Download Lipids 2 - Website of Neelay Gandhi

Intro to lipids
Acyl group = Fatty Acid
Sphingolipids
ONLY in eukaryotes
Sphingomyelins
MOST Common
Galactocerebrosides Focus on this one too
Plants do NOT make cholesterol
Lipid Storage Disease
Fabry’s, Farber’s, Tay-Sach’s ****
Digestion of Lipids (Look at Stick Diagram)
Stomach, duodenum
Absorption
By small intestine
Pancreatic lipase hydrolyzes TAG to form 2-MAG & 2 Acyl chains
Lipolysis is accelerated by bile
Chylomicrons contain (requires B48 apoprotein)
TAG
Phospholipids
Cholesterol
Fat Soluble Vitamins
Why do they use lacteal system?
Fate of absorbed lipid (exogenous)
Glycerol (can become G3P  Glycolysis)
Cell membrane
Adipose
Beta oxidation
Produced by liver is endogenous
Lipid Catabolism
In adipocytes
Insulin activates lipase phophatase  deactivates Hormone Sensitive TAG Lipase A (active)
Epinephrine (Glucagon)  + cAMP  + Protein Kinase A  + HS TAG Lipase A – P
HSTAGL-A:
TAG  DAG + NEFA  3 NEFA + Glycerol
NEFA travel in body bound to albumin
Oxidation of Fatty Acids
Beta
Occurs mitochondria and peroxisomes
Alpha
Occurs in peroxisome
Omega
Occurs in Smooth ER
TAG is subjected to lipolysis by LPL
Before oxidation (in cytoplasm)
Activation Step
Thioester formed btw COOH & NEFA
Thiol group of CoASH  Acyl-CoA
Catalysed by thiokinase
Mitochondrial Matrix: LCFA ***
Carnitine
LCFA need carnitine to cross mito membrane
CPT1 inhibited by Malonyl-CoA & CHO-rich meal (why?)
Short & Medium can diffuse, but Long Chains need Carnitive
VLCFA use peroxisomes
Beta Oxidation
Draw on board and talk about
OHOL
Know enzymes
Energy chart (use chart)
Diseases
Look at website
Beta Oxidation of odd chain FA’s
Regular Beta oxidation until last 3
End up with Propionyl CoA  Succinyl CoA (glucogenic)
Beta Oxidation of unsaturated FA’s
Produces less energy
Uses Enoyl-CoA isomerase to change from cis to trans
Oleic, Linoleic, Linolenic use this pathway
Peroxisomes
Peroxisomal alpha oxidation
Shortening of fatty acid 1 C at a time
Two Functions:
Oxidation of branched chain fatty acids
Production of odd chain fatty acids found in brain tissue
Refsum’s Disease (know it)
Phytanic acid cannot be converted to Pristanic Acid  build up of phytanate and phytol
Last step goes to mitochondria for beta oxidation
Isobutyryl-CoA, Acetyl CoA and Propionyl-CoA  Succinyl CoA (glucogenic)
Beta oxidation
Difference: deals with VERY long chain fatty acids (>20 C)
Disorders
See Clinicals
Omega Oxidation
In Smooth ER
Ketone Bodies
Due to excessive Acetyl-CoA
High fat

High Beta Oxidation (So High Acetyl CoA)
Low carbohydrate

Gluconeogenesis (OAA gets taken away)
Types of Ketone Bodies
1.
Acetone
2.
Acetoacetate
3.
Beta-hydroxybutyrate
Ketogenesis chart (don’t have to know)
Liver can MAKE Ketone Bodies, but cannot USE them (no enzyme)
Enzyme: Succinyl-CoA:Acetoacetate transferase
Ketogenesis
HMG CoA Synthase is RATE LIMITING STEP
Utilization
Heart and Brain can use Ketone Bodies during starvation
Cardiac Cells prefer Ketone Bodies
Brain can use them grudgingly
Uncontrolled Diabetes
=
pathological
Fasting/Starvation
=
physiological
Print Insulin Cascade Chart and Explain Control and Hormones
Fatty Acid Synthesis (aka Biosynthesis)
CHO  Fat
Acetyl-CoA is precursor to FA synthesis
Glycolysis  Pyruvate  PDH  Acetyl-CoA  TCA
Fatty Acid Synthesis
Acetyl-CoA  ACCase  Malonyl-CoA  FAS  Palmitate  Modified to Long Chain Fatty Acid
Malonyl CoA inhibits CPT-1
Malate Citrate Shuttle (show picture and go over)
ACCase (Acetyl-CoA Carboxylase)
In mitochondria (why?)
Multifunction protein
Requires Biotin
Components:
Biotin Carboxylase
Transcarboxylase
Biotin Carboxyl Carrier Protein
Picks up CO2 from HCO3 and turns Acetyl-CoA to Malonyl CoA
Rate Limiting Step
Draw Control Picture (pg21 lipid packet)
Activated by Citrate
Inhibited by Palmitate
Phosphorylation is Deactivation
Insulin activates Phosphatase  removes Phosphate so activates ACCase
Glucagon/Epinephrine  Protein Kinase A (aka?)  phosphorylate ACCase (deactivate)
FAS
Types
I:
Multifunctional, in animals
II:
Multienzyme, in plants
III:
Elongase (we got it)
Three domains
Homodimer
CRDR
KAS
Domain I:
Condensation
Domain II:
Reduction and Dehydration (he’ll write oxidized i/o dehydration)
Domain III: Releases Palmitic Acid
Has thioesterase that releases thioester bond with ACP
Carbon Origin
Start with Acetyl CoA Synthase
Add Malonyl-CoA (3C) and lose CO2 (-1 C)
So, it will ALWAYS run 7 times
1st two carbons from Acetyl-CoA, last 14 carbons from Malonyl-CoA
Fate of Palmitic Acid
Elongation Reactions
In ER:
In Mitochondria:
Microsomal, Principle Way to Elongation
At Carboxy End
Two Carbons from Malonyl-CoA
ACCase occurs in cytosol
Uses Acetyl-CoA (why?)
1.
Malonyl-CoA will inhibit CPT-1
Because Acyl is out and cannot be brought in
2.
Bunch of ACCase in mitochondria
Desaturation of Fatty Acids
Mammals lack enzymes to desaturate beyond 9th position
Mammals cannot synthesize
Linoleic Acid (C18:2)
9, 12
alpha-linolenic acid (C18:3)
9, 12, 15
Arachadonic (C20:4)
5, 8, 11, 14
Omega Fatty Acids (ω or n)
Total # of carbons – Last double bond (highest #) = omega #
Oxidation and Synthesis (Page 27)
Read Chart Out
Regulation of Fatty Acids
ACCase is Rate Limiting Step, so regulated
Short Term
+ citrate
- Palmitoyl CoA
Long Term
Gene Expression
Increase in Glucose and decrease in fat (long term)
TAG Synthesis
Kennedy Pathway
Know Phosphatase Step (Control Step)
Three Acyl Transferase
Cholesterol
Acetyl-CoA  HMG  HMG CoA Reductase  Mevalonate  Isoprene  Squalene (30 C)
Isoprenaline + Isoprenaline (5 + 5)
10 C + Isoprenaline (5)
15 C + 15 C
 10 C
 15 C
 30 C (Squalene)
Squalene gets cyclised by Cyclase
 Lanosterol  - 3 C  Cholesterol (how many carbons? 27)
HMG CoA Reductase
Controlled by:
Hormonal Control
Glucagon phosphorylates and inactivates HMG CoA Reductase
Insulin dephosphorylate and activates HMG CoA Reductase
High cholesterol levels inhibits biosynthetic pathway by:
Increasing rate at which HMG CoA reductase is degraded (shortens ½ life)
Decreases rate of enzyme synthesis
Drugs
Look at website
Inactivated by Phosphorylation
ACCase, PDH, Glycogen Synthase, Bifunctional Protein, HMG CoA Reductase