Biochemistry sfa 2073 lipid metabolism
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BIOCHEMISTRY SFA 2073 Lipid Metabolism. NIK NORMA NIK MAHMOOD-Ph.D FACULTY OF SCIENCE AND TECHNOLOGY ISLAMIC SCIENCE UNIVERSITY OF MALAYSIA. Digestion & Absorption.

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Biochemistry sfa 2073 lipid metabolism

BIOCHEMISTRYSFA 2073Lipid Metabolism

NIK NORMA NIK MAHMOOD-Ph.D

FACULTY OF SCIENCE AND

TECHNOLOGY

ISLAMIC SCIENCE UNIVERSITY OF MALAYSIA


Digestion absorption

Digestion & Absorption

  • Lipids that gets into the digestive system are dietary lipids, normally free fatty acids, cholesterols and triglycerides (TAG) and many minor components.

  • Digestion starts in the duodenum portion of small intestine:

    - is mix with bile that contains HCO3ˉ ions and bile salts to solubilize fat. This process is called emulsification. The big lipids droplets are broken down into smaller droplets.

    (bile is made in liver and stored in gall bladder between meals. When there is food, bile is delivered to the intestine from gall bladder via bile duct)


Biochemistry sfa 2073 lipid metabolism

- TAG is acted by lipase secreted by pancreas

liberating monoglyceride and two fatty acids.

Monoglyceride, cholesterol and f.fasand bile salts form amphipathic micelles. These micelles keep the insoluble lipid components in soluble aggregates from which small amounts are released and absorbed by epithelial cells via diffusion.

- Free fatty acids and monoglycerides then recombine into triacylglycerols at the smooth ER and together with cholesterols moves on to Golgi to be converted to chylymicrons. It enters interstitial fluid, then taken up by the lacteals in the intestinal wall and delivered to liver via hepatic portal vein for processing.


Biochemistry sfa 2073 lipid metabolism

exposure to a large aggregate of triglyceride, the hydrophobic portions of bile acids intercalate into the lipid, with the hydrophilic domains remaining at the surface. Such coating with bile acids aids in breakdown of large aggregates or droplets into smaller and smaller droplets.


Biochemistry sfa 2073 lipid metabolism

  • Pancreatic lipases hydrolyse triglyceride into monoglyceride and free fatty acids. The activity of this enzyme is clipping the fatty acids at positions 1 and 3 of the triglyceride, leaving two free fatty acids and a 2-monoglyceride.

    **Lipase is a water-soluble enzyme


Biochemistry sfa 2073 lipid metabolism

  • Lipids, and products of their digestion are transported through aqueous compartments within the cell as well as in the blood and tissue spaces in the forms LIPOPROTEINS

    Why in the form of LIPOPROTEINS?

  • Large portion of the lipids’ structures comprise of C-C &C-H rendering lipids hydrophobic in nature i.e lipids are insoluble in aqueous environmentthuscreates problem to its transport within body-medium which is aqueous in nature.

    Dietary triacylglycerols (Tag) & cholesterol and in-vivo Tag and cholesterol (synthesized in liver), must be converted to the soluble form to overcome the problem. This is achieved by forming LIPOPROTEINS


Lipolysis

Lipolysis

  • Is the breakdown of fat (Tag) stored in fat cells into free fatty acids + glycerol + mono & diglycerides which is catalysed by enzyme lipase

  • Induced by hormone epinephrine , norepinephrine, glucagon and adreno corticotropic hormone

  • the lipolytic products are then released into the blood

  • The free fatty acids bind to serum albumin and transport to tissues that require energy. The energy is generated by catabolic β-oxidation pathway (a 4 steps pathway/cycle)


Biochemistry sfa 2073 lipid metabolism

  • How the hormones induce lipolysis ? The hormones trigger 7TM receptors, which activate adenylate cyclase. This results in increased production of cAMP, which activates protein kinase A, which subsequently activate lipases found in adipose tissue.

  • β–oxidation of free fatty acid

    Fatty acid degradation and synthesis are relatively simple processes and essentially the reverse of each other.


Biochemistry sfa 2073 lipid metabolism

  • f.f.a first are activated to acyl-CoAcatalyse by Acyl-CoA synthase (ACosyn)prior to transport into mitochondria.


Biochemistry sfa 2073 lipid metabolism

  • acylCoA not permeable to inner mitochondria membrane, hence carried across bycarnitine carrier systeminto mitochondrion matrix. It is by conjugation to carnitine.

  • carnitine carrier system consisted of 2 enzyme-units CAT I & CAT II

AcylCoA + Carnitine → Acyl-carnitine + Co-ASH

Carnitine Acyl Transferase


Biochemistry sfa 2073 lipid metabolism

Carnitine (a quaternary ammonium compound)is hydrophilic amino acid derivative, produced endogenously in the kidneys and liver from lysine and methionine of diet’s meat and dairy products. Carnitine binds acyl residues conjugated with coenzyme A.


Biochemistry sfa 2073 lipid metabolism

Carnitine + Acyl-CoA

Inner membrane

+ CoASH

matrix

CAT II

Acyl-carnitine

Acyl-CoA

Intermembrane space

ACosyn

CAT I

cytosol

+ CoASH

Fatty acid

Outer membrane

CAT: carnitine Acyl transferase

ACosyn: acyl-CoA synthetase

Simplified mitochondrial layout


Biochemistry sfa 2073 lipid metabolism

  • Followed by (4 steps )

  • - oxidation by FAD

  • - hydration

  • - oxidation by NAD+

  • - thiolysis

  • The cycle then repeats on the larger fragment while acetyl-CoA fragment channeled to Krebs Cycle


Biochemistry sfa 2073 lipid metabolism

  • oxidation by FAD/Acyl-CoA DH : The activated fatty acid is oxidized to introduce a double bond.

Step 1


Biochemistry sfa 2073 lipid metabolism

  • Hydration/Enoyl-CoA Hydratase: to introduce an oxygen via formation of alcohol

Step 2


Biochemistry sfa 2073 lipid metabolism

  • oxidation by NAD+/Hydroxy-CoA- DH: the alcohol is oxidized to a ketone.

Step 3


Biochemistry sfa 2073 lipid metabolism

  • Thiolysis- Thiolase/CoA-SH : cleaving of the acylCoA into two fragments, acetyl CoA and an acylCoA of fatty acid chain two carbons shorter.

Step 4


Biochemistry sfa 2073 lipid metabolism

Steps: 1 and 2 3 and 4


Biochemistry sfa 2073 lipid metabolism

  • β-oxidation of unsaturated fatty acids poses a problem. Unsaturated f.a are the cis type. This prevents the formation of the required bond orientation, trans-δ2 bond, in the enoyl intermediate. These situations are handled by an additional of two enzymes.


Anabolism of fatty acid in human

Anabolism Of Fatty Acidin Human

  • Process occurs in cytoplasm of liver (major) and adipose tissue cells.

  • Fatty acids are formed by the following 3 rxn-stages:

    i- acetyl-CoA Carboxylase rxn

    ii- fatty acid synthase rxn

    iii- desaturase rxn

  • This process is the de novo synthesis of F.A

  • The initiator substrate acetyl-CoA is the product of β-oxidation catabolic pathway


Biochemistry sfa 2073 lipid metabolism

Cytoplasm

Mitochondria

Acetyl CoA

Acetyl CoA

synthesis

citrate

β-oxidation

citrate

Fatty Acid

oxaloacetate

Fatty Acid

ATP-citrate lyase

NADH

oxaloacetate

Citrate synthase

NADH

malate

NAD+

malate

Malate DH

NADP+

NAD+

Malic enzyme

NADP+

pyruvate

NADPH

NADPH

pyruvate

transporter

Malate-oxaloacetate shuttle: Transfer OF Acetyl CoA from Mitochondria to

cytoplasm


Biochemistry sfa 2073 lipid metabolism

Oxidation

Fatty Acid &

Cholesterol

Steroid hormones

Ketone bodies

Glucose

Pyruvate

Fatty Acids

Ketogenic

Amino Acids

ACETYL-CoA

SOURCES AND UTILIZATION OF ACETYL-CoA


Acetyl coa carboxylase rxn

Acetyl-CoA Carboxylase rxn

  • Initiator to fatty acid synthesis is acetyl-CoA

  • Acetyl-CoA carboxylase catalyses carboxylation of acetyl-CoA to malonyl-CoA via 2-steps reaction.

  • The enzyme is biotin bound. In mammals acetyl-CoA carboxylase is a large enzyme controlled by conversion inactive ══> active (inactive: protomers (4 subunits; one biotin); active: 1 unit)

    conversion promoted by citrate, but inhibited by fatty acyl CoA.Also

    by hormonal controlled: in liver by glucagon – PO4rylation to inactive form; in adipose tissue by adrenalin (epinephrin)– PO4rylation to inactive form

    Additional note

  • Acetyl-CoA originated from pyruvate in mitochondria and transported to cytosol as citrate by condensing with oxaloacetate

  • In cytosol citrate is broken down to yield acetyl-CoA and oxaloacetate by ATP-citrate lyase.

  • Acetyl-CoA undergoes carboxylation by Acetyl-CoA carboxylase to malonyl-CoA


Biochemistry sfa 2073 lipid metabolism

Figure at right is expansion of reaction in figure on left


Biochemistry sfa 2073 lipid metabolism

reaction at site 2


Biochemistry sfa 2073 lipid metabolism

  • ATP-dependent carboxylation of the biotin, carried out at one active site (1)

  • transfer of the carboxyl group to acetyl-CoA at a second active site (2).

  • Reaction is spontaneous,

    HCO3- + ATP + acetyl-CoA → ADP + Pi + malonyl-CoA


F atty a cid s ynthase rxn

Fatty acid synthase rxn

  • The reaction is a multi-steps .

  • The enzyme(in mammal) is a very large polypeptide of many domains that includes an acyl carrier protein domain.

  • Has a number of prosthetic grps.

  • Individual domain catalyses a single step .

  • the precursor of fatty acid synthesis is malonyl-CoA

  • the initial action is binding of acetyl-CoA (2C) and malonyl-CoA (3C) to specific domain of FAS leading to formation of acyl-ACP intermediates -5C (steps 1&2)


Biochemistry sfa 2073 lipid metabolism

  • Followed by formation of β-ketoacyl-ACP (4C) with evolution of CO2 (step 3)


Biochemistry sfa 2073 lipid metabolism

  • β-ketoacyl is reduced to an alcohol, by electron transfer from NADPH (step 4).

  • Dehydration yields a trans double bond (step 5).

  • Reduction at the double bond by NADPH yields a saturated Acyl-ACP chain- 4C (step 6). This is 1 cycle.


Biochemistry sfa 2073 lipid metabolism

  • Acyl-ACP and malonyl ACP then repeat step 3 and reaction proceeds to step 7.


Biochemistry sfa 2073 lipid metabolism

  • Acyl chain lengthens by 2C / cycle.

  • Elongation process stops when acyl 16C is formed. Hydrolysis of the ester bond takes place with liberation of palmitate.


Biochemistry sfa 2073 lipid metabolism

FAS

**The active enzyme is a dimer of identical subunits.

All of the reactions of fatty acid synthesis are carried out by the multiple enzymatic activities of fatty acid synthaseFAS


Regulation of f f a synthesis

REGULATION of f.f a synthesis

  • The major site of fatty acid synthesisregulation is atreaction catalysed by acetyl-CoA carboxylase (ACC). ACC requires a biotin co-factor


Biochemistry sfa 2073 lipid metabolism

Activity of ACC is associated with conformational change of the enzyme, and conc. of citrate and palmitoyl-CoA. When [citrate] is high, monomeric form associates to the multimeric form. Active conformation is the multimeric form. When [palmitoyl] is high, multimeric form dissociates into monomeric,it becomes inactive.

citrate

(multimeric)n + Pi

n monomeric –PO4

active

inactive

palmitoyl


Catabolism of triglycerides tg

Catabolism Of Triglycerides (TG)

  • Initial rxn is in small intestine where TG is mixed with bile salt.

  • Bile salt are steroids with detergent properties. 2 most abundant componants are cholate and deoxycholate, and they are normally conjugated with either glycine or taurine


Biochemistry sfa 2073 lipid metabolism

Taurocholic acid. In mammal it

exists as Na+ salt. In medical

use, it is administered as cholagogue and choleretic.

Glycocholic acid (Cholic acid+ glycin). It occurs as a sodium salt in the bile of mammals


Biochemistry sfa 2073 lipid metabolism

  • Starts by break-up of the glyceride (TG) into fatty acids and monoacylglycerol by pancreatic lipases. This step takes place because TG cannot be transported across the plasma membrane of the intestinal wall cells (enterocytes) due to its size.


Biochemistry sfa 2073 lipid metabolism

  • The 2 products are transported into the cell. Once in the cell, recombination occurs and triacylglyerols TG1 are reformed.

  • TG1 is combined with dietary cholesterol, newly synthesized phospholipids and protein into compound chylomicrons (a large, low-density lipoproteins).


Biochemistry sfa 2073 lipid metabolism

  • Lipoprotein lipase (synthesize by a number of sources) acts on TG1 portion in the chylomicron liberating F.F.A and glycerol.

    F.F.A is metabolised by either:

    - converted to new TG

    - catabolic pathway(β-oxidation)

    - used in membrane synthesis


Biochemistry sfa 2073 lipid metabolism

  • The glycerol is transported to and absorbed by the liver or kidney where it is converted to glycerol-3-phosphate by the enzyme glycerol kinase,GK. Glycerol 3-phosphate (especially from hepatic) converted into dihydroxyacetonephosphate (DHAP) then glyceraldehyde-3-phosephate(G3P) to join glycolysis and gluconeogenesis pathway.


Biochemistry sfa 2073 lipid metabolism

IN INTESTINE

TG1 in chylomicron

Lipoprotein lipase

F.F.A

Glycerol

Glycerol kinase

TG

Glycerol-3-PO4

Catabolism

β-oxidation

Membrane synthesis

TG

phospholipids

Glucose


Anabolism of triglyceride

Anabolism Of Triglyceride

  • Precursor is L-glycero-3-phosphate

  • Proceed by condensation with acyl-CoA to form lysophospha- tidic acid (l.p.a), catalyse by enzyme E1

Glycerol

PEP

L-glycerol-3-PO4

2

1

*1 is glycerol-3-PO4 DH ; 2 is glycerol kinase

*E1 isglycerol-3-PO4 acyltranferase


Biochemistry sfa 2073 lipid metabolism

Further reactions on l.p.a till formation of TG


Cholesterols

Cholesterols


Cholesterol

CHOLESTEROL

  • Is a soft, fat-like, waxy substance found in the bloodstream and membrane of cells (especially of the liver, spinal cord), and myelin sheaths and some hormones.

  • require by cells as a precursor to bile acids.

  • it is transported in the circulatory system within lipoproteins.


Biochemistry sfa 2073 lipid metabolism

  • The most abundant of the steroids

    **Steroids are complex derivatives of triterpenes They are characterized by a carbon skeleton consisting of four fused rings. 


Biochemistry sfa 2073 lipid metabolism

  • normal adult utilized ~1 gram of cholesterol daily. Approximately 70% of the amount produces by the liver. The other 30% comes from dietary intake

  • Cholesterol is the precursor for all steroids. It is a common component of animal cell membranes and functions to help stabilize the membrane. Thus it is a crucial molecule

    *high levels of it in the blood may contribute to atherosclerosis.


Catabolism of cholestrols

Catabolism Of Cholestrols

  • Is not the usual mode i.e broken- down to smaller molecules

  • Instead it is converted to the more soluble derivatives to facilitate its degradation and excretion.

  • Most important mechanism is the formation of bile acids, in liver.


Biochemistry sfa 2073 lipid metabolism

  • Bile Acids (BA) are mixtures of compounds and possess digestive function as agent for emulsification and absorption of dietary fats. BA are important component of bile.

    Cholic acid and deoxycholate are 2 of the components of BA.


Biochemistry sfa 2073 lipid metabolism

Metabolism of Cholesterol

cholesterol

7-α-hydroxycholestrl

Many2 steps

glycocholate

Cholic acid

(-ve charge)

(-ve charge)

glycine


Biochemistry sfa 2073 lipid metabolism

Oxidation

Hydroxylation

Cholic acid

Hydrogenation


Biochemistry sfa 2073 lipid metabolism

Usually the BA are converted to a more soluble form by conjugation with glycine or taurine

glycine /NH2CH2CO2H

taurine (an a.a)/NH2CH2CH2SO3H

e.g Conjugation:

cholic acid +Glycine→ glycocholate

cholic acid + taurine → taurocholic acid


Biochemistry sfa 2073 lipid metabolism

Taurocholic acid. In mammal it

exists as Na+ salt. In medical

use, it is administered as cholagogue and choleretic.

Glycocholic acid. It occurs as a sodium salt in the bile of mammals


Biochemistry sfa 2073 lipid metabolism

  • Regulation of cholesterols level in blood

    -Absorbed dietary cholesterol increased linearly with the increase of dietary cholesterol intake.

    - The higher the fractional and absolute absorption of dietary cholesterol the lower the rates of biliary secretion, fecal elimination, and cholesterol synthesis (regulate cholesterol elimination and synthesis).

    -high serum levels of total, LDL, and HDL cholesterol were associated with high cholesterol absorption


Anabolism of cholesterol

Anabolism Of Cholesterol

  • Condensation of precursors, acetyl-CoA and acetoacetyl-CoA catalyse by Hydroxymethyl glutaryl CoA synthase (HMG-CoA synthase).

  • Reactions proceed to formation of Mevalonate, catalysed by HMG-CoA Reductase. This rxn is rate-limiting


Biochemistry sfa 2073 lipid metabolism

Reactions occur in cytosol


Biochemistry sfa 2073 lipid metabolism

  • To this structure other rings are added to form the final product

  • Enzyme HMG-CoA Reductase is highly regulated and the target of pharmaceutical intervention.


Biochemistry sfa 2073 lipid metabolism

Regulation ofCholesterolSynthesis:

  • isnotdirect on cholesterol but through B.A

  • B.A is removed from pool by dietary fibers

  • Depletion of B.A induces synthesis of cholesterol: activation of HMG-CoA synthase (Hydroxymethyl glutaryl CoA formation step)and HMG-CoA Reductase (mevalonate formation step)


Biochemistry sfa 2073 lipid metabolism

Catabolism of Phospholipids

The products of these phospholipases are called lysophospholipids and can be substrates for acyl transferases utilizing different acyl-CoA groups. Lysophospholipids can also accept acyl groups from other phospholipids in an exchange reaction catalyzed by lysolecithin:lecithin acyltransferase (LLAT).


Biochemistry sfa 2073 lipid metabolism

  • phospholipase A2, lysophospholipase, and other enzymes are involved in phospholipid metabolism,

  • Phospholipase A2 is an important enzyme, its activity is responsible for the release of arachidonic acid from the C-2 position of membrane phospholipids. The released arachidonate is then a substrate for the synthesis of the prostaglandins and leukotrienes.


Biochemistry sfa 2073 lipid metabolism

  • glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) are

    competitive inhibitors of lysophospholipase activity, inhibits lysophospholipid hydrolysis


Anabolism of phospholipids

Anabolism of Phospholipids

CholineAcetylcholine

CDP-Choline

PE PS PC

**Phosphatidylserine (PS)

Phosphatidylcholine (PC)

CDP: cytidine-5’-diphospho

- CO2

+ CO2


Biochemistry sfa 2073 lipid metabolism

1,2-diglyceride

** CDP: cytosinediphosphate


Biochemistry sfa 2073 lipid metabolism

  • DPGs:diphosphatidylglycerols. Also known as cardiolipins are synthesized by the condensation of CDP-diacylglycerol with phosphatidylglycerols (PG).


Clinical effect

Clinical Effect

  • has not yet been fully evaluated, but scientists have studied the role of choline and phospholipids in age related cognitive decline (ARCD), Alzheimer’s disease, and Parkinson’s disease

  • good dietary intake of phospholipids, cholin lead to an improvement in learning and memory

  • The fatty acid composition of phospholipids can deteriorate with aging and disease.


Biochemistry sfa 2073 lipid metabolism

Regulation of synthesis

  • The fatty acid distribution at the C-1 and C-2 positions of glycerol within phospholipids is continually in flux, owing to phospholipid degradation and the continuous phospholipid remodeling that occurs while these molecules are in membranes.

  • Phospholipid degradation results from the action of phospholipases. There are various phospholipases that exhibit substrate specificities for different positions in phospholipids. In many cases the acyl group which was initially transferred to glycerol, by the action of the acyl transferases, is not the same acyl group present in the phospholipid when it resides within a membrane. The remodeling of acyl groups in phospholipids is the result of the action of phospholipase A1 and phospholipase A2


Lipid profile

LIPID PROFILE

  • Is a presentation of concentration of different lipid components in blood.

  • Normally it involves determination of capillary blood cholesterol and triglyceride of fasting and non-fasting subject.

  • Concentration of the lipid component is determined using a specific test strips and GCT meter

  • Low and high readings are indicative to some form of health state. ** refer manual for details


Lipid metabolic disorder

Lipid Metabolic Disorder

  • Abnormalities in the enzymes in lipid metabolism result in 2 types of disorder.

    1. Lipidosis : case when there is accumulation of specific fatty substances due to abnormalities in the enzymes that are involved in assimilation of the specific fatty substances eg. Gaucher's Disease, Tay-Sachs Disease, Niemann-Pick Disease Fabry’s Disease; rare case: Wolman's disease, sitosterolemia, Refsum's disease


Biochemistry sfa 2073 lipid metabolism

2. Fatty acid oxidation disorder : When body is unable to properly convert fats into energy due to abnormalities of enzymes in the fatty acid oxidation pathway. Eg medium chain acyl-CoA dehydrogenase (MCAD) deficiency


Biochemistry sfa 2073 lipid metabolism

  • Gaucher's Disease, most common.

    - accumulation of glucocerebrosides in liver and spleen, most common in Ashkenazi (Eastern European) Jews leads to enlargment of the organs and brownish pigmentation of skin.

  • Accumulations of glucocerebrosides in the eyes cause yellow spots called pingueculae to appear in the eye

  • Accumulations in the bone marrow can cause pain and destroy bone.


Biochemistry sfa 2073 lipid metabolism

- 3 types :

i) Type 1, the chronic form, with symptom of enlarged liver and spleen and bone abnormalities. More common among adults

ii) Type 2, develops in infancy; infants with the disease have enlarged spleen and severe nervous system abnormalities and usually die within a year.

iii) Type 3, the juvenile form, can begin at any time during childhood. Children with the disease have an enlarged liver and spleen, bone abnormalities, and slowly develop progressive nervous system abnormalities. Children who survive to adolescence may live for many years.

Gaucher's disease can be treated with enzyme replacement therapy


Biochemistry sfa 2073 lipid metabolism

  • Tay-Sachs disease : accumulate gangliosides in tissues, most common in families of Eastern European Jewish origin.

    At early age, children with this disease become progressively retarded and appear to have floppy muscle tone. Spasticity develops and is followed by paralysis, dementia, and blindness.

    Patient usually die by age 3 or 4. Tay-Sachs disease can be identified in the fetus by chorionic villus sampling or amniocentesis. The disease cannot be treated or cured.


Biochemistry sfa 2073 lipid metabolism

  • Niemann-Pick disease: accumulation of sphingomyelin or cholesterol; has several forms, depending on the severity of the enzyme deficiency and thus accumulation of sphingomyelin or cholesterol. The most severe forms tend to occur in Jewish people. The milder forms occur in all ethnic groups.

    The most severe form (type A), children fail to grow properly and have multiple neurologic problems. These children usually die by age 3

    Type B, disease develops fatty growths in the skin, areas of dark pigmentation, and an enlarged liver, spleen, and lymph nodes; may be mentally retarded.


Biochemistry sfa 2073 lipid metabolism

Type C, disease develops symptoms in childhood, with seizures and neurologic deterioration.

Some forms of the disease can be diagnosed in the fetus by chorionic villus sampling or amniocentesis. After birth, the diagnosis can be made by a liver biopsy None of the types can be cured.


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