L14: Lipid Metabolism Flashcards
fatty acid
- long hydrocarbon chains ending in a carboxylic acid group
saturated
- no double bonds
unsaturated
- double bonds
cis configuration
- Hs on the same side
- causes chain to kink
- most double bonds are bound in cis
trans configuration
- Hs on opposite side
- does not kink
- resembles saturated fatty acid
double bonds and Tm
- more double bonds - lower Tm
- cis double bond - lower Tm than trans
length and Tm
- longer length - higher Tm
good for energy storage
- reduced and anhydrous
caloric yield
- oxidation provides a good bit of energy
lack of hydration
- have no H20 so pack well
storage of triglycerides
- stored in adipose cells
- fat cells accumulate around skin and internal organs
- droplets of triacylglycerides coalesce into lipid droplets
- lipid droplets surrounded by a membrane with proteins involved in fatty acid metabolism
issues in lipid digestion
- triacylglycerides are insoluble in water
- enzymes that degrade them are water soluble
solution to insolubility of triacylglycerides
- digestion takes place at lipid-water interfaces
- lipids are emulsified so lipase have access to their surface
- emulsification occurs through chewing, intestinal churning, and bile salts
acid lipases
- lingual
- gastric
alkaline lipases
- pancreatic lipase
degradation and transport of triacylglycerides
- degraded fatty acids form micelles transported to intestine
- reassemble into triacylglycerides and are packing into chylomicrons for release into lymph and blood
- fat cells and muscle bind particles
fat cells use of chylomicrons
- degrade them into fatty acids and monoglycerides for storage
muscle use of chylomicrons
- oxidize them for energy
fasting state hormones
- glucagon (alpha cells) bind glucagon receptor
- epinephrine (adrenal medulla) binds adrenergic receptor
- GCPR pathway
fatty acid mobilization by hormone induction
- glucagon and epinephrine trigger a rise in cAMP that stimulates protein kinase A
- protein kinase A phosphorylates perilipin and hormone sensitive lipase
functions of perilipin
- restructure fat droplets to triacylglycerides are more accessible to mobilization
- triggers release of a coactivator of adipose triglyceride lipase
function of adipose triglyceride lipase
- degrades triacylglycerides into diacylglycerides
- DAG degraded to monoacylglycerol
- monoacylglycerol degraded to fatty acids and glycerol
Chanarin-Dorfman Syndrome genetics
- mutation in coactivator for adipose triglyceride lipase
Chanarin-Dorfman Syndrome result
- fat accumulate throughout body since fatty acids cannot be degraded and released by adipose triglyceride lipase
Chanarin-Dorfman Syndrome symptoms
- dry skin
- enlarged liver
- muscle weakness - can’t break down for energy
- overheating
fatty acid and glycerol transport
- bind to albumin in blood
- since they are not water soluble
glycerol utilization
- absorbed in liver
- converted to glyceraldehyde-3-phosphate
- intermediate in glycolytic and gluconeogenic pathways
fatty acid utilization
- fatty acids separate from albumin and are transported into cell
- enter mitochondria for oxidation to acetyl CoA that enters TCA
activation of fatty acids
- before transport into mitochondria
- fatty acids linked to coenzyme A at outer mitochondrial membrane
- via thioester
thirster linkage between fatty acid and acetyl CoA
- forms acyl-CoA
- catalyzed by fatty acid CoA synthetase
- AMP exchanged for CoA (use of ATP)
conjugation for transport
- conjugation to carnitine to form acylcarnitine by carnitine acyltransferases
- loses CoA
acylcarnitine transport
- shuttled across inner mitochondrial membrane by translocase
once acylcarnitine is in mitochondria
- reaction is reversed
- acyl CoA reformed
- carnitine also reformed for transport back to the cytoplasmic side
carnitine deficiencies cause
- defects in multiple proteins
- including acyltransferases
carnitine deficiencies result
- affects transport of long-chain fatty acids into mitochondria
- lipid deposits accumulate
carnitine deficiencies symptoms
- weakness
- hypoglycemic
- hypoketoic
- precipitated by exercise or fasting
carnintine deficiency example
- systemic primary carnitine deficiency
- defect in translocase
beta oxidation of fatty acids occurs where
- in the mitochondria
four reactions for beta oxidation
- oxidation by FAD and acyl CoA dehydrogenase
- hydration by enol CoA hydrates
- oxidation by NAD+ and beta hydroxyl acyl CoA dehydrogenase
- thiolysis by CoA-beta-keto thiolase
continual degradation of fatty acids
- further degraded by acyl CoA dehydrogenase with different enzymes depending on size of fatty acid
- long
- medium
- short
medium chain acyl-CoA dehydrogenase deficiency result
- accumulation of medium-chain fatty acids and derivates
medium chain acyl-CoA dehydrogenase deficiency symptoms
- lethargy
- hypoglycemia
- sudden death precipitated by fasting or vomiting
key difference between odd-chain and even chain fatty acid metabolism
- end product is one propionyl CoA and one acetyl CoA
- instead of two acetyl CoA
fate of propionyl CoA
- enters TCA cycle after conversion to succinyl CoA
- used to produce glucose via gluconeogenesis
acetyl CoA gives how many ATPs?
- 10
palmitate activation takes how many ATPs
- use 2 ATP to start it
fatty acid energy yield
- n cycles
- n FADH2, n NADH, n H+, n+1 acetyl CoA
main source of ketones
- the liver
- fatty acids
- amino acids from protein breakdown
is acetone an energy source
- no
formation of ketones
- acetyl-CoA formed during fatty acid oxidation only enters TCA cycle in presence of oxaloacetate
- oxaloacetate is present only when an adequate supply of glucose
- during fasting or with diabetes, oxaloacetate is used to form glucose and can’t react with acetyl-CoA
- acetyl-CoA diverted to form ketone bodies instead
what is one way to diagnose if someone has high levels of ketones?
- acetone on the breath
- smells fruity
ketone as fuel
- acetoacetate converted to acetyl-CoA
- d-beta-hydroxybutyrate oxidized to NAD+ to yield acetoacetate
then glucose isn’t present, what does the brain use?
- uses ketone bodies for fuel during starvation
- after about 3 days of fasting
- glycerol converted into glucose
how fatty acid breakdown causes ketone levels to rise
- adipose cells supply fatty acids for breakdown during fasting
- liver converts them into ketone bodies but doesn’t use them for fuel
- supply peripheral organs with a fuel source
- glucose saved for brain
type I diabetes
- cannot produce insulin - take up glucose or curtail fatty acid mobilization
- liver can’t absorb glucose or provide oxaloacetate to process fatty-acid derived acetyl-CoA
- adipose cells release fatty acids that are taken up by liver and converted to ketone bodies
- ketone bodies are strong acids
high levels of ketone bodies
- decrease blood pH
- impair tissue function
- especially in CNS
what organs can synthesize fatty acids
- liver and adipose cells
major source of carbon for fatty acid synthesis
- carbohydrate, but protein can be used
start fatty acid synthesis
- start with acetyl-CoA
transport of acetyl coA
- formed in mitochondria and must be transported to cytoplasm
- reacts with oxaloacetate to form citrate in mitochondrial matrix
- citrate transported to cytoplasm through citrate shuttle and cleaves by ATP-citrate lyase to form acetyl-CoA
bring oxaloacetate back to mitochondria
- oxaloacetate reduced to malate by malate dehydrogenase
- requires NADH
- malate decarboxylated to pyruvate by malic enzymes
- generates NADPH
- pyruvate enters mitochondria and is carboxylated to oxaloacetate by pyruvate carboxylase
energy requirement of fatty acid synthesis
- requires NADPH
- comes from PPP
- or reduction of malate
committed step of fatty acid synthesis
- formation of malonyl CoA by acetyl-CoA carboxylase
formation of malonyl CoA
- glucose -> acetyl CoA
- acetyl coA -> malonyl CoA
biotin
- vitamin B7
fatty acid intermediates attached to
- acyl carrier protein linked to fatty acid synthase
- serine of ACP linked to phosphopantetheine that contains pantothenic acid
pantothenic acid
- vitamin B5
condensation reactions
- ACP transfers reduced product to ketosynthesase and is recharged with another malonyl CoA to extend the chain
- process repeated until thioesterase releases final C16 palmitic acid
synthesis of triacylglycerides
- formed from glycerol-3-phosphate and fatty acid acyl CoA to form phosphatidic acid
- phosphatic acid dephoshorylated to form diacylglyceride
- fatty acyl CoA interacts with diacylglyceride to form triacylglyceride
transport of triacylglycerides
- synthesized in liver
- packages in very low density lipoproteins for transport to adipose cells or muscle
fate of very low density lipoproteins
- on capillaries adjacent to muscle and liver cells they are digested by lipoprotein lipase into fatty acids and glycerol
- fatty acids enter cell and used for energy in muscle and stored in adipose cells and reassembled as triacylglycerides
- glycerol shunted back to the liver for use in triacylglyceride synthesis and glujconeogeneis or glycolysis
regulated step in fatty acid synthesis
- acetyl-CoA - > malonyl CoA
- by acetyl CoA carboxylase
activators of fatty acid synthesis
- citrate
- causes enzyme to polymerize into active filaments and make more fatty acids
inhibitors of fatty acid synthesis
- palmitoyl CoA
- negative feedback
fed state
- energy levels and glucose high
- fatty acid synthesized for storage
- insulin inhibition mobilization and stimulates fatty acid storage
insulin and fatty acid synthesis
- stimulates phosphatase that dephosphorylates and activates acetyl CoA carboxylase
high carb, low fat diets
- increase in amounts of acetyl-CoA carboxylase and fatty acid synthase
- increase in fatty acid synthesis
fasting state
- low energy status (AMP high)
- stimulates AMP kinase
- phosphorylates and inhibits acetyl-CoA carboxylase (enzyme that synthesizes fatty acids)
- utilizes ATP
glucagon
- stimulates breakdown of triacylglycerides from fat cells
tumor cells
- use fatty acid synthesis to generate signaling molecules and membrane phospholipids
- enzymes of fatty acid synthesis over expressed
anti-tumor therapies
- inhibit fatty acid synthesis enzymes
inhibiting beta-ketoacyl-ACP synthase
- reduces phospholipid synthesis and cell growth
- leads to apoptosis
inhibiting acetyl-CoA carboxylase
- induces apoptosis in cancer cell lines
