4- Triglyceride Metabolism and Ketogenesis Flashcards
triglycerides
- storage fats/stored energy (provide more than half energy requirements of liver, heart, and resting skeletal muscle)
- major energy reserve in body
- composed of 3 fatty acids, each with an ester linkage to a single glycerol
-highly concentrated stores of metabolic energy cause they are reduced and dehydrated (stored free of water, so less weight than carb/protein) and yield 9kcal/g of energy instead of 4kcal/g by carb/protein (TG are more reduced)
simple= same fatty acid in all 3 positions
most naturally occurring ones have different fatty acids on the glycerol
adipocytes
- specialized fat cells that store TG
- found under skin and in abdominal cavity/mammary glands
- store neutral lipids as lipid droplets
long term vs. short term energy
short-term: glucose and glycogen, fast delivery
long-term (months): fats like TG, slow delivery
Peripheral tissues need to gain access to fatty acid energy reserve stored in adipocytes… how do they do this?
3 steps
1. TG must be mobilized (degraded to fatty acids/glycerol, then released from adipose tissue and transported to energy requiring tissues)
- Inside tissues they must be activated and transported into mitochondria where enyzmes of B-oxidation reside
- fatty acids must be broken down (oxidized into acetyl-CoA, which can be further processed in the TCA cycle)
How do we get the fat into our usable system?
- from diet
- mobilized stored fat in adipocytes
- convert excess dietary carbs to fats for export to other tissues in liver
- most fats are ingested in form of TG which is degraded to fatty acids for adorption across intestinal epithelim
- TG are not very soluble so they need bile salts with them which are released into the small intestine after a fatty meal
bile salts
- biological detergent (forming mixed micelles to help emulsify fat)
- allows pancreatic lipases to break it up
amphipathic lipid made in liver and stored in gall bladder which is released into the small intestine after a fatty meal
steatorrhea
- inadequate production of bile salts
- lipid malabsorption (typically comes with liver disease/damage)
- large amounts of fats are excreted in the feces
Dietary fatty acids absorbed in small intestine (discuss mechanism)
fats ingested in diet
- bile salts emulsify dietary fat in small intestine (forming mixed micelles)
- Intestinal lipases degrade triacylglycerols
- fatty acids and other breakdown products are taken up by the intestinal mucosa and converted into triacylglycerols
- triacylglycerols are incorporated, with cholesterol and apolipoproteins, into chylomicrons
- chylomicrons move though the lymphatic system and bloodstream to tissues
- lipoprotein lipase, activated by apoC-II in the capillary, converts triacylglycerols to fatty acids and glycerol
- fatty acids are oxidized as fuel or reesterified for storage
chylomicrons
- largest lipoproteins
- released into lymph the blood and bind to lipoprotein lipases (primarily at adipose tissue and muscle), where it is then hydrolyzed into free fatty acids and glycerol for transport into tissues
triglyceride-rich spherical particles also function in the transport of fat-soluble vitamins, cholesterol, and steroid hormones
what happens to chylomicron remnants
-smaller remnants that get taken to the liver…
taken up by liver by endocytosis
- TG can be oxidized to provide energy or precursors for the synthesis of ketone bodies
- if diet has more FA then needed, then TG is packaged into very low density lipoproteins (VLDL) for transport in blood to adipose tissue (for storage as lipid droplets within adipocytes)
lipolysis
mobilization of stored fatty acids
- stimulated by glucagon
- inhibited by insulin
lipid droplet and perilipins
- Lipid Droplet
core: sterol esters and TG
outer layer: monolayer of phospholipids - Perilipins
coat lipid droplets to prevent untimely lipid mobilization .
Steps taken when glucagon is released (need metabolic energy)
- Epinephrine/glucagon, secreted in response to low blood glucose levels, activate adenylyl cyclase in the adipocyte plasma membrane to produce cAMP
- PKA phosphorylates perilipin A and hormone sensitive lipase
- RATE LIMITING STEP. Phosphorylated perilipin causes hormone sensitive lipase in the cytosol to move to the lipid droplet where it can begin hydrolyzing TG to free fatty acids and glycerol.
- free fatty acids pass from the adipocyte into the blood to bind to albumin (10 FA/monomer) to increase their solubility
- Bound fatty acids are carried to tissues (e.g. skeletal muscle, heart, renal cortex) via the bloodstream.
- Fatty acids dissociate from albumin and are moved by plasma membrane transporters into cells to serve as fuel.
what happens to glycerol when TG is broken down?
-adipocytes dont have glycerol kinase so glycerol is released to go back to the liver
glycerol (glycerol kinase) L-glycerol-3-phosphate (glycerol 3-phosphate dehydrogenase) dihydroxyacetone (triose phosphate isomerase) D-glyceraldehyde 3-phosphate
-which can then go into glycolysis
why do type II (insulin-independent) diabetics frequently exhibit hypertriglyceridemia?
partly due to aberrant regulation of hormone-sensitive lipase
degradation of fats
fats are degraded into fatty acids and glycerol in cytoplasm
BUT enzyme that does B-oxidation is in the mitochondrial matrix
- free fatty acids taken up by energy-requiring tissues must fist be activated before they can enter this intracellular organelle
- fatty acids with chain lengths of 14 or more carbons cannot pass directly though the mitochondrial membrane so they first go through the carnitine shuttle (3 rxns)
Carnitine Shuttle
fatty acids with carbons chains of 14 or more go through this shuttle to get into the mitochondrial matrix so they can be degraded by B-oxidation
Carnitine Shuttle (3 steps)
- Esterfication to CoA
- enzyme: acyl-CoA synthetase (2 step rxn)
- occurs in cytosolic side of outer mitochondrial membrane
- uses 2 ATP
Activated long-chain fatty acids are transported across inner mitochondrial membrane….
- Transesterification to carnitine…
- enzyme: carnitine acyltransferase I (CPT1)
- attaches acyl group of CoA to carnitine
….followed by transport (RATE LIMITING STEP FOR B-OXIDATION)
- fatty acyl-carnitine enter maxtrix by facilitated diffusion
- channel: acyl -carnitine/carnitine transporter OR Carnitine/acylcarnitine translocase (CT) that spans inner mitochondrial membrane
-Malonyl CoA inhibits CPT1 isoform in liver and prevents futile cycling in liver
- Transesterfication back to CoA
- enzyme: carnitine acyltransferase II (CPT II)
- occurs on inside of inner mitochondrial membrane
- fatty acyl-CoA and carnitine are released into the matrix, carnitine then reenters the intermembrane space via CT
two separate pools of CoA and fatty acyl-CoA
- Mitochondrial CoA: used in the oxidative degradation of pyruvate (pyruvate dehydrogenase complex reaction), fatty acids and some amino acids. Mitochondrial fatty acyl-CoA is the substrate for β-oxidation
- Cytosolic CoA: used in membrane lipid/fatty acid biosynthesis. whereas the cytosolic fatty acyl-CoA is used for membrane lipid synthesis or it can be linked to carnitine and moved into the matrix for oxidation and ATP production.
carnitine
helps move fatty acyl CoA back to mitochondrial matrix
sources of carnitine
-obtained from diet (meat)
- synthesized by lys and met in liver and kidney BUT NOT SKELETAL MUSCLE OR HEART
- heart and skeletal muscle are completely dependent on carnitine from hepatocytes and diet
diseases from deficiencies of individual components of the carnitine cycle
result in impaired utilization of long-chain fatty acids for energy production and accumulation of toxic amounts of free fatty acids
CPT1 def in liver: impairs liver from synthesizing glucose during a fast, leads to hypoglycemia
CPT2 def: occurs primarily in cardiac and skeletal muscle, where symptoms range from cardiomyopathy to muscle weakness
B-oxidation overview
- fatty acid degradation
- one pass through removes 2 carbons so you need 7 rounds to oxidize 1 molecule of palmitoyl-CoA to 8 acetyl-CoA
- once this occurs then acetyl-CoA is formed and goes into the TCA cycle
or
FADH2 and NADH are formed and go to ETC
ACETYL-COA IS THE MAIN PRODUCT
B-oxidation steps (detailed)
- Dehydrogenation of fatty acyl-CoA
-acyl-CoA dehydrogenase
-produces FADH2
Palmitoyl-CoA —> trans-delta2-enoyl-CoA - hydration of the trans double bond
- second dehydrogenation
- Thiolytic cleavage
- releases molecule of acetyl-CoA and acyl-CoA that is shortened by two carbons
- NOTE: all enzymes in B-oxidation are specific to chain length like acyl-CoA dehydrogenase
- there is an inner mitochondrial membrane-bound trifunctional protein that contains all three long chain enzymes