Professional Documents
Culture Documents
Overview
Digestive lipid metabolism De Novo Synthesis of Fatty acid Synthesis of Triacylglycerols Mobilization of Stored Fats and Oxidation
of Fatty acids
Overview (cont.)
Phospholipid Metabolism Glycolipid Metabolism Metabolism of Prostaglandins and
Related compounds
Cholesterol Metabolism
Blood Lipoproteins
lipase activity
- detergent property of bile salt and peristalsis
> Pancreatic activity
A. Hormonal Control of Lipid Digestion 1. CCK/pancreozymin (+)GB contraction and release of bile; release of pancreatic enzymes; dec. gastric motility 2. Secretin - (+) bicarbonate secretion
1. Triacyglycerol hydrolysis - TAG are acted upon by pancreatic lipase and removes FA at carbon 1 and 3
- products = 2-monoacylglycerol + FA
2. Cholesteryl ester degradation - Cholesterol esterase
- Products: Cholesterol + FA
3. Phospholipids degradation - phospholipase A2 - products: lysophospholipid + FA
Absorption of Lipids by intestinal mucosal cells - FFA, free cholesterol, 2-monoacylglycerol and lysophospholipid together with bile salts from
Excess Cholesterol
Bile
Cholesterol
Cholate
OH
COO -
HO
Cholesterol 7-hydroxylase
HO
OH
Bile Salts
Breakdown products of cholesterol Amphipathic molecules Function to transport cholesterol in the
digestive system
Cholesterol
Bile Salt Phospholipid
Functions of Micelles
Transport cholesterol from the liver into
Bile
ABCG5/G8 Cholesterol
ABCB4 Phospholipid
ABCB11
Canalicular Membrane
Bile Salt
Biliary Lipids
Lipid Class
Bile salts Phospholipids Cholesterol
Jejunum
Ileum Colon
Fat Digestion
Liver Biliary Transport and Storage Duodenum
Jejunum
Ileum Colon
Fat
Dietary Cholesterol
I I I
I I I
I I I I I I
Fat Absorption
Liver Biliary Transport and Storage
Duodenum
Jejunum
Ileum Colon
Cholesterol Absorption
Lymph
Enterocyte
Intestinal Lumen
Cholesterol
ACAT
Cholesteryl Ester
Triglyceride Absorption
Lymph
Enterocyte
Intestinal Lumen
2 Fatty Acid
+
Monoglyceride
DGAT
Triglyceride
Phospholipid Absorption
Lymph
Enterocyte
Intestinal Lumen
Fatty Acid
+
Lysophospholipid
Phospholipid
Chylomicron Formation
Lymph
Enterocyte
Phospholipid Triglyceride
Intestinal Lumen
With apoB48
Cholesteryl Ester
complex
AcetylCoA-ACP transacylase MalonylCoA-ACP transacylase
-ketoacyl-ACO synthase
Palmitoyl thioesterase
Acetyl CoA
and Citrate
Carboxylation of AcetylCoA
Regulators of
Activators:
Coenzyme: Biotin insulin,Inc. CHO intake, fat-free diet Inhibitors: malonyl CoA, palmitoyl CoA,epinephrine, fasting, high fat diet
multienzyme complex
Substrate: AcetylCoA
and MalonylCoA End Product: Palmitic acid Site: Cytosol Priming Molecule: Acetyl CoA Rate-limiting enzyme: Acetyl CoA carboxylase Primary enzyme of synthesis: Fatty acid synthase
Carbons 1-14 of palmitic acid are derived from 7 malonyl CoA ( 2 carbons from malonyl CoA are added 7 times to the priming acetylCoA molecule NADPH + H+ are from HMPShunt
1 AcetylCoA + 7 malonylCoA + 14 NADPH+ 14 H Palmitic acid + 7 CO2 + 6H2O+ Co-A-SH +14 NADP
2. Acetyl-S-ACP + Enzyme SH
3. MalonylCoA + ACP-SH
Acetyl-S-enzyme + ACP-SH
4. Malonyl-S-ACP + Acetyl-S-enzyme -ketoacyl-ACO synthase Acetoacetyl-SACP + CO2 5,6,7 Three steps: 2 reductions + dehydrogenation step: converts ketoacyl group to saturated acyl group The cycle of reactions is repeated 7X, each time incorporating a two-carbon unit from malonyl CoA into the growing fatty acid chain Palmitoyl-S-ACP + H2O Palmitoyl thioesterase Palmitate + ACP-SH
Synthesis of Triacylglycerol
Synthesis of Triacylglycerol
carbons Oxidation: produces FADH2 Hydration: produces NADH Thiolytic cleavage: produces 2 acetylCoA
7NADH x 3 ATP by ETC oxidation 7 FADH2 x 2 ATP by ETC oxidation 8 Acetyl CoA x 12 ATP via Krebs CAC Total (Gross) Less
NET
129 ATP
Renal cortex
Brain
KETOGENESIS
Liver cannot use acetoacetate as fuel ( lacks thiophorase : enzyme for the conversion of acetoacetate to acetoacetylCoA
to 2 acetylCoA which are oxidized by the TCA
Conditions
Starvation Severe DM Rapid mobilization
of fat
Result to ketonemia
AcetoacetylCoA is converted
ketoacidosis
Cholesterol Synthesis
Cholesterol Balance
Duodenum
Jejunum
Ileum Colon
Fecal excretion (0.4 g/d)
Duodenum
Jejunum
CM apoB48
Absorption ~50%
Ileum Colon
Fecal excretion (1.2 g/d)
Cholesterol Balance
Synthesis (1.2 g/d)
Liver
Cholesterol Bile salts
Duodenum
Jejunum
Ileum
Colon
Cholesterol
LDL
Cholesterol
ACAT
NPC1L1
Cholesteryl Ester
ABCG5/G8
Cholesterol
ACAT
NPC1L1
Ezetimibe
Cholesteryl Ester
ABCG5/G8
CM apoB48
Triglyceride
Cholesteryl Ester
Liver Duodenum
VLDL apoB100
Ezetimibe
Jejunum
Ileum
CM Remnant apoB48 CM apoB48
Colon
Dual Inhibition
Presence of Triglycerides
MTP ApoB
MTP
Cholesteryl Esters
Cholesterol
Dietary/Biliary
Synthesis
Presence of Triglycerides
MTP ApoB
MTP
Cholesteryl Esters
Ezetimibe
Dietary/Biliary
Cholesterol
Synthesis
MTP ApoB
MTP
Cholesteryl Esters
Ezetimibe
Dietary/Biliary
Cholesterol
Statin
Synthesis
Dual Inhibition
LDL apoB100
Liver Duodenum
X
VLDL apoB100
Statin
Ezetimibe
Jejunum
Ileum
CM Remnant apoB48 CM apoB48
Colon
Conclusions
Cholesterol balance is regulated by both synthesis
and absorption
Inhibition of cholesterol absorption may be
The very first symptom for 1/3 of all the heart attacks that occur each and every day is . . .
INSTANT DEATH !
Stress, Smoking, Lack of exercise, Poor nutrition and of course, Genetics all contribute to HEART DISEASE! But the real culprit is,
HIGH
CHOLESTEROL!
Hepatic Tissue
Extrahepatic Tissue Outside Cells Connective Tissue (Blood) Within Cell Membranes
Cholesterol is needed
Cholesterol esterification for transfer from one
lipoprotein (HDL) to other lipoproteins (VLDL, IDL & LDL) Bile synthesis for emulsification of dietary fat Steroid hormone synthesis Androgens Estrogens Corticosteroid Glucocorticoids
binds to the liver Cholesterol is transferred to other lipoprotins (VLDL, LDL, IDL) Lecithin/Cholesterol AcylTransferase (LCAT) converts cholesterol to cholesteryl esters Cholesterol esters transferred to other lipoprotein (VLDL, LDL, IDL)
wall as part of repair of disrupted endothelial lining due to endothelial dysfunction if the carrier LDL is oxidized
metabolism Tissues need cholesterol for hormone synthesis to modulate membrane fluidity
Framingham Study
70% of men with Coronary Heart Disease (CHD) had <44
mg/dL HDL-cholesterol
1.5 % risk 7.2 % risk
if
HDL-c
> 35 mg/dL
if t-chol/HDL-c > 5 HDL-c & Trigly are low if t-chol/HDL-c > 5 HDL-c < 35 mg/dL Trigly > 200 mg/dL
11.5 % risk
LDL-c
107 mg/dL
Evaluation: The low HDL-c is a high risk for Filipinos
(including arteries) to the liver Removing cholesterol from arterial wall Inhibiting growth of new plaques
Enhances stability of plaques and inhibits plaque
rupture
Provides cholesteryl esters to LDL Protects LDL-cholesterol from oxidation by acting as a good anti-oxidant when HDL
attaches to LDL
vascular endothelium Reduced adhesion of leukocytes (early phase of atherogenesis), prevent formation of new plaques, maintain integrity vascular endothelium
Phospholipid Synthesis
Desaturation of Stearoyl-CoA
Functions of PPAR
PPAR gamma plays a critical role in the regulation of
cholesterol homeostasis by controlling the expression of a network of genes that mediate cholesterol efflux from cells Responsible for degeneration of ABC-I, cholesterol transporter from the cells to HDL-3 transport in plasma Inhibits production of apolipoprotein & C3 which destroys Apo-B (ligand that binds LDL to its receptors) and LDL accumulates Apo-B ligand function can also be destroyed y oxidation of the protein
kappa B (NFkB), a nuclear receptor normally at rest in the cell but may be activated during atherosclerosis
Produce cellular or macrophage apoptosis
PUFA (omega-3 ?)
LipoProteins