Fat Metabolism Flashcards
___ ___ ___ ____ can generate a lot of acetyl CoA. In the liver, Acetyl CoA from beta-oxidation can be used to synthesize ___ ____, which other tissues can use as a metabolic fuel.
Fatty acid beta-oxidation
Ketone bodies
Fatty acid beta-oxidation occurs in the ____. It has the the highest ____ generating potential compared to other metabolic pathways.
Mitochondria
Energy
Fatty acids consumed in the diet and synthesized de novo are stored in ____ as _____.
Adipocytes
Triacylglycerides
- Short chain fatty acids: ___ or less carbons
- Medium chain fatty acids: ___ to ___ carbons
- Long chain fatty acids: ___ to ___ carbons
- Very long chain: __ or more carbons
6
6 to 12
13 to 21
22
____ fatty acids are solid at room temperature. _____ (double bonds) fatty acids have a lower melting point.
Saturated
Unsaturated
____ and ___ fatty acids are essential in the diet.
Linoleic
Linolenic
____ ___ ____ cuts the first fatty acid from triglyceride to make diacylglyceride. ___ ___ ____ then cuts off the remaining fatty acids.
Adipocyte triglyceride lipase
Hormone sensitive lipase
Adipocyte triglyceride lipase cuts the first fatty acid, forming ___ which is transported into the cytoplasm by ___ ___. The fatty acid transporter is a complex with ____.
Palmitate
Serum albumin
CD36
Insulin ____ hormone sensitive lipase. Glucagon ____ it.
Inhibits
Activates
Fatty acids are transported into the cytoplasm by binding the extracellular Ligand domain of ____, this domain is composed of ____ amino acids to facilitate binding to fatty acids.
CD36
Hydrophobic
Palmitate is activated by linkage to _____. This reaction is catalyzed by ____ ____ ___ ____. There are different synthetases for different chain lengths
CoASH
fatty acyl CoA synthetase
palmitoylCoA must cross the impermeable ___ ____ ___ in order for Beta-oxidation to take place. This occurs via ____ ___.
Inner mitochondrial matrix
Carnitine shuttle
____ ____ is transported across the inner mitochondrial membrane
Fatty acylcarnitine
In the fasted and starved states, the body wants to ____ fatty acids and the carnitine shuttle is ___.
Burn
Active
____ ____ ____ I is a major regulator of fatty acid catabolism. Malonyl CoA is an Allosteric _____ of CPT I. Insulin promotes the production of malonyl CoA. ____ inhibits the production of malonyl CoA by inhibiting ___ ___ ___ (ACC).
Carnitine palmitoyl transferase
Inhibitor
AMPK
acetyl CoA carboxylase
CPT I deficiency is an inherited autosomal recessive disorder. It is the failure to import fatty acids into the ____, resulting in ____ ____ in the fasted state.
Diagnosis: increased free ___, ___, and free ___ ___ in the blood.
Mitochondria
Hypoketotic hypoglycemia
Carnitine, acyl-CoA, and fatty acids
CPT II is also an inherited autosomal recessive disorder. Three types:
1. Adult onset: characterized by ___ pain, ___, and ____ after prolonged exercise or fasting
2. Neonatal onset
3. Infant onset
Both are characterized by ____, ___, and often fatal.
Diagnosis: increased long chain ___ ___ ___ molecules in the blood.
Muscle
Weakness
Myoglobinuria
Hypoglycemia
Irritability
Fatty Acyl Carnitine
Beta oxidation of fatty acids is a multiple step process. In each cycle, two ___ of the fatty acid chain are oxidized to ___ ___.
4 steps:
___, ___, __, and ___
Carbons
acetyl-CoA
Oxidation, hydration, oxidation, cleavage
Palmitoyl CoA:
The ___ carbon is the first carbon away from the functional group. The ___ carbon is the second carbon away from the functional group.
Alpha
Beta
Beta oxidation of long chain fatty acids overview:
At the end of beta oxidation of long chain fatty acids, one acetyl CoA can be used in the ___ ___, producing a total of ___ ATP.
TCA cycle
10
There are a total of ___ acetyl CoA molecules made from 1 mol of palmitoyl. ___ FAD and ___ NADH are made. Leading to a total of ___ ATP.
8
7
7
106
Summary of beta-oxidation of palmitate:
Beta oxidation of a twenty carbon fatty acid such as ___ ___ yields ____ ATP.
Stearic acid
134
Medium chain Acyl CoA dehydrogenase deficiency (____) is frequent in northwestern European ancestry. It presents in infants with fasting ____ ___, hepatic encephalopathy, and sudden death.
Diagnosis: elevated medium chain ____ in the blood.
Prognosis: if identified before severe hypoglycemic episodes it’s okay. Fasting tolerance improves with age.
MCAD
Hypoketotic hypoglycemia
Acylcarnitine
____ ___ ___ has a similar presentation to MCAD. It occurs after eating unripe ackee fruit which contains ____, which inhibits medium and short chain acyl CoA dehydrogenase.
Jamaican vomiting sickness
Hypoglycin
In summary, during fasting, the decreased insulin/glucagon ratio stimulates ___ ___ ___ to free fatty acids from triacylglycerols stores in adipose tissue. The free fatty acids then travel to energy requiring tissues where they undergo ___ ___ in the mitochondria to produce energy.
Hormone sensitive lipase
Beta-oxidation
The ____ cannot use fatty acids as fuel because they can’t cross the ___ ___ ___. Instead, the liver converts fatty acids into ___ ___, which can be used in the brain.
Brain
Blood brain barrier
Ketone bodies
Regulation of ketone body synthesis:
In the fasted state, hepatocytes do not consume much ___. Increased levels of beta-oxidation in the liver results in abundant ___ and ___ __.
ATP
NADH
acetyl CoA
Regulation of ketone body synthesis:
Elevated levels of NADH in the liver drives the TCA cycle ___, oxaloacetate is converted to ___ which is then used in gluconeogenesis. The reduction of oxaloacetate diverts the acetyl CoA into ___ ___ ___, rather than the TCA cycle.
Backwards
Malate
Ketone body synthesis
Ketone body synthesis in the liver requires three molecules of ___ ___ which form the branched ________ ___. Removal of one acetyl CoA leaves the ketone acid ____.
Acetyl CoA
3-hydroxy-3-methylglutaryl CoA
Acetoacetate
Acetoacetate is reduced to ____ which is the most abundant ketone body. Acetoacetate can also be decarboxylated to ____ non-enzymatically, which is responsible for the characteristic fruity breath in a person in ketoacidosis.
Hydroxybutyrate
Acetone
Ketone body production is driven by ___ ___ ___ ___. It produces acetyl CoA, the substrate for ketone body synthesis. It also produces ____ which drives acetyl CoA towards ketone body synthesis rather than the TCA cycle.
Fatty acid beta oxidation
NADH
Ketone bodies produced by the liver can be used as fuel by the ___, ___, and ___ __. They are converted back into acetyl CoA and oxidized in the ____ ___.
Brain, heart, skeletal muscle
TCA cycle
____ is the depression of blood pH by excessive ketone body production. It can be caused by starvation or diabetes.
Ketoacidosis
Ketone body production is a compensation for ____. The absence of elevated ketone bodies in a hypoglycemic patient suggests a defect in ___ ___ ___, such as medium chain Acyl CoA dehydrogenase deficiency (MCAD).
Hypoglycemia
Fatty acid metabolism
Most dietary unsaturated fats have ___ double bonds. Enoyl CoA hydratase can only accept substrates with ___ double bonds. ____ ___ ____ converts cis to trans double bonds.
Cis
Trans
Enoyl CoA isomerase
Oxidation of ____ fatty acids yield less useful energy that ___ fatty acids.
Unsaturated
Saturated
Unsaturated fatty acid additional energy requiring step, indicated by the green arrow below:
Very long chain fatty acids are degraded in ___ through a process similar to beta-oxidation but the first step donates ___ to molecular oxygen rather than FAD. Instead of producing energy, this first step produces ____.
Peroxisomes
Hydrogen peroxide
Long chain fatty acids:
During degradation in Peroxisomes, beta oxidation continues until chains are __ to ___ carbons, then are transferred into mitochondria to complete beta-oxidation.
4 to 6
Long chain fatty acids:
Acetyl CoA and short chain fatty acids produced by peroxisomal degradation, enter the ____ through ____ based transport.
Mitochondria
Carnitine
Overview of peroxisomal oxidation of very long chain fatty acids (>22 carbons):
Picture compares beta oxidation to peroxisomal oxidation
w-oxidation:
If there is a disruption in beta oxidation, fatty acids can be metabolized on the ____ ___. Cytochrome p450 enzymes can oxidize the ___ terminal carbon to a carboxyl, producing a ____ fatty acid. Both ends terminate in ____. Acetyl CoA is cleaved from both ends until the ___ are broken down to medium chain ___, these may be used by other tissues or excreted in the urine.
Endoplasmic reticulum
w
Dicarboxyl
Carboxyls
Dicarboxyls
Dicarboxyls
Branched chain fatty acids such as ___ and ___ acids are products of chlorophyll breakdown and are the main dietary source of branched chain fatty acids. They are broken down in ____, similar to very long chain fatty acids.
Phytanic
Pristinic
Peroxisomes
Branched chain fatty acids:
Breakdown of phytanic acid, first the ___ carbon is oxidized to carbon dioxide. Then beta-oxidation occurs, alternately releasing ____ CoA and ___ CoA.
Alpha
Propionyl
Acetyl
Odd chain length fatty acids:
Beta oxidation occurs normally until the chain is ___ carbons long. Then ___ makes one molecule of acetyl CoA and one Propionyl CoA
Five
Thiolase
____ cut phospholipids at different locations. Phosphatidylinositol 4-5 bisphophate is a substrate for ____ __, the products are diacylglycerol and inositol 1,4,5 trisphosphate.
Phospholipases
Phospholipase C
In the liver and adipose tissue, fatty acids are synthesized from ___ ___ during times of carbohydrate abundance. Fatty acids are packaged into triacylglycerol and exported from the liver in very ___ ___ ____.
Acetyl CoA
Low density lipoproteins
Triacylglycerol synthesis:
____ are the main storage form of fatty acids in the body.
Fatty acids are synthesized from ____ derived carbon in the liver and adipose cells whenever ingested calories ___ the requirement for energy.
Triacylglycerols
Carbohydrate
Exceed
The pyruvate/Malate cycle has two functions in lipogenesis:
1. Transports acetyl CoA from the ___ to the ____
2. Malic enzymes generate ____ to power fatty acid synthesis
Mitochondria
Cytosol
NADPH
When carbohydrate energy is abundant, the ___ ___ ____ is active and also contributes NADPH reducing power for fatty acid synthesis.
Pentose phosphate pathway
Fatty acid synthase (FAS) consumes _____ generated in the cytosol by the pentose phosphate pathway and Malic enzyme
NADPH
Fatty acid synthesis overview:
First step of fatty acid synthesis:
Cytoplasmic acetyl CoA is converted to ___ ___ by the addition of carbon dioxide. ___ ___ ____ catalyzes this reaction using biotin as a cofactor.
Malonyl CoA
Acetyl CoA carboxylase
Acetyl CoA carboxylase is the ___ ____ step in fatty acid synthesis. Citrate allosterically ____ it. Xylulose 5-phosphate ____ transcription. Insulin ___ transcription. Insulin stimulates ____ and activation.
Rate limiting
Activates
Increases
Increases
Dephosporylation
____ ___ allosterically inhibits acetyl CoA carboxylase. Phosphoylation by ___ and ___ inhibits acetyl CoA carboxylase.
Palmitoyl CoA
AMP
PKA
Acetyl CoA carboxylase regulation:
The product of acetyl CoA carboxylase reaction, ___ __, allosterically inhibits Carnitine palmitoyl transferase (CPT1), which stops ___ ___ of fatty acids while fatty acid synthesis is occurring.
Malonyl CoA
Beta-oxidation
____ ___ ____ activity fine tunes the regulation of fatty acid beta oxidation. It is activated by ____ phosphorylation.
Malonyl CoA decarboxylase
AMP-K
Fatty acid synthesis sequence compared to beta-oxidation sequence:
Fatty acid synthesis:
Fatty acid synthase (FAS) is a large enzyme with multiple activities. It is a ____ and each subunit has two important ___ atoms.
Homodimer
Sulfur
FAS:
One sulfur atom is from a ____ side chain on another protein subunit of FAS. The other sulfur is _____ group covalently linked to a serine residue on the Acyl carrier protein subunit of FAS.
Cysteine
Phosphoantetheinyl
Fatty acid synthesis: first step is bond formation:
Two ____ units from ___ ___ are first added to the phosphopantetheinyl sulfur and then transferred to the cysteine sulfur.
Carbon
Acetyl CoA
Fatty acid synthesis: first step is bond formation:
Two carbons units from __ ___ are added after the carbons from acetyl CoA. The acetate from the cysteine carbon is transferred to the ____ and is ___.
Malonyl CoA
Malonyl
Decarboxylated
Fatty acid synthesis: second step is reduction:
The keto group is reduced to an ___. ____ oxidation powers the reaction.
Alcohol
NADPH
Fatty acid synthesis: third step is dehydration:
Water is removed and a carbon carbon ___ bond is formed.
Double
Fatty acid synthesis: fourth step is reduction:
The carbon carbon double bind is reduced. Oxidation of _____ powers the reaction.
NADPH
All three reactions of reduction, dehydration, and reduction again are catalyzed by ___ ___ ___, a multisubunit cytosolic enzyme. Two ____ are oxidized each cycle.
Fatty acid synthase
NADPH
Fatty acid synthase:
The four carbon fatty acid chain is transferred from the _____ to the ____. A new ___ ___ can bind the phosphopantetheinyl and the process of chain ____ continues for another cycle. Cycles continue until the Acyl chain is ___ carbons long- ____.
Phosphopantetheinyl
Cysteine
Malonyl CoA
Elongation
16
Palmitate
Fatty acid synthesis:
Palmitoyl CoA can be elongated two carbons at a time in the ____ ___.
Endoplasmic reticulum
Fatty acid synthesis:
Unsaturated:
The body can unsaturate carbon carbon bonds between carbon number ___ or lower from the ____ ___ end. ___ and ___ are the two most important dietary unsaturated fatty acids.
10
Carboxylic acid
Linoleic
Linolenic
Fatty acid unsaturation:
Molecular oxygen is the electron acceptor for the creation of carbon carbon double bonds by fatty acyl ___ ___. The energy ultimately comes from oxidation of ____.
CoA desaturase
NADH
The 18 carbon Linolenic acid consumed in the diet can be converted to ___ ___ by elongating and introducing two carbon-carbon double bonds.
Arachidonic acid
After fatty acids are synthesized in the liver, they are packaged as ____, ____, __ ____, or ____.
Triacylglycerides, glycerophospholipids, ether phospholipids, or sphingolipids
Overview of lipogenesis:
Overview of fatty acid synthesis:
___ ___ ____ generates Acetyl CoA and helps fine tune the pool of malonyl CoA, which coordinately regulates ___ ___ ___ and serves as substrate for ___ ___ ___.
Malonyl CoA decarboxylase (MCD)
Fatty acid oxidation
Fatty acid synthesis
In the fasted state, malonyl CoA decarboxylase (MCD) is ____ by AMPK. Acetyl CoA carboxylase (ACC) is ____ by AMPK.
Activated
Inactivated
In the absence of malonyl CoA decarboxylase (MCD), cells can not turn on ___ ___ ___ ___ in response to low energy conditions. Deficiency is associated with metabolic ___, ____, developmental delays, seizures, and cardiomyopathy.
Fatty acid beta oxidation
Acidosis
Hypoglycemia
In lipid metabolism disorders, a high ___ and low __ diet leads to normal development.
Carbohydrate
Fat
