Week 8 Flashcards
lipid metabolism
Fatty acids (FA) (function, synthesis, stimulator)
used as fuel in the body
Synthesized from glucose
Stimulated by insulin
Triacylglycerol (TAG)
Function, synthesis, transport/location
is the storage form of FA made in the liver.
Major dietary lipid
Travel in circulation as chylomicrons (dietary) or VLDL (endogenously synthesized)
How are Dietary Lipids digested?
Emulsified in small intestine by bile salts and Pancreatic lipase and colipase
Pancreatic lipase and colipase function
Hydrolyzes TAGs into free FAs and esterified glycerol
pancreatic esterases function
remove fatty acids from other compounds (cholesterols, etc)
What happens to Lipid/Bile micelles
Lipid portion is absorbed into the intestinal epithelial cells
(Chylomicrons)
Bile is resorbed in the ileum, to be re-used.
Do short and medium FA chains need bile?
No, they are absorbed directly into cells & will enter blood, transported by serum albumin
Synthesis of Chylomicrons
- Free FAs and 2-MG are re-formed into TAG in the intestinal smooth endoplasmic reticulum
- TAGs must be transported in lipoprotein particles due to insolubility
chylomicrons function
Transport of dietary fats
Newly released chylomicrons are called ‘nascent’
ApoE
ligand for membrane receptors on many cells (esp liver), allows entry into cell
ApoCII
activator of lipoprotein lipase (LPL)
Capillary endothelial cells, muscle and adipose tissues
chylomicron maturation
HDL in lymph and blood will transfer proteins to chylomicron, ‘maturing’ it
What tissues use oxidation of FA as a fuel source? And when?
primary fasting fuel source in cardiac, skeletal muscle, and liver
What tissues use the conversion of FAs to ketone bodies?
major fasting fuel source for brain, gut, etc.
Long Chain FAs are a predominant source of…
predominant source of oxidation for fuel during fasting states
Transport of Long Chain FAs
what releases them, how it travels through the blood, how it gets to the liver, and final destination when in the cell
Released from adipocytes by lipases
Travel in hydrophobic pocket of albumen through the blood
Transported into cell either via passive diffusion through bilayer or facilitated with fatty acid binding protein
Inside the cell, the FA is transported to mitochondria
Activation of Long Chain FAs
Must be activated by acyl-CoA before they can be oxidized
Acyl-Coa synthetase only activates…
long chain FAs, and is in ER, outer mitochondrial membrane, and peroxisome membrane
Very long chain synthase location
present in peroxisomes
medium chain synthetase location
present in mitochondrial matrix of liver and kidney cells.
Transport of Long Chain FA into MT
Carnatine serves as the transporter between outer and inner mitochondrial membranes
β-Oxidation
Sequentially cleaves the fatty acyl group into 2C acetyl-CoA units, starting with the carboxyl end attached to the CoA.
β carbon must be oxidized first
β-Oxidation: step 1
double bond formed between β and α carbons
β-Oxidation: step 2
water donates OH to β-carbon; and H to α-carbon
β-Oxidation: step 3
hydroxyl group of β carbon oxidized to a ketone
β-Oxidation: step 4
bond between α and β carbons is cleaved by adding a coenzyme A (CoASH) to the βcarbon
Energy Yield of β-Oxidation
1 mole of palmityl-CoA converted to 8 mole of acetyl CoA yields:
28 mole ATP
Oxidation of Odd-Chain-Length FAs
Will undergo β oxidation rounds until there are 5 carbons left
Oxidation of Medium-Chain FAs
Activated to acyl-CoA derivatives, then oxidized to acetyl CoA via β-oxidation spiral
Medium-chain-length acyl-CoA synthetase has a broad range of…
specificity
Can bind drugs which are approx. same size
Salicylate (aspirin metabolism) and Valproate (anti epileptic)
where are very long chain FAs oxidized?
exclusively in peroxisomes
what tissues can not use FAs as fuel source?
RBCs (no mitochondria!)
Adipocytes
Brain
Ketone bodies function
serve as major source of energy in these tissues
where are ketone bodies synthesized? released? what is it converted into?
Synthesized in liver from acetyl CoA (generated in β-oxidation)
Released into the blood as ketone bodies – re-converted to acetyl CoA in tissues for TCA cycle
Ketogenic diets
High protein, low carb diets are considered ‘ketogenic’
High amounts of ketogenic amino acids
How is Ketogenesis regulated?
inhibited by insulin and feeding
activated by fasting and increases in cAMP and lipolysis
Skeletal muscle preferences for Fuel Sources
Skeletal muscle will preferentially use FAs over glucose as fuel as FA concentration increases in blood
FA Synthesis
what stimulates it, location, precursor, products
Stimulated when excess calories are ingested.
Occurs primarily in the liver, process begins with glycolysis, citrate from glycolysis moves to cytosol and reforms acetyl CoA. Acetyl CoA is converted to malonyl CoA.
What is FA Synthase Complex? What does it create?
Large enzyme complex, many subunits. Creates 16 C long chain called palmitate
Activation and conversion of Palmitate
Activated to Palmitoyl CoA
Converted to TAG in the liver
De-saturation of Fatty Acyl CoA
location, molecular requirements, restrictions
Occurs in endoplasmic reticulum
Requires NADH, O2, and cytochrome b5
Some cannot be synthesized, so must be obtained from diet
Omega 3 fatty acids (ω 3 FA) and Omega 6 fatty acids (ω 6 FA)
Synthesis of TAG and VLDL
Occurs in the liver and adipose tissue using G3P from glycerol or DHAP
Lipoprotein lipase (LPL)
Delivers of VLDL TAGs. Cleaves TAG into FA and glycerol
Km of muscle LPL
Has a low Km. Allows it access to fuel source even when levels are low
Km of adipose LPL
Has a high Km. Will only work in fed state (storage)
Fasting – Adipocytes Release FA
When insulin is low, adipocytes will break down their stores of TAGs into FAs and glycerol
Hormone sensitive lipase
Glycerophospholipids and Sphingolipids are lipids that aren’t used for fuel. What other functions do they have?
Cell membranes (phosphatidyl choline, etc) Signaling molecules (PIP2, arachidonic acid, etc) Myelin sheath (sphingomyelin)
Synthesis of Glycerolipids
Glycerol 3-P + 2 activated FAs form phosphatidic acid
Hydrophilic head-groups are added to third carbon of the glycerol
Polar uncharged OR charged
Degradation of Glycerophospholipids
Phospholipases in cell membrane or lysosomes degrade glycerophospholipids
Cholesterol synthesis: Part 1
Synthesis of mevalonate from acetyl-CoA
Committed and rate limiting step
Cholesterol synthesis: Part 2
3 phosphates are added to mevalonate to activate it
Forms activated isoprenes (5 carbons)
isomers
Cholesterol synthesis: Part 3
Six of these activated isoprenes are condensed to eventually form Squalene
Cholesterol synthesis: Part 4
Forming ring structures from the squalene
VLDLs transport
Transport endogenous fats
Liver to peripheral (muscle, adipose)
IDLs transport
Remnants of VLDLs not taken up by the liver
Still contain some TAGs and cholesterol
LDLs transport
low density lipids
After some TAGs removed from IDL (usually to liver)
Rich in cholesterol
Deliver to liver (~60%)
Deliver to adrenocortex, gonads, etc (steroid synthesis)
HDL and Reverse Cholesterol Transport
Maturing HDLs are picking up cholesterol of tissues
To prevent it from diffusing back to the tissues, LCAT within the HDL will convert it to a cholesterol ester, thus trapping it inside the HDL
HDL will then deposit the excess cholesterol back to the liver
Cholesterol ester transfer protein (CETP)
mediates the swapping of TAGs with cholesterol esters between VLDLs and HLDs
Apoproteins function
serve as receptor ligands/directing to specific tissues
maturation of HDLs
Accumulate phospholipids and cholesterol from vascular endothelial lining
Fills the empty inner core of the nascent HDL, becomes more round = mature HDL
