Human Biosciences 3001 Lipids and Health 2024 PDF

HUMAN BIOSCIENCES 3001 Lipids and Health October 29, 2024: fatty alcohols, ether phospholipids, halogenated fatty acids, & waxes  Last class… PI, PS, and PG synthesis & functions Barth syndrome Fatty alcohols  18:1n-9 fatty acid versus fatty alcohol (Oleol) Fatty alcohol...

HUMAN BIOSCIENCES 3001 Lipids and Health October 29, 2024: fatty alcohols, ether phospholipids, halogenated fatty acids, & waxes  Last class… PI, PS, and PG synthesis & functions Barth syndrome Fatty alcohols  18:1n-9 fatty acid versus fatty alcohol (Oleol) Fatty alcohol synthesis requires acyl-CoA reductase Two acyl-CoA reductases exist: – Acyl-CoA reductase 1 – Acyl-CoA reductase 2 Acyl-CoA reductase 1 primarily reduces C16 and C18 unsaturated fatty acids Acyl-CoA reductase 2 reduces all saturated fatty acids  Acyl-CoA reductase reaction Both acyl-CoA reductase 1 and acyl CoA- reductase 2 use ‘activated’ fatty acids to carry out their reactions =O R-C-S-CoA + 2NADPH + 2H+ R-OH + CoASH + 2NADP+ Acyl-CoA reductase  Fatty alcohol functions… Used in industry for production of non- ionic detergents and surfactants In us, used for synthesis of other lipids Ether-linked phospholipids  Ether-linked phospholipids Ether-linked PL are primarily a specialized group of PL that account for ~20% of all of the classes of PL in vivo The ether-linked lipids have an ether bond in the sn-1 position that can also be accompanied without (termed plasmanyl) or with (termed plasmalogen) a 1′ cis double bond – An ether with a 1′ cis double bond is better known as a vinyl ether  General structure of plasmanyls and plasmalogens Plasmanyl Plasmalogen H2C-O-R H2C-O-CH=CHR O= O= R-C-O-CH R-C-O-CH H2C- P -X H2C- P -X  Ether-linked phospholipids (cont.) To an individual cell, the absence of ether- linked lipids is not lethal However, the absence of ether-linked lipids is detrimental to tissues – Disruption of their synthesis in mice leads to impaired neurological and eye development – In humans, extremely rare genetic defects in ether-linked lipid synthesis leads to impaired brain development, rhizomelia (truncated limb bones), and infantile death  Ether-linked phospholipids (cont.) Ether-linked lipids exist in many tissues and in the plasma via lipoproteins Of interest: – Tissues typically have ethanolamine plasmalogens, but the heart has a disproportionately higher amount of choline plasmalogens vs. ethanolamine plasmalogens – 10% of PL on lipoproteins are ethanolamine based... 1/2 of this is ethanolamine plasmalogen via ONLY the liver (a tissue with one of the lowest levels of plasmalogens)  Ether-linked PL synthesis I II I: DHAP acyltransferase II: Acyl-CoA reductase  Ether-linked PL synthesis (cont.) CDP-ethanolamine:1-alkyl-2-acyl-sn-glycerol ethanolaminephosphotransferase (attaches ethanolamine to phosphate) CDP-choline:1-alkyl-2-acyl-sn-glycerol cholinephosphotransferase (attaches choline to phosphate) Plasmanyl (ie. plasmanylethanolamine) Plasmalogen (ie. ethanolamine plasmalogen)  Platelet activating factor (PAF) PAF is a plasmanylcholine produced by endothelial cells and various white blood cells (basophils, neutrophils, monocytes, macrophages, mast cells) PAF triggers extremely potent pathological responses associated with asthma, hypertension, inflammation, allergic responses, and anaphalaxis with as little as 100 pM in the bloodstream  Synthesis of PAF PAF is synthesized by two routes: – Remodeling route: activated by inflammatory events & primary route for pathogenesis The fatty acid in the sn-2 position of plasmanylcholine is rapidly replaced with acetate – De novo route: maintains minimal concentrations to regulate normal cellular functions Synthesized over several steps starting with a lyso-plasmanyl acid  Biological responses to PAF Physiological: – ↑ Bronchoconstriction – ↑ Pulmonary resistance – ↓ Lung compliance – ↑ Pulmonary edema – ↑ Hypertension – ↑ Heart rate – ↑ Hypersensitivity  Biological responses to PAF (cont.) Biochemical: – ↑ Intracellular [Ca++] – ↑ Superoxide synthesis – ↑ Eicosanoid synthesis (from arachidonate) – ↑ Phosphoinositide utilization – ↑ Pro-inflammatory cytokine synthesis – ↓ Anti-inflammatory cytokine synthesis  Functions of plasmalogens Not really clear, but current studies suggest: – Plasmalogens are typically enriched with PUFAs, thus they are believed to act as a supply of essential fatty acids during dietary fatty acid deficiency – It is also believed that the vinyl ether bond acts as an antioxidant to scavenge damaging reactive oxygen species Plasmalogens and halogens in vivo  Myeloperoxidase makes bleach in vivo! Curr. Med. Chem. 13:3271  Formation of 2-chloro fatty aldehyde HOCl or HOBr can attack the vinyl ether bond to generate a 2-Cl (or Br) fatty aldehyde and lysoPC From http://lipidlibrary.aocs.org/Lipids/ethers/image014.gif Formation of 2-chlorolipids from plasmalogens PLASMALOGEN HOCl LysoPC (attack of vinyl ether bond) 2-CHLOROPALMITAL (reduction) (oxidation) 2-CHLOROPALMITOL 2-CHLOROPALMITATE Function of 2-halogenated lipids 2-Halo fatty aldehydes can be oxidized into a 2-halo fatty acid or reduced into a 2- halo fatty alcohol 2-Bromopalmitate can regulate gene expression through activation of a transcription regulator (PPAR-δ), and it can reduce the activity of cholesterol transporters The functions of other halogenated lipids are not known Let’s make some wax…  Wax synthesis Wax synthesis involves the condensation of a fatty acid and a fatty alcohol – Fatty acids and fatty alcohols of at least 10 carbons in length can be used in the synthesis The class of enzymes responsible are wax ester synthases Beeswax synthesis  Next class… EITHER: – Dr. Harding; OR – A free class! – Pay attention to the course newsfeed for what will happen…