Medical Biochemistry Robert F. Waters, PhD Lipid Overview

Medical Biochemistry II: Lipids

Fatty Acid Overview:

Fatty Acid Nomenclature Delta System Omega System Saturated vs. Unsaturated Cis vs. Trans Carbon Numbering Alpha carbon, etc.

Fatty Acid Structure

Fatty Acid Structure Cont:

Fatty Acid Composition

Fatty Acids and “Good and Bad Cholesterol” Saturated FA Raise Good and Bad Cholesterol Monounsaturated FA Raise HDLs and Lower LDLs Polyunsaturated FA Maintain HDLs and Lower LDLs Trans fatty acids Lower HDLs and Raise LDLs

Essential Fatty Acids Linoleate (GLA) Linolenate Arachidonic Acid is essential and may be formed from dietary linoleic acid Note: Essential FAs are because we do not have enzymes to produce double bonds beyond carbon 9 Conjugated FA in “Organic Beef” Cancer treatment?

Fat Storage Control Mechanism Leptin System (Not well known yet) Small molecular weight protein produced by white adipose tissue Has numerous metabolic effects where one is in the hypothalamus---- Leptin with its receptor molecule suppresses food consumption by increasing the release of corticotropin-releasing hormone and suppression of something called a neuropeptide Y

Lipid Peroxidation Inhalation of high concentration of oxygen causes excessive peroxidation of unsaturated FAs Polyunsaturated FA susceptible to spontaneous peroxidation (non-enzymatic) Autocatalytic Due to presence of oxygen and some metal ions like Fe++ Daisy chain effect Causes membrane damage and allows for greater cytotoxicity (less selective permeability)

Peroxidation Continued

Reducing Peroxidation Antioxidants (Reduce oxidative damage) Vitamin E (  -tocopherol) Functionally related to the status of— Selenium Vitamin C Iron  -carotene Sulfur containing amino acids Overall anti-oxidant defense

Reducing Peroxidation-Selenium The more the selenium, the less vitamin E is necessary Selenium associated with glutathione peroxidase which is involved in free radical reduction

Reducing Peroxidation-Vitamin C Water soluble free radical scavenger and reducing agent Complements vitamin E function Involved in the formation (rejuvenation) of reduced vitamin E

Reducing Peroxidation-  - carotene Precursor to vitamin A Free radical scavenger Quencher of singlet oxygen

Reducing Peroxidation-Iron Removal of transition metal ions especially Fe++ is important in prevention of hydroxyl radicals (  OH)

Reducing Peroxidation-Sulfur Containing Amino Acids Muscular dystrophy occurred in animal studies when fed a Vitamin E deficient diet along with lacking selenium and sulfur containing amino acids Sulfur containing amino acids is necessary for the synthesis of reduced GSH N-acetylcysteine Methionine (SAMe)

Vitamin E Lipid soluble Collective term for all the tocopherols and tocotrienols Difference in double bond location

Vitamin E Absorption/Transport Lumen of intestine Tocopherol ester hydrolyzed to free tocopherol by pancreatic lipases Packaged in chylomicrons Stored in liver and packaged in VLDLs Transported to peripheral cells Bound to a protein to facilitate transfer between membranes  -tocopherol transfer protein

Vitamin E Biological Function Protects membranes from oxidative damage (Anti-oxidant)

Not All Vitamin E’s Are The Same Biopotency based on pharmaceutical or synthetic form of vitamin E called all-rac-  -tocopheryl acetate

Foods Rich in Vitamin E Nuts Seeds “Margarine” Vitamin E and unsaturated fatty acids?

Vitamin A and Carotenoids Fat soluble vitamin Exhibit biological activity of retinol Alcoholic form of Vitamin A Over 530 carotenoids found in nature with less than 50 have Vitamin A activity NOTE: The term “retinoids” describe retinol like compounds NOT necessarily biological activity

Structure of “Retinoids” Three basic structural components  -ionone ring Polyunsaturated chain Polar end group Vitamin A is stored as retinyl esters Retinol esterified with long chain fatty acid Loss of polar end group

Not All Vitamin A’s are the same Synthetically the  -ionone ring has been replaced Varieties of aromatic rings are added

Vitamin A Absorption and Metabolism Absorption of retinyl esters Hydrolysis by retinyl ester hydrolase by a pancreatic and brush border membrane form of the enzyme All trans form is preferred

Carotenoids Absorbed at lower efficiency than retinol May be broken down immediately Or, stored in liver and adipose tissue False child jaundice Oxygen scavenger (Anti-oxidant itself)

Breakdown of Carotenoids

Storage and Mobilization of Vit.A Stored as retinyl esters Esterification with long chain fatty acids that make retinol very hydrophobic and therefore accumulates into droplets Esterification enzymes ARAT-acyl CoA:retinol acyltransferase LRAT-lecithin:retinol acyltransferase Both ARAT and LRAT are membrane integrated enzymatic proteins

ARAT-acyl CoA:retinol acyltransferase

LRAT-lecithin:retinol acyltransferase

Movement of Retinol Between Tissues

Retinoids and the Retina

Synthesis of Retinal & Retinoic Acid Retinol may be converted to retinal Dehydrogenation of retinol with electron acceptors NAD+ and NADP+ Retinoic acid is produced from further oxidation from retinal Converted into other metabolites Not known true nature of retinoic acid Involved in genetic control Oxidation may be involved with Cytochrome P450 (Microsomal)

Retinol Binding Proteins RBP-retinol binding protein Synthesized in liver Mainly a carrier of retinol in plasma RBP is bound to TTR (transthyretin) TTR is a carrier of thyroid hormones in blood Binding of RBP to TTR prevents plasma loss of small molecular weight RBP by glomeruli filtration

Food Sources of Vitamin A Preformed retinol Liver Whole and fortified milk Eggs Carotenoids Yellow-orange vegetables and fruits Carrots, sweet potato Dark-green leafy vegetables Spinach, broccoli

Toxicity and Vitamin A Toxicity associated with excessive intake Retinoic acid

Vitamin A Deficiency Rare in developed countries Depressed immune function Night blindness Xerophthalmia (misshapen cornea) Drying of conjunctiva and cornea Xerosis blindness