LECTURE 5 (Lipid degradation) Flashcards
What are the properties of Fatty acids in the body?
- Stored in adipose tissue (as TAGs)
- Serve as the body’s major fuel storage reserve
- Yield from complete oxidation of Fatty acids to CO2 and H2O is 9 kcal/g (higher than in proteins + carbohydrates)
What is Hormone-sensitive lipase?
An enzyme that removes fatty acid from TAG in adipocytes
ACTIVATION: by glucagon and epinephrine
What happens when Fatty acids are released from TAG?
Free fatty acids move through the cell membrane of adipocyte -> Bind to plasma ALBUMIN -> Transported to tissues -> Oxidised for energy
What happens to Glycerol released during TAG degradation?
It cannot be metabolised by adipocytes because they lack GLYCEROL KINASE -> Glycerol is transported through the blood to the liver where it can be phosphorylated -> Glycerol phosphate can be used to form TAG in liver or converted to DHAP
Why is Glycerol easily transported to liver?
Glycerol is water-soluble
Which processes are Facilitated by Insulin?
- Glucose entering White adipose tissue via GLUT 4
- Lipogenesis (conversion into fatty acids)
- Esterification of fatty acids into TAGs
Which process is inhibited by Insulin?
Breakdown of TAGs into Fatty acids
Describe Fatty acid breakdown
- Fatty acids transported via Albumin
- Taken up by tissues
What is Fatty acid breakdown not used by?
- RBC: glycolysis only (no mitochondria)
- BRAIN: glucose and ketones only
Why does brain metabolism not favour the burning of fatty acids to provide energy?
- ATP generation linked to B-oxidation of fatty acids demands more O2 than glucose -> enhance risk for neurons to become HYPOXIC
- B-oxidation of fatty acids generates SUPEROXIDE
[poor anti-oxidative defense in neurons -> severe oxidative stress] - Rate of ATP generation from Fatty acids to too slow
[cannot keep up with rapid, continuous neuronal firing]
What happens when Fatty acids reach tissues?
Fatty acids metabolised by BETA-OXIDATION mitochondrial pathway -> 2-carbon units are removed from FAs -> Produces acetyl-CoA, NADH and FADH2
What is the function of the Carnitine shuttle?
Transport long-chain fatty acyl CoA subunits across mitochondrial membranes from outside to inside
Describe the steps of Beta-oxidation of Fatty acids
1) Fatty acid conversion into FATTY ACYL-COA
2) Transport of fatty acyl-CoA from cytosol into inner mitochondria
3) Beta-oxidation
What is the Carnitine shuttle inhibited by?
MALONYL-COA
Explanation: When fatty acid synthesis occurs in cytosol -> newly make palmitate cannot be transferred into mitochondria and is degraded
What are the properties of Carnitine?
- Obtained from meat
- Synthesised from lysine and methionine
- De novo synthesis only in liver & kidney
- Skeletal muscle contains 97% of all carnitine in body
Describe Carnitine deficiencies
CAUSES:
- Malnutrition or strictly vegetarian diet
- Liver disease (decreased synthesis)
- Increased requirements (trauma, burns, pregnancy)
- Hemodialysis (decreased synthesis, loss through membranes)
MAJOR CONSEQUENCE:
Inability to transport long-chain fatty acids (LCFA) to mitochondria -> accumulation of LCFA in cells
SYMPTOMS:
- Muscle weakness
- Cardiomyopathy
- Hypoketotic hypoglycaemia
[ explanation: when fasting tissues overuse glucose & poor ketone synthesis without acid breakdown ]
Describe Primary Systemic Carnitine deficiency
A rare metabolic disorder in which the body cannot properly process fats into energy. There is a mutation affecting carnitine uptake into cells which inhibits transport of LCFAs into mitochondria -> Toxic accumulation.
SYMPTOMS:
- Weakness & Hypotonia
- Hypoketotic hypoglycaemia
- Hepatomegaly
Treatment:
- Avoid prolonged fats
- Adopt diet high in carbs and low in LCFA
- Supplemented with medium-chain fatty acids and carnitine
Infantile phenotype presents during the first two years of life
Which Fatty acids can cross the inner mitochondrial membrane without the aid of carnitine?
Fatty acids shorter than 12 carbons
What does Beta-oxidation generate?
- NADH
- FADH2
- Acetyl-CoA
Which enzyme adds a double bond between alpha and beta carbons?
Acyl-CoA dehydrogenase
[first step in Beta-oxidation]
Acyl-CoA dehydrogenase is a family of which 4 enzymes?
- Short (2-6)
- Medium (6-12)
- Long (13-21)
- Very-long (>21)
chain fatty acids
Describe Medium-chain Acyl-CoA dehydrogenase (MCAD) deficiency
An autosomal recessive disorder that decreases the ability to break down 6-12 carbon fatty acids into acetyl-CoA causing an accumulation of FATTY ACYL CARNITINES IN BLOOD
SYMPTOMS:
- Hypoketotic hypoglycaemia
- Dicarboxylic acids in urine
- High acylcarnitine level
Why is hypoglycaemia found in MCAD deficiency?
Gluconeogenesis is shutdown
[ explanation: pyruvate carboxylase activity depends on acetyl-coa and these levels are low in the absence of beta-oxidation ]
SYMPTOMS:
- Vomiting
- Lethargy
- Seizures
- Coma
- Can lead to sudden death in infants or children (SIDS)
Exacerbated in fasting/infection
TREATMENT:
- Avoid fasting
Describe Odd-chain fatty acid metabolism
- Beta-oxidation proceeds until 3 carbons remain
- PROPRIONYL-COA -> SUCCINYL-COA -> TCA CYCLE
- Odd-chain fatty acid -> can be used in gluconeogenesis -> to produce glucose
Which acid is elevated in B12 deficiency?
Methylmalonic acid/MethylMalonyl-CoA
What does Oxidation of molecule of Palmitoyl CoA to CO2 and H2O produce?
- 8 acetyl-CoA
- 7 NADH
- 7 FADH2
- 131 ATP
What is the net yield of ATP from palmitate?
Activation of fatty acid required 2 ATP -> Net yield from palmitate is 129 ATP
What is Peroxisome involved in?
- Beta-oxidation of Very long-chain fatty acids (VLCFA)
- Alpha-oxidation of branched-chain fatty acids
- Catabolism of amino acids and ethanol
- Synthesis of cholesterol, bile acids and plasmalogens
What are the Peroxisome Clinical Correlations?
- Zellweger syndrome
- Refsum disease
- Adrenoleukodystrophy
Describe Zellweger syndrome
Autosomal recessive disorder of Peroxisome biogenesis due to mutated PEX genes
SYMPTOMS:
- Hypotonia
- Seizure
- Hepatomegaly
- Early death
Describe Refsum disease
Autosomal recessive disorder of alpha-oxidation causing buildup of PHYTANIC ACID due to inability to degrade it
SYMPTOMS:
- Scaly skin
- Ataxia
- Cataracts/night blindness
- Shortening of 4th toe
- Epiphyseal dysplasia
Describe Adrenoleukodystrophy
X-linked recessive disorder of beta-oxidation causing VLCFA buildup in adrenal glands, white (Leuko) matter of brain and in testes
