This document summarizes lipids that are important physiologically and their roles in health and disease. It discusses major lipids like fatty acids, triglycerides, phospholipids, sterols, and lipoproteins. Specific fatty acids like saturated, unsaturated, omega-3 and omega-6 are explained. The roles of lipids in brain development, cancer prevention and various lipid-related disorders are highlighted. Atherosclerosis and its pathological progression are also diagrammatically represented.

1. LIPIDS OF PHYSIOLOGICAL SIGNIFICANCE & ITS ROLE IN HEALTH AND DISEASES Presented by, Shruti Sharma (D.Phil Scholar)

2. Why lipids are important- Lipids are important to the body because;- Important constituent of the cell membranes. Helps in the absorption of fat soluble vitamins. Maintains membrane fluidity. Acts as a thermal insulator and cellular metabolic regulator. Hormone synthesis. Organ padding . •

3. Major lipids of physiological significance;- Fatty acids ;- basic units of fat composed of chains of carbon atoms with an acid group at one end and hydrogen atoms attached all along their length. Present as either esterified or unesterified form in fats and oils.

4. Classification of fatty acids;- Fatty acids Saturated FA Unsaturated FA

5. Saturated fatty acids;- • Saturated fatty contains no double bonds (having no points of unsaturation ). Saturated fats- considered as harmful. It increases total cholesterol level and TGs level. Hypercholestrolemic SFAs are-Myristic acid & Lauric acid.

6. Unsaturated fatty acids;- Unsaturated fatty acid: a fatty acid with one or more points of unsaturation. Unsaturated fats are found in foods from both plant and animal sources. Unsaturated fatty acids are further divided into monounsaturated fatty acids and polyunsaturated fatty acids.

7. Divisions of unsaturated fatty acids;- Unsaturated Fatty acids MUFA PUFA Eicosanoids

8. Monounsaturated fatty acids ;- Monounsaturated fatty acid: a fatty acid containing one point of unsaturation, found mostly in vegetable oils such as olive, canola, and peanut . They are considered as beneficial for human health. MUFA Cis FA Trans FA

9. Cis- unsaturated fatty acids;- In cis bonds , the two pieces of the carbon chain on either side of the double bond are either both “up” or both “down,” such that both are on the same side of the molecule. Significance – Decreases total cholesterol and TGs level. Increases HDL level.

10. Trans unsaturated fatty acids;- Trans fatty acids are produced by hydrogenation process. Hydrogen atoms are on the opposite sides of the molecule. Eg.cis-oleic acid trans-elaidic acid PHYSIOLOGICAL EFFECTS OF TRANS FATTY ACIDS - SERUM LIPIDS -SYSTEMIC INFLAMMATION -ENDOTHELIAL-CELL FUNCTION

11. SERUM LIPIDS— >raises levels of low-density lipoprotein (LDL) cholesterol reduces levels of high-density lipoprotein (HDL) cholesterol >increases the ratio of total cholesterol to HDL cholesterol, a powerful predictor of the risk of CHD >increase the blood levels of triglycerides , of Lp(a) lipoprotein, and reduce the particle size of LDL cholesterol: further raise the risk of CHD. >trans fatty acids have markedly adverse effects on serum lipids Physiological effects of trans fatty acids continued…

12. Systemic inflammation— inflammation: an independent risk factor for atherosclerosis, sudden death from cardiac causes, diabetes, and heart failure the inflammatory effects of trans fats may account in part for their effects on cardiovascular health For example, the difference in C-reactive protein levels ; 2.1 percent vs 0.9 percent intake: an increase in cardiovascular risk of approximately 30 percent. Physiological effects of trans fatty acids continued…

13. ENDOTHELIAL-CELL FUNCTION-- increased levels of several markers of endothelial dysfunction: for eg;- soluble intercellular adhesion molecule, soluble vascular-cell adhesion molecule, and E-selectin Physiological effects of trans fatty acids continued…

14. Polyunsaturated fatty acids;- Polyunsaturated fatty acids (sometimes abbreviated PUFA) are those fatty acids where unsaturation occur more than two points, found in nuts and vegetable oils such as safflower, sunflower, and soybean, and in fatty fish. They possess protective role on human health.considered as beneficial for consumpmtion.

15. Increase esterification process of cholesterol & prevents its absorption. By increasing the synthesis of eicosanoids. Acts as an anti platelet aggregating factor, so decreases the chances of clot formation. Decreases the synthesis of the precursor of VLDL AND TGs. Increases clearance of LDL cholesterol. PUFA continued;-

16. Omega-3-fatty acids- Benefits- >Lower PGE2s level >Anti-inflammatory >Lower triglyceride and cholesterol levels >Benefits vision and >brain function >Decrease Skin >inflammation >Inhibit platelet adhesion >Increase insulin sensitivity

17. Omega-6 fatty acids- Linoleic fatty acid Arachidonic acid Benefits- Platelet aggregation, cardiovascular diseases, and inflammation. Reduce the symptoms of eczema and psoriasis. Clear up different types of acne.

18. Eicosanoids;- These compounds are derived from long chain polyenoic fatty acids (20-carbon). Examples of eicosanoids ;- Prostaglandins. Prostacyclines, Thromboxanes Leukotrienes lipoxins They have roles in: Inflammation Fever Regulation of blood pressure Blood viscosity Male fertility Female conception Muscle cotraction Blood clotting Tissue growth Regulation of sleep/wake cycle Bronchocostriction Asthma.

19. Triglycerides;- Structure Glycerol + 3 fatty acids Functions Energy source--9 kcals per gram Form of stored energy in adipose tissue. Insulation and protection Carrier of fat-soluble vitamins Sensory properties in food

20. Phospholipids;- main lipid constituent of cell membrane. Structure Glycerol + 2 fatty acids + phosphate group also considered as derivative of ‘ phosphatidic acid ’. Functions Main lipid constituent of cell membranes Lipid transport as part of lipoproteins Emulsifiers Cell signalling process. phospholipids Phos.choline phos.inositol cardiolipin lysophospholipid plasmalogens sphingomy.

21. Sterols ;- Steroids are the compounds contains cyclic steroid nucleus namely cyclo pentanophenanthrene ring. Cholesterol- best known steroid because of its association with atherosclerosis and heart diseases. Contains same steroid nucleus. Exclusively present in animals . Functions;- --Bile acids – Sex hormones – Adrenal hormones – Vitamin D --Cardiac glycosides

22. Glycolipids;- --widely distributed in the body Fatty acids + sphingosine +carbohydrate Also k/a glycosphingolipids. Present in cell membrane and nervous tissues. It contributes to cell surface carbohydrate Other glycolipids are;- Cerebrosides- simplest form of glycolipids.contains ceramides. eg. Galactosylcerebrosides glucosylcerebrosides Gangliosides – predominantly found in ganglions.Complex glycolipids

23. Lipoproteins;- Lipoproteins are th macromolecular complex of lipids and proteins. Transportation of lipids in the blood. Structure of lipoproteins ;- Hydrophobic lipids (TG, CE) in core; Hydrophilic lipids (UC, PL) on surface

24. Classes of lipoproteins ;- Chylomicrons, VLDL, LDL HDL > 30 nm 9–15 nm 20–22 nm D<1.006 g/ml D=1.019-1.063g/ml D=1.063-1.21 g/ml Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000; 149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994

25. Apolipoproteins— Apo AI (liver, small intestine) Structural; activator of lecithin:cholesterol acyltransferase (LCAT) Apo AII (liver) Structural; inhibitor of hepatic lipase; component of ligand for HDL binding Apo A-IV (small intestine) Activator of LCAT; modulator of lipoprotein lipase (LPL) Apo A-V (liver) Direct functional role is unknown; regulates TG levels.

26. Apoprotein continued… Apo B-100 (liver) Structural; synthesis of VLDL; ligand for LDL-receptor Apo B-48 (small intestine) Structural; synthesis of chylomicrons; derived from apo B-100 mRNA following specific mRNA editing Apo E (liver, macrophages, brain) Ligand for apoE receptor; mobilization of cellular cholesterol

27. Apoprotein continued… Apo C-I (liver) Activator of LCAT, inhibitor of hepatic TGRL uptake Apo C-II (liver) Activator of LPL, inhibitor of hepatic TGRL uptake Apo C-III (liver) Inhibitor of LPL, inhibitor of hepatic TGRL uptake

28. Chylomicrons ;- TG rich . Synthesized in intestine. Transports endogenous TGs. Hydrophobic Core Triglyceride (93%) Cholesteryl Esters (1%)

29. VLDL;- rich in CE and TGs- Surface Monolayer Phospholipids (12%) Free Cholesterol (14%) Protein (4%) Hydrophobic Core Triglyceride (65%) Cholesteryl Esters (8%)

30. LDL;- cholesterol rich. Surface Monolayer Phospholipids (25%) Free Cholesterol (15%) Protein (22%) Synthesized from VLDL in blood circulation. Transports cholesterol from liver and delivers to other tissues.

31. High density lipoprotein- Surface Monolayer Phospholipids (25%) Free Cholesterol (7%) Protein (45%) Promotes re-esterification process of cholesterol.

32. HDL Subpopulations Rye et al. Atherosclerosis 1999;145:227-238. Apolipoprotein Composition A-I HDL A-I/A-II HDL A-II HDL Particle Shape Discoidal Spherical Lipid Composition TG, CE, and PL Particle Size HDL 2b HDL 2a HDL 3a HDL 3b HDL 3c

33. The Effects of Various Types of Fat on Blood Lipid Levels • Saturated Fat – Increases total cholesterol – Increases LDL-cholesterol • Polyunsaturated Fat – Decreases total cholesterol – Decreases LDL-cholesterol – Decreases HDL-cholesterol • Monounsaturated Fat – Decreases total cholesterol – Decreases LDL-cholesterol – Increases HDL-cholesterol

34. Omega-3 Fat – Decreases total cholesterol – Decreases LDL-cholesterol – Increases HDL-cholesterol – Decreases serum triglycerides • Trans Fat – Increases total cholesterol – Increases LDL-cholesterol

35. Role of lipids in health and diseases – omega-3 FAs . Docosahexanoic acid and brain development- It is becoming increasingly evident that long-chain PUFA from the (n-3) family appear to be neuroprotective and that long-chain PUFA from the (n-6family) may also have unique properties in affecting neurobiology. It is found in very high concentrations in the cell membranes of the retina and cerebral cortex . Whelan et al,(2008) focused on docosahexaenoic acid (DHA),4 a PUFA that is preferentially deposited in brain phospholipids and has been linked to dementia, Parkinson disease, Alzheimer disease (AD),cognitive function, mental stability, suicide, depression, bipolar disorders, impulsivity, aggression, etc. (3–10). The content of DHA in the brain is 12–15%, 10- to 20-fold higher than any other (n-3) PUFA.

36. Arachidonic acid and the brain-- One of the most important changes in this field is the link between arachidonic acid (AA) content and brain function. The level of AA in the brain is comparable to that of DHA. At 8–11% of the fatty acid phospholipids, it is severalfold higher than any other (n-6) PUFA (by comparison, linoleic acid content is ;1%). Connell et al,(2007 ) demonstrated that dietary AA appears to influence plasticity and preserve hippocampal membrane fluidity and may provide some protection to oxidative stress via the activation of peroxisomal proliferatoractivated receptor-g (17). Furthermore, it has been shown that AA, as well as DHA, activates syntaxin-3, a critical factor in the growth and regeneration of neurons.

37. Prevention of cancer;- Marine-derived fatty acids have been found to inhibit proliferation and promote apoptosis in breast, prostate, and colon cancer cell lines cultured outside the body Studies in animal models of cancer also indicate that increased intake of EPA and DHA decreases the occurrence and progression of mammary, prostate, and intestinal tumors

38. Lipids related disorders ;- lipid disorders Common disorders Hypercholetrolemia Hypertriglyceridemia Hyperlipoproteinemia ketosis CVD Fatty liver Obesity cancer Uncommon disorders Metabolic disorders of cerebrosides. Lipidoses / lipid storage diseases Multiple sclerosis. Infant respiratory distress syndrome Xanthomatosis. Retinitis pigmentosa. Phrynoderma / Toad skin. Disorders of EFAs deficiency. Zwellweger’s disease.

39. ATHEROSCLEROSIS : As LDL particles penetrate the walls of the arteries, they become oxidized-LDL and next are scavenged by the body’s white blood cells. • These foam cells are then deposited into the lining of the artery wall. • This process, known as atherosclerosis, causes plaque deposits to enlarge, artery walls to lose elasticity, and the passage through the artery to narrow.

40. Diagrammatic representation of the disease (atherosclerosis)-

41. Metabolic disorders of cerebrosides Dermatitis,skeletal deformation,hoarseness. ceramide ceramidase Ref- Harper’s biochemistry Farber’s disease Enlarged liver and spleen sphingomyelin sphingomyelinase Niemann-pick disease Enlarged liver and spleen, eroison of long bones ,mental retardation glucosylceramide B-glucosidase Gaucher’s disease Mental retardation,complete loss of myelin sheath. galactosylceramide B-galactosidase Krabbe’s disease Skin rashes,kidney failure galactosylceramide A-galactosidase. Fabry;’s disease Mentalretardation,blindness,muscular weakness. symptoms gangliosides Lipid accumulating hexosaminidase Enzyme deficiency Tay –sachs disease diseases

42. Lipoprotein disorders ;- Hyperlipoproteinemias- --do-- Chylomicron and VLDL Ref- Harper’s biochemistry --do-- v May/may not increase TGs Overproduction of TGs lv high TGs and cholesterol Abnormality in apo -e lll high TGs and cholesterol Overproduction of apo-b llb Very high cholesterol Deficiency of LDLreceptors lla increase Risk of athersclerosis chylomicrons Increased plasma lipid most Deficiency of lipoproteinlipase Metabolic defect l Hy. Lipo.types

43. Infant repiratory distress syndrome- Caused due to the deficiency of the lung surfactant dipalmitoyl lecithin . It prevents collapsing of the alveoli and also decreases the surface tension . Deficiency is common in young infants. Xanthomatosis;- Deposition of yellow-orange colours lipids occurs in the liver ,spleen and flat bones. Usually related with severe hypercholesterolemia and hyperlipidemia. Phrynoderma or Toad skin ;- Caused due to the deficiency of essential fatty acids. Horny eruptions occurs on posterior and lateral limbs.poor wound healing. Multiple sclerosis;- It is a demyelinating condition. loss of both phospholipids and sphingolipids occurs from white matter. Neurodegeneration is common.

44. Defects in the metabolism of essential fatty acids - Cystic fibrosis,Acrodermatitis enterohepatica,Hepato renal syndrome, Crohn’s disease,Cirrhosis, Alcoholism, Reye's syndrome etc. Zwellweger’s disease;- Rare disorder. occurs due to the accumulation of long chain polyenoic fatty acids in the brain. Causes loss of functions and neural degeneration . Dicarboxylic aciduria- It is characterized by the excretion of C6-C10 dicarboxylic acid due to the lack of mitochondrial acyl coA dehydrogenase enzyme.

45. Common Atherogenic dyslipidemias ) 􀂃 polygenic inheritance – dietary component – secondarily enhanced by insulin resistance (see further why) 􀂃 prognosis of combined hyperlipidemia is worse than that of hypercholesterolemia 􀂃 main features – impaired clearance of TAG by LPL (􀀪 insulin) from chylomicrons -> increased TAG and increased delivery of TAG for liver – increased production of VLDL by liver (􀀪 insulin) from TAG, FFA from adipose tissue (􀀪 insulin) and glucose (􀀪 insulin) – therefore increased conversion of VLDL to LDL – low HDL

46. Fatty liver;- When lipids accumulates excessively in liver, then it causes fatty liver. Dropletes of TGs are found in the entire hepatic cytoplasm, this causes impairment in liver function. Fatty liver may occur due to two main reason- Increased synthesis of TGs. Impairment in lipoprotein synthesis. Fatty liver is associated with the fibrotic changes and cirrhosis.

47. Tangier Disease >Autosomal codominant disorder due to mutations in both alleles of ABC1 gene • Extremely marked reduction in HDL-C and apoA-I • Markedly accelerated catabolism of apoA-I and >apoA-II • Cholesterol accumulation: − Enlarged orange tonsils − Hepatosplenomegaly − Peripheral neuropathy

48. References-- 1) Connell E, Darios F, Broersen K, Gatsby N, Peak-Chew SY, Rickman C, Davletov B. Mechanism of arachidonic acid action on syntaxin- Munc18. EMBO Rep. 2007;8:414–9 2) Granner,K. and Robert,K.(2006). Harper’s illustrated biochemistry .27 th edition.Tata McGraw Hills publication. 3)Satyanarayan,U. (2006). Biochemistry .3 rd edition. Books and Allied (P)Ltd. 4) Whelan ,J.(2008 ).(n-6) and (n-3) Polyunsaturated Fatty Acids and the Aging Brain: Food for Thought. Abstract J. Nutr. 138: 2521–2522.

49. Thank you.