Fatty Acids Flashcards
Fatty acids structure & 4 fxns
- Structure*: Long hydrophobic hydrocarbon tail + terminal carboxylic acid at one end
- Function*:
- Major long-term storage of energy in our body as triacylglycerides
- Endogenous fuel source during fasting (so the brain can keep using glucose)
- FA oxidation yields acetyl CoA that can be converted into ketone bodies, which after glucose is the main E for the brain
- Structural component of membrane phospholipids
General properties of lipids
- Heterogeneous
- Amphipathic (hydrophilic and lipophilic properties)
- Relatively insoluble in aqueous environments
- Compartmentalized in membranes, TG lipid droplets, lipoproteins, or associated with albumin
Why do unsaturated FAs make the membrane more fluid?
double bonds induce kinks in the membrane so FAs don’t pack as closely together
Nomenclature of FAs
The carboxylic acid carbon is #1; carbon#2 is alpha; carbon#3 is beta; the last one is omega.
of carbons:# of double bonds (delta#of carbon where double bound starts)
Animal sources generally contain ___ and ___ FAs.
Vegetable oils, seafoods, and fish oisl contain mainly ___ and ___ FAs.
Animal - saturated & monounsaturated FAs
Vegetable oils, seafood, fish oils - linoleate & polysunsaturated FAs
“-enoic acid” vs “-anoic acid”
“-enoic” = unsaturated FA
“-anoic” = saturated
How are omega-FAs named?
Numbered and named from their omega-carbon end.
Ex) “Omega-3” indicates the carbon that begins a double bond numbered this time from the w- end.
The most common saturated FAs are __ and ___.
What is the clinical importance of saturated fats?
Palmitic acid & Stearic acid
Saturated fats increase the risk of atherosclerosis, coronary heart disease, andstroke; negatively affectscholesterol
LImit it to <7% of daily caloric intake!
Palmitoleic acid & oleic acid are
common monounsaturated FAs in our diet
a-linolenic acid
eicosapentaenoic acid
docosahexaenoic acid
linoleic acid
arachnidonic acid
polyunsaturated FAs in our diet
Hydrogenation
Reducing cis-double bonds to saturated single bonds, increasing melting temp and shelf-life
Also increase trans-double bonds, which are implicated in cardiovascular risks
DHA & EPA are important w-3 FAs that can be generated from ALA (another w-3 FA)
What is their importance?
DHA is an essential nutrient in the brain and retina at all developmental stages
Both are important to prevent CVD (and other chornic diseases like HTN, stroke, cacner, inflammatory disease, etc)
ALA
EPA
DHA
Linoleic acid
ARA
a-Linolenic acid (ALA, 18:3, w-3): must be supplied in diet
Eicosapentaenoic acid (EPA, 20:5, w-3)
Docosahexaenoic acid (DHA, 22:6, w-3)
Linoleic acid: must be supplied in diet
Arachidonic acid (ARA, 20:4, w-6)- a prostaglandin/leukotriene precursor
What are the essential FAs (can’t be synthesized de novo, must get from diet)? What’s their importance?
a-Linolenic acid [18:3, delta9,12,15]: precursor for other w-3 FAs, including DHA and EPA
Linoleic acid [18:2, delta9,12]: precursor for the w-6 FA, ARA (substrate for prostaglandin synthesisis)
DHA & ARA are added in milk for growing children
Scaly dermatitis (ichthyosis) and visual or neurological impairments indicate
essential FA deficiency.
If linoleic acid is deficient in the diet
arachidonic acid becomes essential
Palmitic acid, Oleic acid, Linoleic acid, a-linolenic acid, arachidonic acid.
Saturated or unsaturated (mono or poly)? w-3 or w-6?
(Don’t need to know where the double bond is)
“SOLA” = 18’s with increasing #s of double bonds
Structure of triacylglycerol/triglycerides (form of free FA storage)
Glycerol backbone with 3 FA’s esterified to it (carboxylic acid group of each FA forms an ester bond to one of the OH groups on the glycerol)
The middle FA is usually unsaturated
Functions of TGs
- Storage form for most of our energy needs
- Physical cushion in adipocytes for organs
- Thermal insulation (brown fat)
- Carrier for the absorption and transport of fat-soluble vitamins (ADEK)
In the well-fed state, FAs are assembled into..
In the fasting state, FAs are…
Well-fed: FA assembled into TGs and stored into fat droplets in adipocytes.
Fasting state: FA are hydrolyzed from TGs and mobilized to other tissues for B-oxidation
TGs vs glycogen
FAs vs glucose
TGs are less hydrated (anhydrous) than glycogen, so they weigh less and take up less space.
FAs are more reduced than glucose, so they produce more energy upon oxidation.
Fat digestion begins with salivary and gastric lipases.
In response to lipids, the intestinal mucosa releases
- releases cholecystokinin (CCK)
- –> stimulate gallbladder to secrete bile
- –> stimulate pancreas to secrete lipases
Fat digestion in the intestine
- Bile salts emulsify fats into mixed micelles, increasing their accessibility to lipases
- TGs are degraded by the lipases to form free FAs and 2-monoacylglycerol
- Lipid-soluble components diffuse from the micelle into the intestinal mucosa while free FAs are converted back to TGs
- Mucosal cells package TGs, cholesterol, cholesteryl esters, phospholipids, and specific apolipoproteins (ApoB-48) into chylomicrons
Chylomicrons
apolipoprotein complex that transports dietary TGs to the peripheral cells
Composed of phospholipids, cholesterol, and apolipoproteins on the outside; TGs and cholesteryl esters on the inside
TG makes up the bulk of it
Cholesteryl ester
Cholesterol -OH group esterified to the carboxyl group of an fFA
Fat digestion after the intestine releases chylomicrons
- Chylomicron is released into the lymphatic system, then bloodstream to reach tissues
- In the capillaries, ApoC-II (a chylomicron apolipoprotein) activates lipoprotein lipase
- Lipoprotein lipase converts chylomicron TGs to free FAs and glycerol
-
Free FAs enter peripheral cells and are converted back to TGs for
- storage in adipocytes or
- oxidized for fuel in muscle cells.
Steatorrhea
Increase of lipids (esp vitamins & essential FAs) in the feces
Caused by disturbance of lipid digestion and/or absorption –> deficiencies
Tx: Increase short- and medium FAs in the diet because they don’t require incorporation into micelles to be taken up by intestinal mucosa
TG synthesis occurs where?
in the intestine, the liver, and adipose cells.
TG synthesis (well-fed state)
-
Glycerol 3-phosphate produced from
- DHAP reduction (in liver and adipose) or
- Glycerol phosphorylation (in liver)
- FA chain is activated by CoA
-
Acyl transferase attaches FA to carbon-1 of glycerol-3-phosphate, then again to carbon-2 –> phosphatidic acid
- This can also be a substrate for phospholipid synthesis.
- Phosphatidic acid phosphatase removes the phosphate at carbon-3 –> 1,2-Diacylglycerol (DAG)
- Acyl transferase attaches FA to carbon-3 of DAG –> TG
Why is the liver able to make TGs whether well-fed or fasting?
- It has both
- G3P dehydrogenase to turn DHAP (well-fed) to G3P
- Glycerol kinase to turn Glycerol (fasting) into G3P
In contrast, adipose cells only have G3P dehydrogenase
In the fasting state, what happens when adipocytes hydrolyze TGs into free FAs and glycerol?
Glycerol goes to the liver for phosphorylation
Free FAs leave to be used by other cell types.
This set up prevents the reverse reaction (fFAs turning back into TGs) from happening in the adipocyte.
Hormonal mobilization of adipose TGs
- Glucagon/epinephrine signal through GPCRs to elicit a cAMP-dependent 2nd msger cascade to PKA
-
PKA phosphorylates and activates hormone-sensitive lipase and perilipin
- Perilipin coats fat droplets; unphosphorylated, it prevents lipase from penetrating
- Lipase penetrates and hydrolyzes TGs into glycerol and free FAs
- Free FAs enter the blood and ride on serum albumin to enter other cell types
- In muscle cells, they are oxidized as fuel
After TG hydrolysis in peripheral tissues, what happens to the fFAs and glycerol in well-fed vs fasting states?
-
Free FAs:
- Half used by peripheral tissue for E
- Half go to the liver to be repackaged into new TGs that are
- exported to the peripheral cells (fasting)
- stored back in adipocytes (well-fed)
-
Glycerol: Go to the liver may be used for
- gluconeogenesis (fasting)
- turned into G3P for TG synthesis (well-fed)
Insulin
- stimulates the synthesis and secretion of
- inhibits hydrolysis of
Insulin (well-fed)
- stimulates synthesis and secretion of lipoprotein lipase by adipocytes to hydrolyze TGs in circulating apolipoprotein complexes
- The liver uses the fFAs to make new TGs, which are exported for other peripheral cells.
- The adipocytes use the fFAs to make new TGs in fat droplets
- Inhibits hydrolysis of TGs
Muscle cells’ use of TGs in the well-fed vs fasting state
Whats the exception?
Well-fed: Muscle cells want to use glucose - not TGs- so they don’t express lipoprotein lipase.
Fasting: glucose needs to be reserved for the brain, so muscle cells express lipoprotein lipase as a mechanism to gain an alternate fuel source - fFAs.
Cardiac muscle always secretes lipoprotein lipase bc they get most of their E from FA metabolism.
B oxidation is activated by fasting, prolonged exercise, and glucagon/epinephrine.
Where does it occur? What are the products?
Mitochondrial matrix
1 NADH, 1 FADH2, and 1 Acetyl CoA (can be oxidized or turned to ketobone bodies)
Activation of FA - How/where/when does it occur?
- Mobilized FAs from adipocytes enter the cytosol
- Fatty acyl CoA synthetase activates it w/ CoA
- Transport into the mitochondria for B-oxidation
FA-Carnitine shuttle uses two enzymes, ____ on the ___membrane and ___ on the ___ membrane to move FA-CoA into the __
Carnitine acyl transferase I (CAT I) in the OMM
Carnitine acyl tranferase II (CAT II) on the IMM
Move CoA from cytosol into the mitochondrial matrix
CAT I turns FA-CoA to FA-Carnitine, which passes thru the OMM AND IMM into the matrix. CAT II in the matrix turns it back to FA-CoA, releasing free carnitine to shuttle back out to the cytosol.
Carnitine can be produced from our liver and kidney, but most is obtained from diet.
Primary vs secondary carnitine deficiency
-
Primary carnitine deficiency:
- Autosomal recessive
- CAT I or CAT II malfunctions or Improper renal absorption of carnitine/carnitine trasnport
- –> Liver can’t utilize LCFAs for fuel
- Encephalopathy, hypoglycemia, coma, death in infancy/childhood
-
Secondary carnitine deficiency caused by
- liver disease (inadequate carnitine)
- malnutrition
- increased carnitine requirements (pregnancy, burns, trauma)
- hemodialysis
Tx of carnitine defciencies
high carb, low LCFA diets
Carnitine & MCFA supplements
Monitor glucose to avoid hypoketotic hypoglycemic encephalopathies
B oxidation is 4 repeating reactions:__,__,__,__
It shortens the fatty acyl chain from the carboxyl end by __ carbons to generate FADH2, NADH, and acetyl CoA
- Oxidation by acyl-CoA dehydrogenase –> FADH2
- Hydration by enoyl-CoA hydratase
- Oxidation by B-hydroxyacyl CoA dehydrogenase –> NADH
- Cleavage by acyl-CoA acetyltransferase
Shortens the chain by 2 carbons
All rxns occur between a- and B-carbons.
Palmitate’s B oxidatoin yields 7 FADH, 7 NADH, and 8 acetyl-CoA.
In total, B oxidation of palmitate yields 108 ATP
Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)
- AR
- Deficiency in the acyl-CoA dehydrogenase for medium-length acyl chain (6-10 carbons)
- –> Accumulation of octanoic acid in blood; hypoglycemia; muscle weakness; sleepiness; vomiting; coma
- High 6-10C mono- and dicarboxylic acids in urine
- Sudden infant death syndrome (SIDS)
- Tx (children can live healthy lives):
- Low fat, high carb diet
- Avoid fasting
w-FA oxidation is a minor route used for ___ oxidation (10-12C).
Where does it occur and what does it produce?
For MCFA oxidation
Occurs in the ER of liver and kidney cells
Carboxylic acid is produced at the w-end, making the FA a dicarboxylic acid that can undergo B-oxidation in the mitochondria
Why do you see dicarboxylic acids in urine for MCADD?
MCADD prevents normal B-oxidation
–> w-FA oxidation is upregulated, producing dicarboxylic acdis
Normal B-oxidation produces acetyl CoA
B-oxidation of odd-numbered FA produces ___, which can be converted to ___.
Produces proprionyl CoA, which can be converted to succinyl CoA (a CAC intermediate)
What 2 cofactors are required to convert propionyl CoA from odd chain length FAs to succinyl CoA?
Biotin adds CO2 to produce methylmalonyl-CoA
Vitamin B12 is required for a mutase to convert L-methylmalonyl-CoA to succinyl-CoA
Methylmaloinic acidemia is caused by
problem with the mutase that turns L-methylmalonyl-CoA to succinyl-CoA
–> can’t oxidize odd-chain length FAs, branched amino acid chains, or replenish key CAC intermediates.
3 ways that oxidation of very long-chain FAs (VLCFAs, 20+ C’s) is different from normal B-oxidation
- Occurs in the peroxisome
- Transport into peroxisome doesn’t require carnitine
- In the initial oxidation reaction to produce the delta2 trans-enoyl-CoA and FADH2, the FADH2 is oxidized back to FAD and O2 is reduced to H2O2
- Eventually<strong> VLCFAs are oxidized to MCFAs and SCFAs</strong> –> they leave peroxisome with acetylCoA as carnitine derivatives and<strong> enter the mtiochondria</strong>
Two disease states result in elevated VLCFA levels in blood and tissues:
Zellweger
X-linked adrenoleukodystrophy
- Zellweger syndrome: inability to target peroxisomal matrix proteins to the peroxisome
- X-linked adrenoleukodystrophy: inability to transport VLCFAs across peroxisomal membrane
a-oxidation: oxidize branched-chain FA
- Occurs in the peroxisome
-
a-hydroxylase introduces an -OH on a-carbon and removes the carboxyl group
- The old a-carbon is now the new carboxyl-carbonn –> normal B-oxidation yields 3C propionyl-CoA, instead of acetylCoA
Refsum Disease
- Genetic defect in Phytanoyl-CoA hydroxylase (the a-hydroxylase involved in the a-oxidation of Phytanic acid)
- –> high levels of Phytanic acid in blood & tissues
- Severe neurological problems: chronic polyneuropathy, cerebellar dysfunction, blindness, deafness
- Tx: don’t eat foods w/ phytanic acid
FA synthesis is the reverse of B-oxidation and occurs in the cytosol (esp in hepatocytes and adipocytes).
What are the steps
Synthesis: condensation > reduction > dehydration > reduction
In every round of FA synthesis, 2-carbon acetyl units are incorporated in the growing FA chain.
This acetyl unit is donated from ___
malonyl CoA, a 3 carbon molecule.
During condensation, CO2 is removed and the remaining acetyl group is donated.
What enzyme makes acetyl CoA -> malonyl CoA for FA synthesis?
How does this enzyme work?
Acetyl-CoA carboxylase
-
Biotin carrier protein swings between two domains
- In the biotin carboxylase domain, biotin becomes carboxylated & activated with CO2 –> swivel to..
- In the transcarboxylase domain, the CO2 is donated to acetyl-CoA to form malonyl CoA
The carnitine shuttle is a point of FA regulation (once in, you can’t get out), but what is the main regulation of synthesis vs oxidation?
-
Wellfed: Acetyl-CoA carboxylase (ACC)isunphosphorylated & active
- Acetyl-CoA –> malonyl CoA for FA synthesis
- Also inhibits CAT I to prevent B oxidation
- Fasting: ACC is phosphorylated & inactive, malonyl CoA is low –> B oxidation prevails
In the well-fed state, blood glucose and insulin is high. What does this do to ACC?
- Insulin activates a phosphatase that maintains ACC in unphosphorylated & active state
- Glucose > pyruvate > acetyl CoA > *malonyl CoA*
- –> malonyl CoA inhibits CAT1 and is used for FA synthesis
ACC is activated by
insulin & citrate
remember how citrate part of how mitochondrial AcetylCoA is transported into the cytosol
LCFAs & Glucagon’s impact on ACC
- Glucagon stimulates PKA to phosphorylate ACC into its inactive form
- –> stimulates B oxidation since CAT I are free
- LCFA also inhibits ACC –> B oxidation of LCFAs
Why are ketone bodies produced during fasting?
During fasting, free FA can be broken down in the liver into acetyl-CoA and ultimately to ketone bodies that enter the bloodstream and can be used by other tissues (muscle) for energy, thus saving the glucose for the brain (though it can also use KBs)
The ketone bodies are __ and __.
What happens to them in muscle tissue?
acetoacetate & B-hydroxybutyrate
Converted back to acetyl CoA in muscle tissue and oxidized for energy.
Explain why T1 diabetes is associated with acetone breath, ketonemia, ketonuria, and diabetic ketoacidosis
In a T1D, circulating glucose isn’t taken up by cells –> fFAs are oxidized and KBs are produced.
Acetoacetate can spontaneously decarboxylate into acetone –> acetone breath, ketonemia, keonuria, and diabetic ketoacidosis
Compare and contrast teh structures of FAs, TGs, sphingolipids, glycolipids, and cholesterol
FA: long hydrocarbon tail w/ terminal carboxylic acid at one end
TGs: glycerol back bone with 3 esterified FA chains
Sphingolipids & glycolipids: sphingosine backbone with an amide-linked FA + phosphate + polar group (glycolipid doesn’ thave the phosphate
Cholesterol: 4-ring steroid structure, with a hydrophilic OH group and an acyl tail at the other
Hwo does phospholipid synthesis differ from TG synthesis?
TG synthesis: 2 FAs are activated by acyl-CoA synthetase, and then esterified by acyl transferase at C1 & C2 to glycerol-3-phosphate –> phosphatidic acid. The phosphate group is removed and a third FA is activate dand esterified at C3.
Phospholipids: Instead of removing the phosphate group of phosphatidic acid, a polar head group is added
