levels. Determines how many LDL receptors are available on the hepatocytes.

• Once LDL brings to LDLR, which then leaves LDL particle into the lysosome where it is disassembled, then LDLR goes back and repeats process. Once LDL levels are enough, PCSK9 is secreted into blood, binding to LDLR, this complex is then internalized, now both the LDLR and PCSK9 are disassembled by Lysosome, making less LDLRs available.

Therapeutic Implications

• Inhibition of PCSK9 provides a new method for lowering low-density lipoprotein cholesterol (LDL-C) levels in the blood.

• They now use siRNA to inhibit PCSK9 before it even enters the blood, which can lead to a significant reduction in LDL-C levels by preventing the formation of the PCSK9-LDLR complex and preserving the availability of LDL receptors on the cell surface.

Normal Circulating Lipids Values and Ratios

• Lipid Form Normal Range:

  • Triglycerides: 0-210 mg/dL

  • Cholesterol: 50-200 mg/dL

  • HDL: 30-90 mg/dL

  • VLDL: 5-40 mg/dL

  • LDL: 50-140 mg/dL

• Cholesterol Ratios:

  • Chol:HDL: 3.7-6.7

  • LDL:HDL: 3.3-4.4

• Lower chol doesn’t equal less mortality risk. Ideally, you are in the middle of that range for the least possible danger.

• What’s the problem?: Insulinemia, or insulin resistance can lead to elevated LDL levels, which may contribute to cardiovascular issues despite having lower overall cholesterol levels. Fasting: Insulin levels should be low, if they are high, this means you need to produce more insulin for blood glucose levels regulation —> Increases chance of heart problems.

Page 51: HDL Metabolism

Reverse Cholesterol Transport

• **Mechanism: ** Transfer of cholesterol from peripheral tissues back to the liver via HDL (high-density lipoprotein).

• Intestine and Liver make HDL —> Nascent HDL(Discoidal, contains phospholipids, Chol and LCAT enzyme) —> Goes into non-hepatic tissues through ABCA-1 protein(Allows flow of Chol from tissues to HDL) —> Chol levels heighten, meaning an equilibrium could happen, instead, HDL uses LCAT to esterify Chol with fatty acids and make it into Cholesterol Ester(HDL becomes spherical) —> Goes to Liver where SR-B1 anchors HDL so it can gain CE then unloads it until the HDL is fully absorbed by Liver to make a new HDL

Lipoprotein Role in Metabolism

• Key players include cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP). HDL gives CE to Chylomicrons using CETP and receives Phospholipids from Chylomicrons using PLTP. HDL does this same thing with VLDL when they interact.

• Drug that reduces CETP was trying to reduces CE production and increase HDL in the circulation, but was not successful. Only ways to increase HDL is to exercise or eat saturated fats(Which also increases LDL, but they balance each other)

Page 52: VLDL Metabolism

Description of VLDL Function

• VLDL (Very Low-Density Lipoprotein) transmits(endogenously) lipids generated by the liver to peripheral tissues.

• Gives rise to LDL (Low-Density Lipoprotein).

Composition of VLDL

• Contains ApoB-100 (originating from the liver) and triglycerides as key components.

VLDL transformed into TG in the liver —> Comes out as nascent VLDL(ApoB-100, E and CII) —> Bumps into HDL and gains more E and CII from HDL and becomes a mature VLDL —> Goes into non-hepatic tissues as fatty acids(stored in adipose, oxydized in others) through LPL and ApoCII, or makes glycerol(becomes IDL) —> Returns APoE and CII to HDL —> Goes back into Liver(Fat made from extra sugar: dinovo lipid synthesis) or becomes LDL(Which goes into tissues to deliver Cholesterol so they can make hormones. Oxydized LDL creates inflammation, which promotes building of plaque).

Page 53: Chylomicron Metabolism

Chylomicron Overview

• Chylomicrons deliver dietary triglycerides to organs and peripheral tissues.

• Composed of dietary triglycerides and transport proteins (ApoB-48 from the intestines).

• VLDL and LDL enriched with ApoB-100 that originates in liver. Only one ApoB per particle since it functions as receptor ligand.

• Apo-E exists in three isoforms and is present in almost all lipoproteins.

• HDL contains apoproteins A-I, A-II, A-IV and C

Chylomicron Metabolism

• Small Intestine TG —> Lymphatics —> Chylomicron and HDL encounter(Chylo receives ApoCII and ApoE and is now able to go into the blood and move on) —> Non-hepatic tissues(muscle, heart, adipose), LPL(enzyme on capillary of tissue) recognizes ApoCII and breaks down TGs into free fatty acids and glycerol. —> Lipogenesis(TG created from fatty acids and glycerol already in tissue from sugar) —> Chylomicron remnants(Shrunk chylomicron) continues in circulation and bumps into HDL again(giving back ApoCII and ApoA —> Liver then takes ApoE and ApoB-48 and makes it into fatty acids, chol, amino acids and glycerol

Page 54: Lipid Absorption in the Intestine

Mechanism of Action

• Micelles interact with the microvilli at the brush border of the intestine, allowing movement of lipids into enterocytes.

• Transport depends on protein-dependent and independent processes in the duodenum and jejunum(Lipids present through diffusion or FATP1-4/CD36, fatty acids transporters and NPC1L1 that transports chol).

• Emulsification by bile promotes absorption.

Role of Apoproteins

• Distribution and exchange of lipids in body, dictate the fate of lipoproteins.

• Confer water solubility and regulate activity of key enzymes in lipoprotein metabolism

• Mediate particle removal from circulation by binding to specific receptors located on cell surface in various organs and tissues

Lipid Transport in Blood

• Chylomicrons: From the intestines, dietary lipids, 97% TGs

• VLDL: From the liver, TGs made by body, 70% TG

• LDL: Liver, Originates from VLDL, 50% Chol

• HDL: Reverse chol transport, takes it back to the liver so it can use it, 50% protein

• The less amount of TG present, the lesser the density of the protein, but the higher the diameter. Density x Mass / Volume

Page 55: Digestion and Absorption of Lipids

Lipid Digestion Process

Lipids insoluble in H2O generally, enzymes that digest them are secreted in aqueous solutions. Specialized system needed for lipids to be accessed by their enzymes.

1. Initiation by lingual lipase.

2. Continued in the stomach with gastric lipase.

• Lingual and gastric lipases hydrolyze preferably TGs containing short and medium FAs(Fat entering in duodenum made up of about 70% TGs with remainder composed of mixture of partially hydrolyzed lipid products: Fatty acids and 1,2-DAG)

• Hydrolysis of triglycerides occurs, especially those with short/medium chain fatty acids.

Role of Co-lipase

• Bile salts inhibit lipase by displacing enzyme from substrate at surface of lipid droplet

• Co-lipase(contained in pancreatic juice) reverses bile salt inhibition to ensure effective lipolysis by binding pancreatic lipase to lipid droplets.

• TGs and 1-2DAGs present in lipid droplets, turns into LCFAs, 2-MAGs(Glycerol with one FA), 1-MAGs(In position one), presence of free cholesterol and phospholipids(especially lyso).

• All of them go into enterocyte microvilli(Bile acids and salts maintain them emulsified —> forming micelles(mini lipid droplets made up of LCFAs, 1-2MAGs, free chol, and Lyso) —> Absorbed into enterocytes —> LCFAs and 1-2MAGs put back together as TG inside enterocyte, mix with chol and lyso to form water-soluble chylomicrons(Also contain lipid-soluble vitamins A, D, E and K)

• ApoB-48 is a protein that plays a crucial role in the assembly and secretion of chylomicrons from enterocytes, facilitating the transport of dietary lipids through the lymphatic system(through lacteal).

Page 56: Oil Heating and Heart Disease

Saturated Fat and Vegetable Oil Consumption

• Examines the link between fats consumed and heart disease deaths from 1900 to 2010.

Toxicity of Cooking Oils

• Concentrations of toxic aldehydes vary when oils are heated at 180 °C, influencing health risks.

• Oils high in polyunsaturated fatty acids (PUFAs) are prone to oxidative damage when heated.

Page 57: Histology of Vascular Lipid Deposits

Pathological Changes in Arteries

• Represents different grades of lipid deposits and infiltrating macrophages in arterial walls.

• Grade progression from intimal thickening without lipid deposits to complex fatty streaks with foam cells.

Page 58: Cholesterol synthesis pathway

• Liver makes 800-1500mg of cholesterol everyday

• Fatty acids into Acetyl-CoA

• Acetyla-CoA into HMG-CoA —> Into mevalonate —> Into Squalene and finally Into Cholesterol(Rate-limiting step limits overproduction of cholesterol by controlling the flow of enzymes through the amount of cholesterol present inside the body)

• Entherohepatic Circulation: The process by which bile acids are recycled from the intestine back to the liver, playing a crucial role in cholesterol metabolism and homeostasis.

Page 59: Phospholipids and Sterols

Phospholipids

• Amphiphilic nature(attracts both water and fat soluble substances) allows them to be the ideal structural components to form cellular membranes.

• Provide compounds(ex: arachidonic acid) for synthesis of elcosanoids and intracellular signaling as well as cell anchorage(ex: phosphatidyfinositol)

Sterols

• Class of lipid characterized by a four-ring core structure(or steroid nucleus)

• Classified by core structure; cholesterol is the most common sterol in animals.

• Most popular is cholesterol in animals(abundant in brain and nerve tissues: necessary for normal function). Present in meat, egg yolk, poultry and dairy products. Also used to make bile salts, steroid hormones, membranes, lipoproteins and vitamin D3

Page 60: Triglyceride Overview

Function of Triglycerides

• Found in adipocytes(subcutaneous fat) for energy storage, insulation, and taste enhancement of food. Visceral adipose tissue provides mechanical support for internal organs. Serve as carriers of lipid soluble vitamins(A, D, E, K)

• Largest proportion of consumed lipids, providing significant energy yield compared to glucose.

• Contains glycerol and fatty acids linked by ester bonds(o bound to two C atoms to replace H, which is stored. Add water to break this bond so it can be used for fatty acids or glycerol).

• Glucose: 32 ATP

• Palmitate: 106 ATP for the same process

Page 61: Trans-Fatty Acids

Hydrogenation Process

• Food industry adds H to unsaturated fatty acids(Hydrogenation, most often partial). Converts unsaturated fatty acids to trans-fatty acids, extending shelf life and resisting oxidation(reduces chance of becoming rancid).

• Regular ingestion of trans fatty acids associated with heart disease, raising LDL(bad) and lowering HDL(good) cholesterol levels. Also promotes weight gain, promotes visceral fat accumulation, induces inflammation.

Page 62: Omega-6 and Omega-3 Fatty Acid Ratio

Dietary Recommendations

• No established ideal ratio; recommendations focus on increasing intake of omega-3 from dietary sources (e.g., fatty fish: salmon, herring and mackerel, grilled, baked or broiled instead of fried).

• Caution with supplements recommended due to potential side effects(Bleeding, wound healing interference, raise LDL, supress immune function).

• Trans fatty acids: Only a small fraction of occuring fatty acids, found in milk and meat products. Have H next to double bonds on opposite side of carbon chain

Page 64: Omega 3 and 6 Fatty Acids

• Exert opposing metabolic effects

• Regular consumption of omega 3 is associated with: Reduced BP and blood clots, reduced risks of heart disease and stroke, improved defence against inflammatory diseases.

• Omega 6 can have inflammatory effect and be harmful

Page 65: Essential Fatty Acids

• Linoleic acid

• Alpha-linoleic acid

• Humans lack delta 12 and 15 desaturases. enzymes that incorporate double bonds at such positions. Only plants have them

• Retarded growth, dermatitis, kidney lesions and early death can occur if fat is completely taken out of diet

Page 66: Fatty Acids and Their Composition

Types of Fatty Acids

• Short-chain(2-4 Cs), Medium-chain(6-12 Cs), and Long-chain(14-26) depending on carbon count.

• Classification into saturated and unsaturated based on double bonds(Staurated: Palmitic acid 16:0, Oleic acid 18:1)

• Monosaturated: MUFAs(Oleic and palmitoleic acids)

• Polysaturated: PUFAs(Linoleic and arachidonic acids)

Page 67: Lipids

Main Types of Lipids Found in Foods

• Fatty acids

• Phospholipids

• Sterols

Functions

• Energy Storage and production

• Insulation and padding

• Cell signaling

• Structural support

• Inflammatory responses

• Hormonal production