BIOCHEMISTRY SFA 2073 Lipid Metabolism. NIK NORMA NIK MAHMOOD-Ph.D FACULTY OF SCIENCE AND TECHNOLOGY ISLAMIC SCIENCE UNIVERSITY OF MALAYSIA. Digestion & Absorption.
Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.
NIK NORMA NIK MAHMOOD-Ph.D
FACULTY OF SCIENCE AND
ISLAMIC SCIENCE UNIVERSITY OF MALAYSIA
- 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.
**Lipase is a water-soluble enzyme
Why in the form of LIPOPROTEINS?
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
Fatty acid degradation and synthesis are relatively simple processes and essentially the reverse of each other.
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
CAT: carnitine Acyl transferase
ACosyn: acyl-CoA synthetase
Simplified mitochondrial layout
Steps: 1 and 2 3 and 4 carried across by
i- acetyl-CoA Carboxylase rxn
ii- fatty acid synthase rxn
iii- desaturase rxn
Cytoplasm carried across by
Malate-oxaloacetate shuttle: Transfer OF Acetyl CoA from Mitochondria to
Oxidation carried across by
Fatty Acid &
SOURCES AND UTILIZATION OF ACETYL-CoA
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
Figure at right is expansion of reaction in figure on left carried across by
reaction at site 2 carried across by
HCO3- + ATP + acetyl-CoA → ADP + Pi + malonyl-CoA
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
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.
(multimeric)n + Pi
n monomeric –PO4
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
F.F.A is metabolised by either:
- converted to new TG
- catabolic pathway(β-oxidation)
- used in membrane synthesis
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
*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.
**Steroids are complex derivatives of triterpenes They are characterized by a carbon skeleton consisting of four fused rings.
*high levels of it in the blood may contribute to atherosclerosis.
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
Oxidation Approximately 70% of the amount produces by the liver. The other 30% comes from dietary intake
Usually the BA are converted to a more soluble form by conjugation with glycine or taurine
taurine (an a.a)/NH2CH2CH2SO3H
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
-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
Reactions occur in cytosol conjugation with glycine or taurine
Regulation of productCholesterolSynthesis:
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).
competitive inhibitors of lysophospholipase activity, inhibits lysophospholipid hydrolysis
PE PS PC
1,2-diglyceride (GPE) are
** CDP: cytosinediphosphate
Regulation of synthesis synthesized by the condensation of CDP-diacylglycerol with phosphatidylglycerols (PG).
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
- 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.
- 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
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.
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.