Lipid Biochemistry Flashcards
3 things that impact TGL breakdown
insulin decreases it
epineprine and cortisol increase it
Hormone sensitive lipase turns TGL into glycerol (end destination: glucose in the liver) and fatty acids (to be beta oxidized inthe liver)
What happens to fatty acids in the liver?
Beta oxidation –> acetyl CoA
Impacts on gluconeogenesis in the liver
Glucagon and cortisol increase it via DHAP
alpha oxidation
is a process by which certainFAs are broken down by removal of a single carbon from the carboxyl end.
In humans, a oxidation is used inperoxisomes ** to break down dietary phytanic acid, which cannot undergob oxidation due to its β-methyl branch, intopristanic acid.
Enzymatic deficiency in a-oxidation
(most frequently inphytanoyl CoA dioxygenase)
leads toRefsum’s disease, in which the accumulation of phytanic acid and its
derivatives leads to neurological damage.
Other disorders ofperoxisome biogenesis also prevent a oxidation from occurring.
Acetyl CoA’s destination
Citric Acid cycle or linked together (2 of them) to form ketone bodies –> muscle and brain
omega oxidation
process ofFA metabolism in some species of animals.
It is an alternative pathway tob oxidation that, instead of involving the β carbon, involves the oxidation of the ω carbon (the carbon most distant from thecarboxyl group of the FA).
The process is normally a minor catabolic pathway for medium-chain fatty acids (10-12 carbon atoms), but becomes more important when β oxidation is defective.
b-oxidation
the process by which FA molecules are broken down in the mitochondria to generate acetyl-CoA, which enters the citric acid cycle, and NADH and FADH2, which are used by the electron transport chain to generate ATP.
There are at least 25 enzymes and specific transport proteins in the β oxidation pathway.
Of these, 18 have been associated with human disease asinborn errors of metabolism.
The trip from FA to ATP
FA–> beta oxidation –> acetyl CoA–> TCA cycle/ ox phos –> ATP
insulin resistance
FA-CoA –> DAG and Ceramide which can lead to insulin resistance
Short vs Long chain FAs
Short chain FAs (2-4 C) and Medium chain FAs (6-12 C) diffuse freely into mitochondria to be oxidized
Long chain FAs (14-20 C) activated first then transported into mitochondria by a Carnitine shuttle to be oxidized
Very long chain FAs ( >20C) enter peroxisomes via unknown mechanism for oxidation
Activation of FAs
- long chain FAs (LCFA) must be activated by ATP and CoA by AcylCoA synthetase – Fatty acyl CoA
- short chain FAs are activated in mitochondria
- when FA is activated, ATP converted to AMP and PPi (pyrophosphate)
- 2 high energy bonds required for FA activation
Transport of Fatty acyl CoA from cytosol into mitochondria
Cytosolic Fatty acyl CoA reacts with Carnitine forming Fatty acyl Carnitine by
- CAT I (carnitine acyl transferase 1) or CPT I (carnitine palmitoyl transferase I)
- Fatty acyl Carnitine passes to inner mitochondrial membrane, reacts with CAT II (CPT II)
- Fatty acyl Carnitine reforms Fatty acyl CoA and enters mitochondrial matrix and b-oxidation
Fatty acid activation, Transport, and b-oxidation
Long chain FAs are activated on outer mitochondrial membrane
Fatty acyl synthetase binds FA + CoA FA-CoA
Carnitine acyltransferase 1 (CAT-1 or CPT I) replaces CoA with carnitine to form FA-carnitine
FA-carnitine translocates across inner mitochondrial membrane by the carnitine transporter
Carnitine releases FA and it is shuttled back across the membrane to transport more FA
Carnitine acyltransferase-2 (CAT-2 or CPT-II) transfers Fatty acyl group back to CoA
FA-Acyl CoA then undergoes b-oxidation and forms Acetyl CoA
Myopathic CAT/CPT deficiency
mucle aches, weakness myoglobinuria provoked by prolonged exercise, esp. if fasting biopsy: elevated muscle triglyceride most common form: AR, late onset
MCAD deficiency
fasting hypoglycemia no keton bodies (hypoketosis) C8-C10 acyl carnitines in blood vomiting coma, death AR with variable expression
Carnitine deficiency:
- leads to impaired carnitine shuttle activity
- decreased LCFA metabolism
- accumulation of LCFAs in tissues and wasting of acyl-carnitine in urine produces
cardiomyopathy, skeletal muscle myopathy, encephalopathy and impaired liver function
due to inherited CTP-I or CPT-II deficiency (rare disorders - autosomal recessive inheritance)
impaired carnitine synthesis due to liver disease
disorders of b-oxidation
- CPT-I deficiency produces fasting hypoglycemia, inability to use LCFAs as fuel by liver
- CPT-II deficiency – common, muscle weakness upon exercise, hyperammonemia, death
CPT-I and II treated by
avoiding fasting, dietary restrictions of LCFAs, carnitine supplement
What is the rate-limiting step of FA oxidation?
carnitine on the outer mitochondrial membrane
Pathogenesis of carnitine deficiency
Many diseases have been linked to deficiency of Carnitine, CPT-I and CPT-II
Symptoms range from mild muscle cramping to severe weakness and even death
Muscle, kidney and heart tissues are primarily affected
Muscle weakness during prolonged exercise – important characteristics
of CPT deficiency
Muscle relies on FAs as a long term source of energy
Medium chain (C8 - C10) FAs does not require carnitine to enter
mitochondria are oxidized normally in these patients
Causes of Carnitine deficiency:
Inadequate intake (e.g., due to fat diets, lack of access, or long term TPN-total parenteral nutrition)
Inability to metabolize carnitine due to enzyme deficiencies (e.g., CPT deficiency)
Decreased endogenous synthesis of carnitine due to severe liver disorder
Excess loss of carnitine due to diarrhoea, diuresis, or hemodialysis
A hereditary disorder in which carnitine leaks from renal tubules (Primary carnitine deficiency)
Increased requirements for carnitine when ketosis is present or demand for fat oxidation is high (e.g., 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
Clinical manifestations of Carnitine deficiency
Carnitine deficiency may cause muscle necrosis, myoglobinuria, hypoglycemia,
fatty liver, muscle aches, fatigue, and cardiomyopathy.
Most common presentation is progressive cardiomyopathy with or without
skeletal muscle weakness beginning at 2-4 years of age. Energy deprived
muscle cells are damaged
Some patients may present with fasting hypoglycemia during the 1st year of
life before cardiomyopathy becomes symptomatic.
Blockage of the transport of LCFAs into mitochondria deprives the patient of
energy production, as the FA oxidation is impaired; glucose oxidation supplies
the minimum energy needs resulting in hypoglycemia
Compensatory ketosis in carnitine induced hypoglycemia is not observed as
Acetyl CoA is not available for ketone body production
The main source of Acetyl CoA is FA oxidation and that is impaired in carnitine
deficiency
General Carnitine deficiency leads to:
Symptoms and the age at which symptoms appear depend on the cause
Carnitine deficiency may cause:
muscle necrosis, myoglobinuria
lipid-storage myopathy, hypoglycemia, fatty liver, and hyperammonemia
muscle aches, fatigue,confusion, and cardiomyopathy.
hypoketotic hypoglycemic encephalopathy, accompanied by hepatomegaly, elevated liver transaminases
Cardiomyopathy is the other classic presentation (affecting older children); onset may occur with rapidly progressive heart failure
Cardiomyopathy can also be observed in older patients with a metabolic presentation, even if they are asymptomatic from a cardiac standpoint
Pericardial effusion has also been observed in association with primary carnitine deficiency
CPT-I deficiency?
CPTI deficiency is thought to cause serious disorders of fatty acid metabolism
The nucleotide sequences of cDNA and genomic DNA encoding human CPTI have been characterized
A relationship between disease and mutation of the human CPTI gene has not been reported
It is very hard to find a case related to CPT-I deficiency relating to its sypmtoms!
