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

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.

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.

Classification of fatty acids;- Fatty acidsSaturated FA

Unsaturated FA

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.

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.

Divisions of unsaturated fatty acids;-

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. MUFACis FATrans FA

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.

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

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

Systemic inflammation

inflammation: an independent risk factor for atherosclerosis, sudden death from cardiac causes, diabetes, and heart failurethe 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

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

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.

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;-

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

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

Eicosanoids;-These compounds are derived from long chain polyenoic fatty acids (20-carbon).Examples of eicosanoids;-Prostaglandins.Prostacyclines,ThromboxanesLeukotrieneslipoxinsThey have roles in:InflammationFeverRegulation of blood pressureBlood viscosityMale fertilityFemale conceptionMuscle cotractionBlood clottingTissue growthRegulation of sleep/wake cycleBronchocostrictionAsthma.

Triglycerides;-

StructureGlycerol + 3 fatty acids

FunctionsEnergy source--9 kcals per gramForm of stored energy in adipose tissue.Insulation and protectionCarrier of fat-soluble vitaminsSensory properties in food

Phospholipids;- main lipid constituent of cell membrane.StructureGlycerol + 2 fatty acids + phosphate groupalso considered as derivative of phosphatidic acid.

FunctionsMain lipid constituent of cell membranesLipid transport as part of lipoproteinsEmulsifiersCell signalling process. phospholipids

Phos.choline phos.inositol cardiolipin lysophospholipid plasmalogens sphingomy.

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

Glycolipids;---widely distributed in the bodyFatty acids + sphingosine +carbohydrateAlso k/a glycosphingolipids.Present in cell membrane and nervous tissues. It contributes to cell surface carbohydrateOther glycolipids are;-Cerebrosides- simplest form of glycolipids.contains ceramides. eg. Galactosylcerebrosides glucosylcerebrosidesGangliosides predominantly found in ganglions.Complex glycolipids

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

Classes of lipoproteins;-Chylomicrons, VLDL,LDL

HDL> 30 nm915 nm2022 nmD

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 bindingApo A-IV (small intestine)Activator of LCAT; modulator of lipoprotein lipase (LPL)Apo A-V (liver)Direct functional role is unknown; regulates TG levels.

Apoprotein continued

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

Apoprotein continuedApo C-I (liver)Activator of LCAT, inhibitor of hepatic TGRL uptakeApo C-II (liver)Activator of LPL, inhibitor of hepatic TGRL uptakeApo C-III (liver)Inhibitor of LPL, inhibitor of hepatic TGRL uptake

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

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

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.

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

HDL Subpopulations

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

Omega-3 Fat Decreases total cholesterol Decreases LDL-cholesterol Increases HDL-cholesterol Decreases serum triglycerides Trans Fat Increases total cholesterol Increases LDL-cholesterol

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. (310). The content of DHA in the brain is 1215%, 10- to 20-fold higher than any other (n-3) PUFA.

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 811% of the fatty acid phospholipids, it is severalfold higherthan 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 proliferatoractivatedreceptor-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.

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

Lipids related disorders;- lipid disordersCommon disordersHypercholetrolemiaHypertriglyceridemiaHyperlipoproteinemiaketosisCVDFatty liverObesitycancer Uncommon disordersMetabolic disorders of cerebrosides.Lipidoses / lipid storage diseasesMultiple sclerosis.Infant respiratory distress syndromeXanthomatosis.Retinitis pigmentosa.Phrynoderma / Toad skin.Disorders of EFAs deficiency.Zwellwegers disease.

ATHEROSCLEROSIS:

As LDL particles penetrate the walls of the arteries, they become oxidized-LDL and next are scavenged by the bodys 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.

Diagrammatic representation of the disease (atherosclerosis)-

Metabolic disorders of cerebrosides

diseasesEnzyme deficiencyLipid accumulatingsymptomsTay sachs diseasehexosaminidasegangliosidesMentalretardation,blindness,muscular weakness.Fabry;s diseaseA-galactosidase.galactosylceramideSkin rashes,kidney failureKrabbes diseaseB-galactosidasegalactosylceramideMental retardation,complete loss of myelin sheath.

Gauchers diseaseB-glucosidaseglucosylceramideEnlarged liver and spleen, eroison of long bones ,mental retardationNiemann-pick diseasesphingomyelinasesphingomyelinEnlarged liver and spleenFarbers diseaseceramidaseceramideDermatitis,skeletal deformation,hoarseness.Ref- Harpers biochemistry

Lipoprotein disorders;- Hyperlipoproteinemias-

Hy. Lipo.typesMetabolic defectIncreased plasma lipid mostRisk of athersclerosislDeficiency of lipoproteinlipasechylomicronsincreasellaDeficiency of LDLreceptorscholesterolVery highllbOverproduction of apo-bTGs and cholesterolhighlllAbnormality in apo -eTGs and cholesterolhighlvOverproduction of TGsTGsMay/may not increasev--do--Chylomicron and VLDL--do--Ref- Harpers biochemistry

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.

Defects in the metabolism of essential fatty acids -Cystic fibrosis,Acrodermatitis enterohepatica,Hepato renal syndrome, Crohns disease,Cirrhosis, Alcoholism, Reye's syndrome etc.Zwellwegers 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.

Common Atherogenic dyslipidemias) polygenic inheritance dietary component secondarily enhanced byinsulin resistance (seefurther why) prognosis of combinedhyperlipidemia is worsethan that ofhypercholesterolemia main features impaired clearance of TAGby LPL ( insulin) fromchylomicrons increasedTAG and increased deliveryof TAG for liver increased production ofVLDL by liver ( insulin)from TAG, FFA from adiposetissue ( insulin) andglucose ( insulin) therefore increasedconversion of VLDL to LDL low HDL

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.

Tangier Disease>Autosomal codominant disorder due to mutations inboth 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

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;8:41492) Granner,K. and Robert,K.(2006).Harpers illustrated biochemistry .27th edition.Tata McGraw Hills publication.3)Satyanarayan,U. (2006).Biochemistry.3rd 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: 25212522.