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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)


- 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.


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.


  • 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


  • 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 through aqueous compartments within the cell as well as in the blood and tissue spaces in the forms

  • 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)


  • How the hormones induce lipolysis through aqueous compartments within the cell as well as in the blood and tissue spaces in the forms ? 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.


  • f.f.a first are activated to acyl-CoA through aqueous compartments within the cell as well as in the blood and tissue spaces in the forms catalyse by Acyl-CoA synthase (ACosyn)prior to transport into mitochondria.


AcylCoA + Carnitine → Acyl-carnitine + Co-ASH

Carnitine Acyl Transferase


Carnitine carried across by(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.


Carnitine + Acyl-CoA carried across by

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


  • Followed by (4 steps ) carried across by

  • - oxidation by FAD

  • - hydration

  • - oxidation by NAD+

  • - thiolysis

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


Step 1


Step 2


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

Step 3


Step 4


Steps: 1 and 2 3 and 4 carried across by


  • β-oxidation of unsaturated fatty acids poses a problem carried across by. 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 Acid carried across byin 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


Cytoplasm carried across by

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


Oxidation carried across by

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 carried across by

  • 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



reaction at site 2 carried across by



F atty a cid s ynthase rxn
F one active site (1) atty 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)



  • β one active site (1) -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.



  • Acyl chain lengthens by 2C / cycle. proceeds to step 7.

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


FAS proceeds to step 7.

**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 proceeds to step 7.

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


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) 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.

  • 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


Taurocholic acid. In mammal it 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.

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





  • 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.


IN INTESTINE 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.

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 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.

  • 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


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


Cholesterols
Cholesterols 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.


Cholesterol
CHOLESTEROL 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.

  • 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.


  • The most abundant of the steroids 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.

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


  • 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 Approximately 70% of the amount produces by the liver. The other 30% comes from dietary intake

  • 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.


  • Bile Acids (BA) Approximately 70% of the amount produces by the liver. The other 30% comes from dietary intake 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.


Metabolism of Cholesterol Approximately 70% of the amount produces by the liver. The other 30% comes from dietary intake

cholesterol

7-α-hydroxycholestrl

Many2 steps

glycocholate

Cholic acid

(-ve charge)

(-ve charge)

glycine


Oxidation Approximately 70% of the amount produces by the liver. The other 30% comes from dietary intake

Hydroxylation

Cholic acid

Hydrogenation


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


Taurocholic acid. In mammal it conjugation with glycine or taurine

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


  • Regulation of cholesterols level in blood conjugation with glycine or taurine

    -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 conjugation with glycine or taurine

  • 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


Reactions occur in cytosol conjugation with glycine or taurine



Regulation of productCholesterolSynthesis:

  • 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)


Catabolism of Phospholipids product

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).


  • 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.



Anabolism of phospholipids
Anabolism of Phospholipids (GPE) are

CholineAcetylcholine

CDP-Choline

PE PS PC

**Phosphatidylserine (PS)

Phosphatidylcholine (PC)

CDP: cytidine-5’-diphospho

- CO2

+ CO2


1,2-diglyceride (GPE) are

** CDP: cytosinediphosphate



Clinical effect
Clinical Effect synthesized by the condensation of CDP-diacylglycerol with phosphatidylglycerols (PG).

  • 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.


Regulation of synthesis synthesized by the condensation of CDP-diacylglycerol with phosphatidylglycerols (PG).

  • 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 synthesized by the condensation of CDP-diacylglycerol with phosphatidylglycerols (PG).

  • 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 synthesized by the condensation of CDP-diacylglycerol with phosphatidylglycerols (PG).

  • 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


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


  • Gaucher's Disease, most common. properly convert fats into energy due to abnormalities of enzymes in the fatty acid oxidation pathway. Eg medium chain acyl-CoA dehydrogenase (MCAD) deficiency

    - 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.


- 3 types : properly convert fats into energy due to abnormalities of enzymes in the fatty acid oxidation pathway. Eg medium chain acyl-CoA dehydrogenase (MCAD) deficiency

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


  • 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.


  • 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.


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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