Triglyceride catabolism Flashcards
What are triglycerides
neutral fats that are storage fats, composed of 3 Fatty Acids each in an ester linkage with a single glycerol
Simple TGs have the same kind of FA in all 3 positions (18:1 triolein)
Most naturally occuring TGs are mixed
Oils are unsaturated FAs, Hard fats are Saturated FAs
TGs are stored in adipocytes, and provides more than half the energy requirements of the liver, heart, and resting sk muscle
They are reduced and dehydrated, double the energy, major energy reserve in the body
How TGs get released from Adipose
Step 1: TG must be mobilized (degraded to FAs and glycerol, released and transported to the energy needing tissues)
Step 2: Inside the tissues the fatty acids must be activated and transported into the mitochondria where the enzymes of B oxidation reside
Step 3: the fatty acids must be broken down (oxidized) into acetyl CoA and further processed in the TCA cyclee
Utilization of dietary lipids
Absorption of FAs as an energy source. Humans will obtain fats from the diet, mobilize fats stored in adipocytes, in liver convert excess dietary carbs to fats for export to other tissues to other tissues
Most Fats are ingested in the form of TGs (not soluble in lumen) which must be degraded to FAs for Absorption across the intestinal epithelium. TGs are incorporated into micelles with the aid of bile salts, amphipathic lipid molecules synthesized from cholesterol in the liver and secreted into the bile stored in the gall bladder thats released into the small intestines following a fatty meal
How dietary fatty acids absorbed in the small intestines
Bile salts (inadequate production–>fatty stools aka steatorrhea) emulsify the dietary fats in the small intestine forming mixed micelles
Intestinal/pancreatic lipases degrade the TGs
Fatty acids and others break down products are taken up by the intestinal mucosa and converted into TGs
TGs are incorporated with cholesterol and apolipoproteins into chylomicrons (which also have fat soluble vitamins cholesterol, and steroids)
Chylomicrons move through the blood vessels and lymphatics to tissues
Lipoprotein lipase, activated by apoC2 in the capillary, converts TGs to FAs and glycerol, chylomicron remnants are taken up by endocytosis in liver
FAs enter the cells and are oxidized as fuel or reesterified for storage
Excess TGs are packaged into LDL for transport in the blood to adipose where they are stored as lipid droplets coated in perilipins for protection
How are TGs liberated from Adipocyte lipid droplets covered in perilin
Step 1: Epinephrine/glucagon is secreted in response to low blood glucose levels and activate Adenylyl cyclase which activates cAMP
Step 2: cAMP protein kinase A (PKA) phosphorylates perilipin A and hormone sensitive lipase
Step 3: Hormone Sensitive lipase in the cytosol moves to the lipid droplet where it can begin hydrolyzing TG to free fatty acids and glycerol. RATE LIMITING STEP
Step 4: released free FAs pass from adipocyte into the blood where they non-covalently bind to serum albumin 10 FAs/albumin to increase their solubility
Step 5: Bound FAs are carried to tissues via the blood stream
Step 6: FAs dissociate from albumin and are moved by plasma membrane transporters into the cells to serve as fuel
What happes to the Glycerol when FAs are liberated from TGs in adipocytes
The glycerol released during TG degradation cant be metabolized by adipocytes because they dont have the glycerol kinase, so the glycerol is transported to the liver and phosphorylated to for glycerol-3 phosphate to enter into glycolysis, gluconeogenisis, or transformed into glyceraldehyde 3 phosphate
Activation of FAs and transport into the Mitochondria
Fats are degraded into FAs and glycerol in the cytoplasm of Adipocytes, but the fatty acid catabolic (B oxidation) pathway enzymes are located in the mitochondrial matrix.
Free fatty acids must be activated before entering the mitochondria. FAs longer than 14 C cannot pass through directly so they need the Cartinine shuttle
Cartinine Shuttle Reactions
Reaction 1: esterification to Fatty-acyl CoA (2 step process converts ATP-> AMP) done by acyl CoA synthetase
Reaction 2: transesterification to carnitine followed by transport: Carnitine acyltransferase 1 (CPT 1) binds carnitine and activated FAs (Fatty acyl-CoA) so that the Fatty acyl/carnitine can enter the inner membrane of mitochondria through the Carnitine/ acylcarnitine translocase (CT)- rate limiting (likes 12-16 carbon)
Malonyl CoA is an allosteric inhibitor of the CPT1 (to prevent futile cycling)
Reaction 3: transesterifcation back to mito-CoA: fatty acyl group is transferred from carnitine to CoA by Carnitine acyltransferase 2 (enzyme on inner surface of innermembrane) So that Fatty acyl-CoA and carnitine are released in matrix with carnitine going in the IMS via CT
Functions of Mitochondrial CoA and Cytosolic CoA
Mitochondrial CoA: is used for oxidative degredation of pyruvate (PDH) , FAs, and amino acids
Cyto CoA: is used for membran/ FA biosynthesis
Sources of carnitine
obtained from diet (primarily meat products) or synthesized by lys and met in the liver only
Any issue with carnitine shuttle leads to long chain fatty acids in such a high amount that become toxic
B-oxidation of FAs
Reverse of FA synthesis
Step 1: Dehydrogenation (puts in a trans bond) and makes trans d enoyl CoA thats catalyzed by acyl-CoA dehydrogenase that depends on the chain length (Very Long, Medium, Short Chain Acyl-dehydrogenase)
VLAD is bound on the inner membran but the other 2 are free floating in the matrix. Produces an FADH2
MCAD deficiency (hypoglycemia, high fat in liver, trtmnt: low fat high carb diet)
Step 2: hydration (enoyl-CoA hydratase) breaks the trans bond, and produces B hydroxyacyl CoA
Step 3: Second dehydration (B-hydroxyacyl dehydrogenase) with NADH Production
Step4: thiolytic cleavage (acyl-CoA acetyltransferase, a thiolase) produces an acetyl CoA and an acyl CoA
The steps all have specific chain length enzymes. The inner membrane has a trifunctional enzyme for the last three steps for long chain, the matrix contains monofunctional enzymes.
The stuff is produced in TCA cycle, in the liver acetyl CoA is used to produce ketone bodies for other tissues
Modification of the B-oxidation pathway
Unsaturated FAs: need an extra isomerase to convert cis double bonds to trans, a reductase to take out a single bond
Odd chain FAs: the last pass through B oxidation yields an acetyl Co A and a propionyl CoA that goes through propionyl CoA carboxylase, epimerase, mutase to yield succinyl CoA to go into TCA cycle (and uses Vitamin B12)
Deficiency in the carboxylase or biotin(B12) leads to PA (encephalopathy)
epimerase or mutase deficiency leads MA
Alpha oxidation
branched chain FAs in peroxisome such as Phytanic ACid (abundant in dairy products)
REfsums diesase
Regulation of FA oxidation
The rate of 3 step carnitine shuttle is the Rate limiting step
Malonyl CoA inhibits CPT1
Regulation of B-oxidation enzymes (depend on NADH and acetyl CoA)
During fasting, AMPK is activated and phosphorylates acetyl CoA carboxylase, lowering malonyl CoA synthesis
Ketogenisis
Acetyl CoA is converted into Ketone Bodies consisting of acetone, B-hydroxybutyrate and acetoacetate
Acetone: produced in small quantities and exhaled
Acetoacetate/ B hydroxybutyrate: go to tissues for TCA
