Transcript Chapter 1
Chapter 5 Lipids 2009 Cengage-Wadsworth Introduction • Simple lipids • Compound lipids – Fatty acids – Triacylglycerols, diacylglycerols, & monoacylglycerols – Waxes • Sterol esters • Nonsterol esters – Phospholipids • Phosphatidic acids • Plasmalogens • Sphingomyelins – Glycolipids – Lipoproteins 2009 Cengage-Wadsworth Introduction • Derived lipids • Ethyl alcohol 2009 Cengage-Wadsworth Structure & Biological Importance • Lipids important in human nutrition: – Fatty acids – Triacylglycerols – Sterols & steroids – Phospholipids – Glycolipids 2009 Cengage-Wadsworth Fatty Acids • Straight hydrocarbon chain terminating with a carboxylic acid group • Fatty acid nomenclature – Delta () system - length, number/ position of double bonds – Double bonds counted from omega (methyl) end 2009 Cengage-Wadsworth Fatty Acids • Essential fatty acids – Linoleic acid & -linolenic acid • n-3 fatty acids – Hypolipidemic & antithrombotic effects – Fish oils are rich sources 2009 Cengage-Wadsworth Triacylglycerols (Triglycerides) • Trihydroxy alcohol (glycerol) to which 3 fatty acids are attached by ester bonds • Nomenclature: stereospecific numbering (sn) • Exist as fats or oils depending on nature of fatty acid components 2009 Cengage-Wadsworth Sterols & Steroids • Sterols – Monohydroxy alcohols with 4-ring core structure called cyclopentanoperhydrophenanthrene (steroid) nucleus – Cholesterol = animal sterol • Component of cell membranes • Precursor for steroids: bile acids, sex hormones, adrenocortical hormones, vitamin D 2009 Cengage-Wadsworth Phospholipids • Glycerophsphatides – Glycerol - core structure – Phosphatidic acid - building block – Usually have saturated FA in position 1 & unsaturated FA in position 2 • Biological roles of phospholipids – Cell membranes, source of compounds, cell functions 2009 Cengage-Wadsworth Phospholipids • Sphingolipids – 18-carbon amino alcohol sphingosine forms backbone – 3 subclasses: • Sphingomyelins - sphingophosphatides • Cerebrosides - glycolipids • Gangliosides - glycolipids 2009 Cengage-Wadsworth Glycolipids • Occur in medullary sheaths of nerves & in brain tissue • Cerebrosides – Ceramide linked to a monosaccharide unit • Gangliosides – Ceramide linked to an oligosaccharide 2009 Cengage-Wadsworth Digestion • Triacylglycerol digestion – Lingual & gastric lipases – Emulsification in the stomach – Emulsification in small intestine - bile – The role of colipase • Pancreatic lipase activation 2009 Cengage-Wadsworth Digestion • Cholesterol & phospholipid digestion – Esterified cholesterol undergoes hydrolysis to free cholesterol & a FA – C-2 FA of lecithin hydrolytically removed to produce lysolecithin & a free FA 2009 Cengage-Wadsworth Absorption • Micelles interact at brush border & lipid contents diffuse out into enterocytes • FA > 10-12 C long re-esterified • Short-chain FA exit into portal blood 2009 Cengage-Wadsworth Transport & Storage • Topics related to transport & storage: – Lipoproteins – Role of the liver & adipose tissue – Metabolism of lipoproteins 2009 Cengage-Wadsworth Lipoproteins • Apolipoproteins – Protein components • Chylomicrons – Transport exogenous dietary lipids • Very-low-density lipoprotein (VLDL) & low-density lipoproteins (LDL) – Transport endogenous lipids 2009 Cengage-Wadsworth Role of the Liver & Adipose Tissue in Lipid Metabolism • Liver – Synthesizes bile salts – Synthesizes lipoproteins – Syntehsizes new lipids from non-lipid precursors • Adipose tissue – Absorbs TAG & cholesterol from chylomicrons through lipoprotein lipase – Stores TAG 2009 Cengage-Wadsworth Role of the Liver & Adipose Tissue in Lipid Metabolism • Metabolism of triacylglycerol during fasting – Adipocytes - lipolysis, release FA into blood – Liver - produces ketone bodies, continues to synthesize VLDL & HDL 2009 Cengage-Wadsworth Metabolism of Lipoproteins • Low-density lipoprotein (LDL) – Transports cholesterol to tissues – Binds with LDL receptor on cells • The LDL receptor: structure & genetic aberrations – Mutant cells can’t bind efficiently; synthesize cholesterol to meet needs – Free cholesterol in the cell serves regulatory functions 2009 Cengage-Wadsworth Metabolism of Lipoproteins – Domains of LDL receptor • Domain 1 - furthest from membrane, contains NH2 terminal of receptor, & rich in cysteine residues • Domain 2 - made of 350 amino acids, possibly site of N-linked glycosylation • Domain 3 - immediately outside plasma membrane, site of O-linked glycosylation • Domain 4 - made of 22 hydrophobic amino acids • Domain 5 - COOH terminal end of protein that projects into the cytoplast 2009 Cengage-Wadsworth Metabolism of Lipoproteins – Types of LDL receptor abnormalities • Class 1 - no receptors synthesized • Class 2 - precursor synthesized but not processed properly; fail to move into Golgi apparatus • Class 3 - synthesized & processed, but processing faulty • Class 4 - receptors bind with LDL but can’t cluster in the coated pits 2009 Cengage-Wadsworth Metabolism of Lipoproteins • High-density lipoprotein (HDL) – Removes unesterified cholesterol from cells/other lipoproteins – Returns it to the liver for excretion in bile – Binds to receptors on hepatic and extra-hepatic cells – Cholesterol acyltransferase (LCAT) 2009 Cengage-Wadsworth Lipids, Lipoproteins, & Cardiovascular Disease Risk • Of interest regarding CVD: – Cholesterol – Saturated & unsaturated fatty acids – Trans fatty acids – Lipoprotein A – Apolipoprotein E 2009 Cengage-Wadsworth Cholesterol • High HDL + low LDL = healthy • Ratios of ApoA to ApoB used to assess CVD risk • Indiviuals respond differently to dietary cholesterol – Absorption or biosynthesis – Formation & receptor-mediated clearance of LDL – Rates of LDL removal & excretion 2009 Cengage-Wadsworth Saturated & Unsaturated Fatty Acids • Positive correlation with CVD – Total fat – Saturated FAs – Cholesterol – Trans fat 2009 Cengage-Wadsworth Saturated & Unsaturated Fatty Acids • Negative correlation with CVD: – Monounsaturated FAs – Polyunsaturated FAs (n-3 & n-6) – n-3 fatty acids • Interfere with platelet aggregation • Reduce release of cytokines • Reduce serum TAG concentration 2009 Cengage-Wadsworth Saturated & Unsaturated Fatty Acids • Proposed mechanisms for effects of FAs: – Suppression of bile acid excretion – Enhanced synthesis of cholesterol & LDL – Retardation of LCAT activity or receptor-mediated LDL uptake – Regulation of gene expression 2009 Cengage-Wadsworth Trans Fatty Acids • Large amounts created through hydrogenation of PUFA • Most abundant: elaidic acid & its isomers • Raise LDL & cholesterol & lower HDL 2009 Cengage-Wadsworth Lipoprotein A [Lp(a)] • Genetic variant of LDL – Attached to a unique marker protein • Associated with atherosclerosis • Apo(a) is structurally similar to plasminogen 2009 Cengage-Wadsworth Apolipoprotein E • ApoE may be involved in atherogenesis • 3 isoforms: apoE2, -E3, E4 • E4 phenotype associated with increased CVD risk 2009 Cengage-Wadsworth Integrated Metabolism in Tissues • Catabolism of tracylglycerols & fatty acids – Mitochondrial transfer of acyl CoA – -oxidation of fatty acids • Energy considerations in fatty acid oxidation – Cleavage of saturated C-C yields 5 ATPs 2009 Cengage-Wadsworth Integrated Metabolism in Tissues • Formation of ketone bodies – Overflow pathway for acetyl CoA – Ketone concentration rises during accelerated FA oxidation + low CHO intake or impaired CHO use • Catabolism of cholesterol – Structure remains intact 2009 Cengage-Wadsworth Integrated Metabolism in Tissues • Synthesis of fatty acids – Basic process: sequential assembly of “starter” acetyl CoA with units of malonyl CoA – Essential fatty acids • Humans can’t introduce double bond beyond 9 site • Lack 12 & 15 desaturases 2009 Cengage-Wadsworth Integrated Metabolism in Tissues – Eicosanoids: fatty acid derivatives of physiological significance • Precursor arachidonate – “Cyclic” pathway (prostaglandins & thromboxanes) – “Linear” pathway (leukotrienes) • Prostaglandins - 20-C FAs with 5-C ring • Prostaglandins & thromboxanes are “hormone-like” in action • Leukotrienes - potent biological actions 2009 Cengage-Wadsworth Integrated Metabolism in Tissues – Essential fatty acid in development – Impact of diet on fatty acid synthesis • Synthesis of triacylglycerols • Synthesis of cholesterol – Cytoplasmic sequence – Conversion of HMG CoA to squalene – Formation of choleterol from squalene 2009 Cengage-Wadsworth Regulation of Lipid Metabolism • Linked to CHO status • Insulin’s presence or absence • Hormone-sensitive triacylglycerol lipase - mobilizes fat • Hormones that stimulate lipolysis • Acetyl CoA carboxylase 2009 Cengage-Wadsworth Brown Fat Thermogenesis • Brown adipose tissue - high vascularity, abundant mitochondria • Special mitochondria promote thermogenesis at expense of ATP – Have H+ pores in inner membranes formed of uncoupling protein (UCP) • Thermogenesis triggered by ingestion of food or prolonged exposure to cold temperatures 2009 Cengage-Wadsworth Therapeutic Inhibition of Fat Absorption: Olestra & Orlistat • Orlestra – Synthetic, non-caloric fat replacement • Orlistat – Interferes with digestion & absorption of dietary fat - 200 kcal deficit – Semisynthetic derivative of lipstatin – Inhibits pancreatic lipase 2009 Cengage-Wadsworth Ethyl Alcohol: Metabolism & Biochemical Impact • The alcohol dehydrogenase (ADH) pathway – ADH in liver cells - NAD+-requiring dehydrogenase - oxidizes ethanol to acetaldehyde • The microsomal ethanol oxidizing system (MEOS) – System of electron transport associated with SER – Tolerance - ethanol induces synthesis of MEOS enzymes 2009 Cengage-Wadsworth Ethyl Alcohol: Metabolism & Biochemical Impact • Alcoholism: biochemical & metabolic alterations – Acetaldehyde toxicity – High NADH:NAD+ ratio • Accumulation of lipids & lactate – Substrate competition • Vitamin A – Induced metabolic tolerance 2009 Cengage-Wadsworth Ethyl Alcohol: Metabolism & Biochemical Impact • Alcohol in moderation: the brighter side – Elevates HDL – Lowers serum lipoprotein – May suppress proliferation of smooth muscle cells underlying the endothelium of arterial walls 2009 Cengage-Wadsworth Perspective 5 The Role of Lipids & Lipoproteins in Atherogenesis 2009 Cengage-Wadsworth Lipids/Lipoproteins in Atherogenesis • Major components of atherogenesis: – Cells of the immune system – Oxidized or otherwise modified lipids & lipoproteins (LDL) • Roles of LDL – Chemoattractant for blood-borne monocytes – Causes transformation of monocytes into macrophages – Inhibits mobility of macrophages so they are trapped in endothelial spaces 2009 Cengage-Wadsworth