What is a mixed micelle?
mixture of bile salts, pancreatic lipase, TGs
How are TGs digested?
TG --pancreatic lipase + collapse--> 2-monoglycerol + 2FAs
What are the 3 functions of collapse?
1. cofactor - improves pancreatic lipase activity2. activated by Trypsin3. displaces bile to allow recycling
1. In what form are lipids absorbed? 2. What happens in lipid malabsorption?
1. packaged in micelles (FAs, 2-monoglycerol, cholesterol, fat-soluble vitamins) and lipids partition out when absorbed 2. results in loss of lipids in feces (steatorrhea) and loss of fat-soluble vitamins A, D, E, K
How are lipids absorbed?
1. fat droplet broken into smaller droplets by lingual lipase in stomach2. pancreatic lipase + collapse release 2-monoglycerol + FAs in duodenum 3. these diffuse to micelles and then to brush border and are absorbed in duodenum, jejunum, ileum4. bile salts are reabsorbed in terminal ileum and sent to portal circulation and then cleared by the liver
What 2 other enzyme reactions are involved in lipid digestion?
1. cholesterol ester -cholesterol esterase-> cholesterol + FA2. phosphatidylcholine -phospholipase A2-> lysophosphatidylcholine + FA
How does chain length affect FA absorption?
1. <10 C chains diffuse to gut epithelium into hepatic portal blood supply2. >=12 C chains transported to ER of gut epithelial cells for re-synthesis into TGs **first need to activated
How are FAs activated?
long chain FAs enter ER and are activated by CoASH to form FA-CoASH
How are TGs synthesized?
activated FAs packaged with cholesterol into nascent chylomicrons and then released into lymphatic system
How do nascent chylomicrons become mature?
interact with high density lipoprotein (HDL) and take up apoprotein CII (apoCII) and apoprotein E (apoE)
What is the composition of chylomicrons?
high TGsrest low protein, cholesterol, cholesterol ester, phospholipid
What happens to mature chylomicrons?
ApoCII activates lipoprotein lipase (LPL) that digests TGs and produces FAs + glycerol1. FAs enter muscle for energy production or adipose for fat storage 2. glycerol metabolized in liver3. chymicron remnants are taken over by liver receptors that recognize apoE, then degraded into component parts
What are 2 examples of fat absorption preventers and their functions?
1. Olestra: lipid produced by esterification of 6-8 FAs with sucrose -> taste like natural lipid, cannot be hydrolyzed to absorbable constituents so excreted 2. Orlistat: non-hydrolyzable analog of TGs-> inhibits pancreatic lipase
When does FA oxidation occur?
between meals, fasting, exercise
How does LCFA oxidation happen?
*LCFA released from TGs by lipases and travel in blood bound in hydrophobic pocket of albumin 1. FA-binding proteins transport FAs across plasma membrane to cytosol2. Fatty acyl-CoA synthase activates FA -> FA-CoA3. Carnitine trasnports FA-CoA to mitochondria 4. beta-oxidation (cleavage) yields NADH, FADH2, acetyl-CoA, FA-CoA (n-2)*if acetyl-coA levels in liver elevated, will be converted into KBs
How are FA-CoAs activated?
1. requires ATP2. FA-CoA has a high energy thioester bond 3. driven by hydrolysis of pyrophosphate
What is the fate of FA-CoAs?
1. energy (beta-oxidation, ketogenesis)2. storage (triacylglycerols)3. membrane lipids (phospho/sphingo
How are FAs transported to mitochondria?
*requires carnitine from diet or lysine side chain 1. CPT1 catalyzes transfer of LCFA-acyl from FA-CoA to carnitine hydroxyl group in OMM to make Fatty Acyl Carnitine *reversible2. Fatty Acyl Carnitine is transported across IMM3. CPTII coverts back to FA-CoA
What is the beta-oxidation spiral?
oxidation of beta-C and cleavage of alpha-beta bond in FA-CoA produces: Acetyl CoA, NADH, FADH2, fatty acyl-coA (n-2)*repeats until all Cs converted to Acetyl CoA
What does the oxidation of palmitoyl CoA produce?
requires 7 cycles 7 NADH, 7 FADH2, 8 Acetyl CoA
What happens to the products of beta-oxidation?
1. e-s from beta-C oxidation conserved in NADH + FADH2 to enter ETC and generate ATP 2. acetyl-CoA enters TCA to generate NADH, FADH2, GTP
What is beta-oxidation of unsaturated FAs?
alot of FAs from our diet are unsaturated --> oleate and linoleate cis double bonds converted to trans
What is beta-oxidation of odd-carbon FAs?
spirals of beta-oxidation produce acetyl-coA + propionyl-CoA -> carboxylation yields methylmalonyl-CoA -> converted to succinyl-CoA with Vitamin B12 -> enters TCA
What is peroxisomal FA oxidation?
*NOT couple to ATP synthesis generates peroxide-> converted to H2O +O2 by catalase in peroxisomes 1. acetyl groups are transferred from CoA to carnitine by acetylcarnitine transferase (CAT) 2. acyl carnitines diffuse from peroxisomes to mitochondria through OMM and IMM via CPT system3. converted back to CoA by CAC/CPTII to enter TCA or beta-oxisation
What is omega-oxidation?
-used in some animals or if beta-oxidation is bad1. FAs oxidized by ER enzymes 2. produce dicarboxylic acids 3. undergo beta-oxidation 4. form compounds with 6-10 Cs that can enter blood 5. can be oxidized in mitochondria or excreted in urine as MC-dicarboxylic acid
What are 4 mechanisms of FA oxidation feedback regulation?
1. hormones (insulin/glucagon) control supply of FAs in blood 2. CPT1 is inhibited by malonyl-CoA3. NADH, FADH2 inhibit beta-oxidation 4. decreased ATP use increases NADH/FADH2
What are the KBs? Where produced? Where used?
1. acetoacetate + beta-hydroxybutyrate 2. made in liver 3. can be used as fuel by all tissues + cells except liver + RBCs3. enter blood, converted to acetyl-CoA + H2O in TCA
How are KBs synthesized?
2 acetyl-CoA --thiolase--> acetoacetyl-CoA + acetyl-CoA --HMG-CoA Synthase --> HMG-CoA --HMG-CoA lyase--> Acetyl-CoA + acetoacetate --> reduced to beta-hydroxybutyrate (enters blood in 1:1 w/acetoacetate) or decarboxylated to acetone (expired by lungs)
What 3 events promote KB synthesis during fasting?
1. increased FA supply from TGs2. decreased Insulin -> dec acetyl-coA carboxylase -> dec malonyl-CoA -> activates CPT1 -> FA-CoA can enter beta-oxidation 3. when FA-CoA levels high in liver (enough NADH + FADH2 for ATP supply) A-CoA are diverted to ketogenesis from TCA
How are KBs used as fuel?
1. acetoacetate forms 2 acetyl-CoAs that can enter TCA2. beta-hydroxybutyrate forms acetoacetate + NADH and yields 21.5 ATP
What happens to KB levels during fasting?
FA levels increase then constant glucose levels decrease then constant KBs levels increase and stay high and can be used as fuel especially for the brain
What are 2 diseases related to FA oxidation and KBs? Functions?
1. carnitine deficiency : lack of membrane transporter for carnitine 2. Jamaican vomiting disorder: inhibition of carnitine by hypoglycin, leads to hypoglycemia, then death