Fatty Acid Oxidation Flashcards
1
Q
Canitine is synthesized from what amino acid?
A
- lysine
2
Q
Carnitine is synthesized in what organs?
A
- liver and kidney
* not in skeletal or heart muscle
3
Q
Carnitine uptake is mediated by what transporter?
A
- OCTN2
* vitamin C required
4
Q
OCTN2 transporter
A
- mediates carnitine uptake into the cell
5
Q
Hormone sensitive lipase in adipose tissue is activated by
A
- glucagon induced phosphorylation
6
Q
Each round of β-oxidation produces
A
- 1 NADH
- 1 FADH2
- 1 acetyl-CoA
7
Q
In muscle acyl CoA from beta oxidation is converted to
A
- sent to TCA cycle to create:
- 3 NADH
- 1 FADH
- 1 ATP
8
Q
In liver acyl CoA from beta oxidation is converted to
A
- ketone bodies
9
Q
β-oxidation of saturated fatty acids occur in
A
- primarily muscle and liver
10
Q
fatty acyl CoA dehydrogenase enzymes
A
- 4 are utilized in the mitochondrial matrix during beta oxidation
11
Q
Medium Chain fatty acyl CoA dehydrogenase deficiency (MCADD) MOA
A
- one of the most common inborn
errors of fatty acid oxidation (1 in 12,000 birth in West and 1 in 40,000 worldwide) - autosomal recesive
- MCFAs accumulate and cause damage to the tissues
- damage liver and brain
- severe hypoglycemia
- misdiagnosis of Reye syndrome or Sudden Infant Death Syndrome (SIDS) is often made
12
Q
Medium Chain fatty acyl CoA dehydrogenase deficiency (MCADD) symptoms
A
- can be triggered once a baby has stopped receiving regular nightly feeds
- vomiting, lethargy, frequently coma, and hypoglycemia which occurs due to tissues dependence on glucose for energy
13
Q
Medium Chain fatty acyl CoA dehydrogenase deficiency (MCADD) diagnosis
A
- Excessive urinary excretion of medium-chain dicarboxylic acids as well as their glycine and carnitine esters
14
Q
Medium Chain fatty acyl CoA dehydrogenase deficiency (MCADD) treatments
A
- high carbohydrate and MC acyl CoA derivatives
- Human milk is particularly rich in LCFAs and infants with MCADD are treated by frequent feeding, avoidance of fasting, and carnitine supplementation
- Deficiences in short and long chain fatty acyl dehydrogenases have similar clinical features
15
Q
Hypoglycin
A
- toxin found in unripe fruit of the Jamaican Ackee tree
- inhibits both short and medium chain acyl CoA dehydrogenases
- This inhibits β- oxidation and leads to nonketotic hypoglycemia.
16
Q
Propionyl-CoA is converted to
A
- succinyl-CoA
* through an ATP-dependent pathway and then enters the TCA cycle for further oxidation
17
Q
Methylmalonyl-CoA mutase
A
- vitamin B12 cofactor
- last part of the steps involved in converting propionyl CoA into succinyl CoA
18
Q
Methylmalonic-aciduria
A
- Defects in methylmalonyl-CoA mutase or deficiencies in vitamin B12 may lead to methylmalonic-aciduria
19
Q
Enoyl-CoA isomerase
A
- isomerizes double bonds in UFAs so that oxidation can continue
- Since UFAs are partially oxidized, less FADH2 and corresponding ATP is produced
- oxidation of UFAs is essentially the same process as for saturated fats, except when a double bond is encountered
20
Q
Peroxisome
A
- abundant in the liver and kidney
- involved in a series of vital cellular reactions:
- free radical detoxification
- rid the cells of toxic peroxides
- site of H2O2 production
- α and β oxidations of fatty acids
- where VLCFAs can only undergo preliminary beta oxidation
- biosynthesis of bile acids, DHA, plasmalogens, hormones
- helping the nervous system work properly
21
Q
α-hydroxylase
A
- adds a hydroxyl group to the α-carbon of phytanic
acid, which then serves as a substrate for the remainder of the normal oxidative enzyme - In subsequent cycles of β-oxidation, acetyl- CoA and propionyl-CoA are released alternately
22
Q
Phytanic acid
A
- branched fatty acid present in the tissues of ruminants and in dairy products and is, therefore, an important dietary component of fatty acid intake
23
Q
Refsum disease MOA
A
- rare, autosomal disorder caused by a deficiency of α- hydroxylase
- Phytanic acid accumulates in the tissues and serum in large quantities
24
Q
Refsum disease symptoms
A
- symptoms are neurologic
* cerebellar ataxia, retinitis pigmentosa, nerve deafness and peripheral neuropathy
25
Refsum disease treatment
- dietary restrictions
| * restriction of dairy products and ruminant meat from the diet can ameliorate the symptoms of this disease
26
Zellweger syndrome MOA
- congenital (autosomal recessive) disorder which results from reduction of peroxisome in the cells of liver, kidney, and brain
- damages the white matter of the brain and also how the body metabolizes particular substances in the blood and organ tissues
27
Zellweger syndrome symptoms
- mental retardation
- poor muscle tone
- poor feeding
- seizures
* from abnormal brain and nervous system development
~ hearing and vision delay, or absent diminished, or absent reflexes
- cysts in the liver affecting liver function
- characteristic facial features
* Head and face enlarged, high forehead, large anterior fontanelle (soft spot), malformed ear lobes,flat-looking face
- Liver is enlarged with impaired function jaundice.
28
Adrenoleukodystrophy MOA
- Fatal demyelinating disease caused by mutations in the ABCD1 gene leading to an absent or non-functioning adrenoleukodystrophy protein (ALDP)
- neurological disorder due to defective peroximal
oxidation of VLCFAs
- The most common peroxisomal disorder affecting males at early ages
29
Adrenoleukodystrophy symptoms
- accumulation of very long chain fatty acids (VLCFA) in tissues and plasma via inhibition of peroxisomal β-oxidation
- Reduction in plasmalogens
- Abnormalities in the white matter of the cerebrum
30
Adrenoleukodystrophy protein (ALDP)
- ATP-binding cassette transporter located in membranes of peroxisomes
- Involved in degradation of very-long-chain-fatty acids (VLCFAs) in oligodendrocytes and microglia
- Lack of the protein disrupts maintenance of myelin
31
ω-oxidation of fatty acids
- alternative / minor pathway of LCFA acid metabolism in endoplasmic reticulum of kidney and liver
- can be induced by:
* Failure of β-oxidation to proceed normally can result in increased ω-oxidation activity
* lack of carnitine or carnitine palmitoyltransferase (CPT) activity preventing fatty acids from entering mitochondria leading to an accumulation of FAs in the cell
32
Deficiencies in carnitine biochemistry
- found in patients undergoing hemodialysis or exhibiting organic aciduria
- Primary carnitine deficiency (systemic) present in 2 ways:
* defective in endogeneous biosynthesis of carnitine
* defect in the OCTN2 gene
33
Primary carnitine deficiency symptoms
- hypoketotic
- hypoglycemic encephalopathy accompanied by hepatomegaly
- elevated liver transaminases
- hyperammonemia
- often misdiagnosed as Reye syndrome or sudden infant death
- Serious complications such as heart failure, liver problems, coma, and sudden unexpected death are also risk factors
34
Myopathic carnitine deficiency MOA
- defect in the muscle
carnitine transporter
- Severe reduction in muscle carnitine levels and normal liver and serum carnitine concentrations
- restricted to muscle, with no renal leak of carnitine or signs of liver
involvement
35
Myopathic carnitine deficiency symptoms
- deficiency can appear in the first years of life, but they may occur later during the second or third decade
- proximal muscular weakness of varying degree
- exercise intolerance
- myalgia
36
Secondary carnitine deficiency MOA
- decrease of carnitine levels in plasma or tissues which are caused by other metabolic disorders
* Inadequate intake (eg, due to fad diets, lack of access, vegetarians)
* Deficiencies in mitochondrial mobilizing enzymes (eg, CAT1 or CAT2)
* Decreased endogenous synthesis of carnitine due to a severe liver disorder
* Excess loss of carnitine due to diarrhea, diuresis, or hemodialysis
* hereditary disorder in which carnitine leaks from renal tubules
* Increased requirements for carnitine when ketosis is present or demand for fat oxidation is high (eg, during a critical illness such as sepsis or major burns; after major surgery of the GI tract)
* Decreased muscle carnitine levels due to mitochondrial impairment (eg, due to use of zidovudine or AZT)
37
Secondary carnitine deficiency treatment
- Avoidance of fasting and strenuous exercise
- Dietary interventions, based on cause
- Carnitine deficiency due to inadequate dietary intake, increased requirements, excess losses, decreased synthesis, or (sometimes) enzyme deficiencies can be treated by:
* In some cases oral L-carnitine may help
* Consuming uncooked cornstarch at bedtime prevents early morning
hypoglycemia
* Some patients require supplementation with medium-chain triglycerides and essential fatty acids
* Patients with a fatty acid oxidation disorder require a high-carbohydrate, low-fat diet
38
Deficiencies in Acyl-CoA Dehydrogenases MOA
- group of inherited diseases that impair β-oxidation result from deficiencies in acyl-CoA dehydrogenases
- The enzymes affected may belong to one of four categories:
* very long-chain acyl-CoA dehydrogenase (VLCADD)
* long-chain acyl-CoA dehydrogenase (LCADD)
* medium-chain acyl-CoA dehydrogenase (MCADD)
* short-chain acyl-CoA dehydrogenase (SCADD)
39
Long-term alcohol consumption can inhibit
- mitochondrial fatty acid oxidation
- promotes the deposition of esterified fatty acids in the liver
* No β-oxidation of FAs
* Fat deposition in the liver
40
Gaucher disease MOA
- Autosomal recessive, mutation in gene encoding glucocerebrosidase
* lysosomal enzyme that breaks down glucocerebroside (GBA) into glucose and ceramide
- Defect leads to accumulation of GBA in macrophages, and subsequent enlargement of macrophages known as "Gaucher cells"
* accumulate most commonly in the spleen, liver, and bone marrow
- Gaucher cells may also be found in lungs, skin, eyes, kidney, heart, and in the nervous system
- In the spleen, accumulation of Gaucher cells leads to enlargement of spleen, and activation of red blood cell (RBC) metabolism
* RBCs break down faster than pruduced; anemia
- most common genetic lysosomal storage disorder
- Type 1 does not affect the nervous system. In contrast, type 2 and 3 are rare and neuronopathic
- high case in Ashkenazi jews
41
Gaucher disease symptoms
- Some individuals may experience no symptoms.
- Generalized lack of energy and stamina due to anemia.
- Type 1 is most common (99% of the cases)
- Extensive and progressive brain damage (types 2 and 3)
- Increased tendency for bleeding and bruising
- Enlarged spleen and liver (hepatoslienomegaly)
- Accumulation in bone marrow and loss of bone density
- Low blood platelets
42
Disorders Associated with Abnormal Sphingolipid Metabolism
- Tay-Sachs disease
- Sandhoff-Jatzkewitz disease
- Fabry's disease
- Sulfatide lipdosis
- Krabbe's disease
- Gaucher disease
- Niemann-Pick disease
- GM1 gangliosidosis
43
Disorders Associated with Abnormal Sphingolipid Metabolism symptoms
- mental retardation in all
| - early mortality in some
