Biochemistry –Second year, Coll. of Medicine-Baghdad Univ. 2011-2012.
Dr.Basil Oied Mohammed Saleh.
Subject:Lipid
Lecture 1 29-3-2011
Lecture 2 6-10-2011
Lecture 3 13-10-2011
Lecture 4 20-10-2011
Introduction to lipid
Objective: Illstrates the meaning of lipid, types and their functions.
Lipid are compounds that are soluble in organic solvents, such as ether and relatively insoluble in water or aqeous media e.g.human body fluid such as blood, seminal and interstitial fluid(water account for about 93 % of blood).The principal unit of different forms of lipid is fatty acid with general formula:
RCOOH; R: is aliphatic carbon chain structure: CH3(CH2)nCH2; n is the number of carbon.
In nature fatty acid may be:
1.Saturated; CH3CH2……., the common one in human body is Palmitic acid(C16)
2.Monounsaturated CH3CH2CH=CH……(one double bond), and 3.Polyunsaturated
CH3CH2CH=CHCH2CH2CH=CH…….(2 or more of double bonds ).The most important of polyunsaturated fatty acids are the Essential Fatty Acids(EFAs).The EFAs are those fatty acids that are required in human body but cannot be synthesized in it, so must be supplied in the diet to support the growth and include:
Linoleic acid C18, 2 double bonds
Linolenic acid C18, 3 double bonds
Arachidonic acid C20, 4 double bonds. The absolute EFAs are the linoleic acid, the precursor of arachidonic acid that is a substrate for Prostaglandins synthesis and the Linolenic acid, the precursor for other ω-3 fatty acids formula important for growth and development.These EFAs are important components of phospholipids of cell membrane and mitochondrial membrane and their deficiencies result in defect in growth and development.Even the incidence of EFAs deficiencies is rare, it can lead to scaly dermatitis, visual and neurologic defects.
Fatty acids also may be:
Short : C2-C4
Medium: C6-C10
Long: C12 and more.
The saturated fatty acids are naturally found in Zigzag form, while the unsaturated fatty acids in kinked form. The degree of unsaturation(number of double bonds) and
the carbon chain length are important in determining of melting point of fatty acids and so of biological membrane fluidity composed of them(permeability to lipid soluble substances).
The important structures of lipid materials are:
1. Triglycerides; Simple lipid
2. Phospholipids; Complex lipid
3. Sphingolipids and Glycolipids; Complex lipid
4. Cholesterol, Cyclolipid
5. Lipoproteins, Male and Female Sex Hormones, Adrenal Cortical Hormones(cortisol and aldosterone), Vitamin D, and other derived lipid: Derived lipid.
Defintions:
Triglyceride; TG (Triacylglycerol):
Are fatty acid ester of glycerol alcohol; 3 fatty acids+ Glycerol (CH2OH-CHOH-CH2OH).
Diglyceride; 2 fatty acids+ Glycerol
Monoglycride: 1 fatty acid+ Glycerol. In nature fatty acids contained in acylglycerol are different in carbon chain length and degree of saturity.
TG represents(its function) the principal storage form of energy in adipose
tissues that needed physiologically in prolonged fasting and starvation and
pathologically, for example in uncontrolled diabetes mellitus. It is also the preferred form of nutrient that is used by muscle in producing of chemical energy ATP under normal conditions. TG forms about 95 % of dietary fat.
The general structure of TG is:
CH2OCOR1
CHOCOR2
CH2OCOR3 : R1,R2,R3 are different fatty acids.TG is considered as nonpolar structure and so not implied in CM formation.
Phospholipids;PL( Phosphoglycerolipids):
These lipids also composed of Fatty acids(R) and Glycerol as TG, but also phosphoric acid(PO4) and nitrogen base. These two latter structures(PO4 and nitrogen base) confer the PL compounds the relative polarity and so their function in CM and mitochondrial membrane structures. The general formula of PL is:
CH2OCOR1 CH2OCOR1
CHOCOR2 CHOCOR2
CH2OPO3-Nitrogen base is PL, while CH2OH is Phosphatidic acid
Type of PL is defined according to the type of contained nitrogen base:
Base PL
Choline Lecithin
Ethanol amine Cephalin
Serine Phosphatidyl serine
Inositol Phosphatidyl inositol triphosphate
And Cardiolipin phospholipid; Diphosphatidyl glycerol.
PLs are also reffered to as amphipathic compounds because of their formation from polar(PO4 and nitrogen base) and nonpolar(fatty acids) structures.
Lecithin PL is:
1.the predominant type of PL in CM
2.the source of choline component of the neurotransmitter, the Acetylcholine
3.the principal lipid component of Lung surfactant(90 % lipid and 10 % protein), its
deficiency in preterm infants is associated with inadequate production or secretion of
surfactant causes Respiratory Distress Syndrome(RDS), the significant cause of death.
Lecithin is made and secreted by pneumocytes to act as surfactant, decrease the surface tension of fluid lining the alveoli so reducing the pressure needed to reinflate alveoli, thereby preventing alveolar collapse(atelectasis)
4. involved in emulsification of fat diet in small Intestine along with Bile salt.
Cardiolipin PL is the principal type of PL that involved in inner mitochondrial membrane structure(important for maintenance of certain respiratory complexes). The laboratory test,
Anti-cardiolipin ACL is used in investigation of abortion or dead infant delivery, because this PL cardiolipin is recognized by antibodies that raised against Treponema Pallidum the bacterium that causes Syphilis. Phosphatidyl inositol triphosphate in CM act as a second messenger(internal messanger) for protein hormones action.
Platelet activating factor PAF and Plasmalogensare compounds that belong to PL structure but differ in containing ether linkage ROR instead of ester linkage ROCOR at C1 of PL. PAF is synthesized and released by a variety of cell types, binds to surface receptors with triggering potent thrombotic and acute inflammatory processes. It causes platelets to aggregate and degranulate, and neutrophiles and
macrophages to produce superoxide radicals, the killing substance of infected bacterium.
Sphingolipids(Phosphoshingolipids: Sphingomyelin):
These are also PL but differ from phosphoglycerolipids(previous types) in their structure: They are composed of Sphingosine alcohol instead of Glycerol. Sphingosine is C18 monoalcoholamine:
CH3(CH2)12CH=CHCHOHCHNH2CH2OH
Sphingosine+fatty acid=Ceramide
Ceramide+Nitrogen base= sphingolipid. Of the most significant type of these PL in humans is sphingomyelin in which the base is choline. It is an important component of myelin sheath of nerve fibers, insulates and protects neuronal fibers of the central nervous system(preventing the short circulation of nerve electrical pulse transmission).
Glycolipids:
These are anthor type of lipid. Their structure are relatively similar to sphingolipid;
Ceramide+ carbohydrate moity(or moities)=Glycolipids. Of which : the simple forms are glucosylsphingolipid and galactosylsphingolipid(only one unit of CHO).The complex forms are Globoside and Gangalioside(2-9 units of CHO).They are found in outer leaflet of plasma membrane and contribute to cell surface
antigen(anti-genicity), cellular interaction(cell-cell adhesion) and blood group(A B O system).
Cholesterol :
Is anthor form of lipid called sterols. Cholesterol is the major sterol in humans. It is
cycloaliphatic carbon chain C27. It is present in blood in two forms: Free chol.(1/3)
and Esterified chol.(2/3). Total chol. Represents the two forms: The free form is relatively polar because of free OH group at C3, while the esterified form is nonpolar because the free OH is occupied by acyl group(fatty acid RCOO) . Cholesterol is
the precursor for synthesis of many vital substances: Male and Female sex hormones
(Androgen such as testosterone and Estrogen, E2 ), vitamin D, Cortisol and aldosterone hormones.Cholesterol is also an important constituent of CM structure.
2. Lipoproteins:
Objective: Illustrate the definition and metabolism of different types of lipoproteins
Lipoproteins LPs are spherical structures composed from lipids and proteins and function in supporting the transport of lipids in circulation. In these structures the water insoluble lipids (TG and esterified cholesterol) are oriented to the core of the spherical LP, while the water soluble lipids(PL, Free chol. and added proteins) are
directed to the surface of LP. However, these structures in their later form still relatively insoluble in systemic circulation and need for addition of specific proteins, called apolipoproteins(apoLPs) to confer them sufficient water solubilitiy and so transporting in blood.There are major five LPs in blood of human body,along with additional sixth one apo a that is related to LPs structurally but not functionally.The five Lps are classified in order of ascending densities by ultracentrifugation as:
1.Chylomicron
2.Very Low Density Lipoprotein (VLDL)
3.Intermediate Density Lipoprotein(IDL)
4.Low Density Lipoprotein(LDL)
5.High Density Lipoprotein(HDL)
Chylomicron(Exogeneous LP):
It is synthesized in small intestine from dietary lipid after being digested and absorbed. The reabsorbed lipid(fatty acids, PLs, free cholesterol) are resynthesized in enterocyte again into TG, PL, and cholesterol ester. These lipid are oriented as mentioned above into spherical structure and converted into LPs after addition of apolipoproteins, principally apo B48 and to a lesser extent apo A I. Chylomicron composed mainly of TG 90 %, and the remainder are PLs, cholesterol and apoLPs.Because of its low density(large size), it is secreted firstly into lymphatic system and gives this system its milky appearance, then passes into systemic circulation, where this LP accepts apo C II into the circulation from anthor LP(HDL).
In blood, chylomicron is transported to adipose tissue and skeletal muscle where there are an important enzyme Lipoprotein Lipase (LPL) which anchored by heparan sulfate to the capillary walls of the most tissues, but predominantly those of adipose tissue and cardiac and skeletal muscle. This LPL catalyze the hydrolysis of TG contained in this LP into Free fatty acids(FFAs) and glycerol in the presence of apo CII as coenzyme. FFAs are taken up by adipose tissues(stored as TG) or muscle for production of energy ATP. Glycerol is transported to the liver to be used in lipid synthesis TG, glycolysis or gluconeogenesis, however it caanot be used by adipose
tissue ?. As more than 90 % of TG is removed from chylomicron by LPL and as the apoCII is returned to HDL, the remainder particle is reffered to chylomicron remnant which is taken up by hepatic receptors via recognition the apo E on the surface of this remnant by endocytosis(engulf process). Components of the engulfed remnant; FFAs, cholesterol, PL and amino acids that are produced and released by lysosomal
enzymes are used by hepatocytes.
Pathological condition: Familial Hyperchylomicronemia(Hyperlipoproteinemia type I).
Is deficiency of LPL or apo CII with resultant hyperchylomicronemia and hypertriglyceridemia(TG 2000-10,000 mg/dl Normal value= 150 mg/dl) even in fasting state. Normally, chylomicron is absent from circulation in fasting state and only present in nonfasting(postprandial condition). This disorder is expressed in childhood period, less than 10 year of age and characterized by the symptoms; severe abdominal pain, acute pancreatitis, eruptive xanthoma and lipemia retinalis.
VLDL (Endogeneous pathway):
VLDL is also composed mainly of TG but with less amount compared with chylomicron (VLDL contains 55-60 % TG). It contains also apo B100, much amount of PL , cholesterol and apoproteins, so with higher density and smaller size than chylomicron.VLDL synthesized endogeneously in the liver from chylomicron remnant(dietary lipid)?? and from those synthesized in the liver from excess ingested CHO??. The pathway of VLDL metabolism is started from its secretion into the systemic circulation in the presence of apo B100. It is transported in the blood to different tissues, mainly the adipose and muscle where there are LPL which acts in the presence of apoCII on the TG contained into the VLDL particles as in chylomicron pathway. After removal of much amount of TG as FFAs and glycerol, VLDL is converted into VLDL remnant which undergoes again subsequent
hydrolysis of TG by LPL to produce what is known: Intermediate density lipoprotein IDL. This IDL which is present normally in blood transiently, is composed from equal molar amount of cholesterol and TG, and mainly apo B100 and apo E. The IDL is either taken up by hepatic receptors which recognize the apo E on the surface of IDL or is converted into LDL after removal of the remaining amount of TG contained into IDL. The IDL lipid migrate into β position in electrophoresis technique.
Pathological conditions: HyperVLDLemia due to deficiency of LPL and / or apo CII with increase in blood level of VLDL and TG. Normally, the increase in TG blood level in fasting and postprandial states reflects the abnormalities in chylomicron and VLDL, respectively ?.
Familial dysbetalipoproteinemia,Broad beta disease(Hyperlipoproteinemia Type III) is abnormal state in lipid metabolism which characterized by appearance of IDL in blood which is normally undetectable or transient due to presence of abnormal or variant of apo E2 on the surface of IDL and prevent its uptake by hepatic receptor.This disorder is characterized by palmar xanthoma, hypercholesterolemia and premature atherosclerosis.
Abetalipoproteinemia is a rare disorder of lipid metabolism characterized by hypo-
chylomicronemia and hypo-VLDL due to defect in enzyme TG Transfer Protein which involved in incorporation of apoB 48 and apo B100 in lipid of these LPs with consequences of accumulation of TG in small intestine and liver(Fatty liver disorder).
Note: The function of chylomicron and VLDL is mainly to transport of TG(and to very lesser extent the cholesterol) present in diet or synthesized endogeneously to peripherial tissues, principally the cardiac and skeletal muscle and adipose tissue.
LDL Low Density Lipoprotein:
This type of lipid or LP is differentiated from other LPs in its principally forming from cholesterol(free and esterified) and only apo B 100. It formed as mentioned before from ILD in the circulation and functions in transporting of cholesterol(not TG) from the liver to the peripheral tissues; cardiac and skeletal muscle, adrenal and gonadal glands?, skin ?and the others. LDL, which scientifically written as LDL-cholesterol(LDL-C) is important for growth and development because of need of the body for cholesterol in CM structure and synthesis of many vital substances?, but it is(LDL-C) also the Bad Lipid because of direct correlation between the blood levels of this lipid and the incidence of atherosclerosis; coronary artery diseases(CADs), cerebrovascular disease(CVD), and the peripheral atherosclerosis.
The metabolism of LDL is mainly by the liver(2/3 of LDL-C) and the remainder(1/3 of LDL-C) by scavenger uptake.The uptake of LDL by the liver is dependent on hepatocellular Receptor uptake of LDL. These Receptors (R) are negatively charged glycoproteins and are distributed in the pits on the CM surface of liver.The hepatic Rs recognize,bind and internalize by endocytosis the LDL particles depending on the presence of apo B 100 and also the apo E on the surface of LDL-C. After endocytosis of R-LDL-C complex(known as endosome), the LDL-C dissociates from complex because of endosomé s low PH and (the LDL particle) is hydrolyzed by lysosomal enzymes to release the amino acids of apo- B100 and the free cholesterol.The cholesterol that carried by LDL particle may derived from dietary lipid(chylomicron remnant) or mainly hepatic endogeneous synthesis. This pathway of LDL-C clearance is very important in removal and regulation of blood cholesterol, but it is saturable pathway. The latter(saturable ) means that when hepatic Rs uptake of LDL-C increased for any reason such as increased dietary cholesterol, the Rs are saturated and the uptake of LDL is stopped with accumulation of cholesterol contained in LDL in circulation; Hypercholesterolemia.