What causes lipid mobilization?
postabsrorptive state, fatty acids used for energy
adipose tissue doesn't respond directyl to glucagon
fall in insulin activates homrone sensitive triacylglycerol lipase (HSL)--hydrolyzes triglycerides, yielding fatty acids and glycerol
epinephrine and cortisol also activate HSL
What happens to glycerol and fatty acids caused by lipid breakdown?
glycerol picked up by liver and converted to dihydroxyacetone phosphate (DHAP) for gluconeogenesis
fatty acids are carreid by serum albumin and distributed to tissues that can use them
What is niacin used for?
inhibits HSL in adipose tissue
fewer fatty acids enter the liver, VLDL isn't assembled in normal amounts
so VLDL and its product LDL are lower in serum
What is fatty acid oxidation?
fatty acids are oxidized in liver, muscle, adipose tissue by beta oxidation
erythrocytes (lack mitochondria) and brain (can't cross BBB) can't use fatty acids
How are different sized fatty acids oxidized?
short chain fatty acids (2-4 C) & medium chain fatty acids (6-12 C) diffuse freely into mitochondria to be oxidized
long chain fatty acids (14-20 C) transported into mitochondria via carnitine shuttle
very long chain fatty acids (>20 C) enter proxidsomes for oxidation
How are long chain fatty acids processed in the mitochondria?
long chain fatty acids actiated by fatty acyl CoA synthase on outer mitochondrial membrane by attaching CoA
fatty acyl portion transferred onto carnitine by carnitine acyltransferase-1 (inhibited by malonyl CoA)
--insulin indirectly inhibits beta oxidation by activaing acetyl CoA carboxylase (FA synthesis) and increasing malonyl CoA; glucagon reverses this process)
carnitine acyltransferase 2 transfers fatty acyl group back to CoA (mitochondrial matrix)
What is beta oxidation in the mitochondria?
beta oxidation reverses the process of fatty acid synthesis by oxidizing and releasing unites of acetyl CoA
--each cycle releases one acetyl CoA and reduces NAD and FAD
FADH2 and NADH are oxidized in the ETC providing ATP
muscle, adipose tissue: acetyl CoA enters TCA
liver: ATP used for gluconeogenesis; acetyl CoA stimulates gluconeogenesis by actiating pyruvate carboxylase
What is the product of beta oxidation of palmitate?
8 acetyl CoA
What occurs in liver beta oxidation during fasting state?
.iver roduces more acetyl CoA from beta oxidation than is used in TCA
much of acetyl CoA is used to syntehsze ketone bodies (two acetyl CoA linked together) that is released into blood for other tissues
What are the two common genetic deficiencies of fatty acid oxidation?
medium chain acyl CoA dehdyrogenase (MCAD) deficiency: primary etiology hepatic
myopathic carnitine acyltransferase (CAT/CPT) deficiency: primary etiology myopathic
What is MCAD deficiency?
non ketotic hypoglycemia associated with block in hepatic beta oxidation
during fasting: hypoglycemia profound due to lack of ATP to support gluconeogenesis
decreased acetyl CoA lowers pyruvate carboxylase activity and limits ketogenesis
symptoms: profound fasting hypoglycermia, low to bsent ketons, lethargy, coma, death if untreated, C8-C10 acyl carnitines in blood, episode may be provoked by overnight fast in infant, older child, often provoked by illness (flu) that cuases loss of appetite and vomiting
treatment: IV glucose
prevention: frequent feeding, high carbohydrate low fat diet
--occurs during metabolic stress by severe fasting, exercise or infeciton (conditions iwth high demands on fatty acid oxidation)
What is ackee?
toxin that acts as inhibitor of fatty acyl CoA dehydrogenase
Jamaican vomiting sickness and severe hypoglycemia
convulsions, coma and death
What symptoms are suggestive of block in beta oxidation?
severe hypoglycemia and absense of ketosis (hypoketosis)
What is CAT/CPT deficiency?
defect in muscle specific CAT/CPT gene
autosomal recessive condition with late onset
symptoms: muscle aches, mild to severe weakness, rhabdomyolysis, myoglobinuria, red urine, episode provoked by prolonged exercise especially after fasting, cold or assocaited stress, symptoms exacerbated by high fat low carbohydrate diet
--muscle biopsy shows elevated muscle TGL detected as lipid droplets in the cytoplasm
treatment: cease muscle activity and give glucose
What is the propionic acid pathway?
even carbon FA yield two acetyl CoA
odd carbon FA yield one acetyl CoA and one propionyl CoA
--converted to succinyl CoA (TCA intermediate) then malate to enter cytoplasm and gluconeogenesis
exception to rule that FA can't be converted to glucose
What does propionyl CoA carboxylase require?
What does methylmalonyl CoA mutase require?
vitamin B12 cobalamin
vitamin B12 deficiency: megaloblastic anemia (same type seen in folate deficiency)
--produces peripherla neuropathy becuase of aberrant FA incorporation into myelin sheets assocaited with inadequate methylmalonyl CoA mutase activitiy
excretion of methylmalonic acids indicates a vitamin B12 deficiency rather than folate
What is ketone body metabolism?
fasting state, liver converts excess acetyl CoA from beta oxidation of fatty acids into ketone bodies, acetoacetate, and 3 hydroxybutyrate (beta hydroxybutyrate)--used by extrahepatic tissues
cardiac, skeletal muscle, renal cortex: metabolize acetoacetate and 3 hydroxybutyrate to acetyl CoA
during fast, muscle metabolizes ketones as rapidly as liver releases them so don't accumulate in blood
after week fo fasting, ketones reach concnetration in blood high enough for brain to begin metabolizing them
--if ketones increased too much in blood-->ketoacidosis
What is ketogenesis?
occurs in mitochodnria of hepatocytes when excess acetyl CoA accumulates in the fasting state
HMG-CoA synthase forms HMG CoA and HMG CoA lyase breaks HMG-CoA into acetoacetate, which is then reduced to 3 hydroxybutyrate
acetone=minor side product; strong odor (sweet, fruity) to breath--diagnostic for ketoacidosis
What is ketogenolysis?
acetoacetate is picked up from blood and activated in mitochondria by succinyl CoA acetoacetyl CoA transferase (enzyme is only in extrahepatic tissues)
3-hydroxybutyrate is first oxidized to acetoacetate
liver lacks enzyme so can't metabolize ketone bodies
What is ketogenolysis in the brain?
12 hours: glucose derived from liver glycogenolysis to glucose derived from gluconeogenesis
1 week: glucose derived from gluconeogensis to ketones derived from fatty acids
in the brain: ketones are metabolized to acetyl CoA and pyruvate dehydrogenase is inhibited
glycolysis and glucose uptake in brain decreased
switch spares body protein by allowing the brain to indirectly metabolize fatty aicds as ketone bodies
What is ketoacidosis?
type 1 insulin dependent diabetes mellitus not adequately treated with inuslin: fatty acid release from adipose tissue and ketone sytnehsis in liver exceed the ability of other tissues to metabolize them
ketoacidosis may occur
infection or trauma (causing an increase in coritosl and epinephrine) may precipitate an episode of ketoacidosis
NIDDM: less likely to have ketoacidosis; can occur after infection or trauma
What is ketoacidosis in alcoholics?
chronic hypoglycemia, often prevent in chronic alocholism favors fat release from adipose
ketone production increases in the liver, but utilization in muscle may be slower than normal because alcohol is converted to acetate in the liver, diffuses into the blood and oxidized by muscle as an alternative source of acetyl CoA
What is associated ketoacidosis?
polyuria, dehydration, and thrist (exacerbated by hyperglycemia and osmotic diuresis)
CNS depression and coma
potential depletion of K+ (although loss may be masked by a mild hyperkalemia)
decreased plasma bicarbonate
breath with a sweet or fruity odor, acetone
What occurs with normal and pathologic ketosis?
normal ketosis: acetoacetate and beta hydroxybutyrate are formed in approximately equal quantities
pathologic conditions (diabetes and alcoholism) ketoacidsosis --> beta hydroxybutyrate is higher than acetoacetate
What are spingolipids?
important constituents of cell membranes
contain no glycerol
hydrophilic region and two fatty acid derived hydrophobic tails
What are the classes of sphingolipids?
cerebrosides: galactose or glucose
gangliosides: branched oligosaccharide chains terminating in the 9-carbon sugar, sialic acid (N-acetylneuraminic acid, NANA)
What is Tay-Sachs?
What is Niemann-Pick?
What is Gaucher?
Ashkenazic Jew, lethargic (anemia), bruise easily (low platelet count), massive hepatomegaly, splenomegaly, pallow, hematologic complications
cytoplasm: PAS stain positive
wrinkled paper cytoplasm
in brain: glucocerebroside arises from breakdown of old red and white cells
in brain: glucocerebroside arises from turnover of ganglioside during brain development and formation of the myelin sheath
What is Fabry disease?
spingolipidoses (usually autosomal recessive) but this is X-linked recessive
mutation inthe gene encoding the lysosomal enzyme a-galactosidase
ceramide trihexoside accumulates inthe lysosome
symptoms: burning sensations in the hands which gets worse with exercise and hot weather; small, raised reddish purple blemishes on skin (angiokeratomas); eye manifestations, especially cloudiness of the cornea; impaired arterial circulation and increased risk of heart attack or stroke; enlargement of heart and kidneys
usually survival into adulthood but with increased risk of CVD, stroke
renal failure is often cause of death