Lipid Metabolism PDF

Lipid Metabolism I could seriously get into some high fat diets!!!!!! Or could you??? 1  Lipid Metabolism Sources: Adipose triacylglycerol (TAG) or triglyceride (TG) Intramuscular TAG or TG (IMTG) Bl...

Lipid Metabolism I could seriously get into some high fat diets!!!!!! Or could you??? 1  Lipid Metabolism Sources: Adipose triacylglycerol (TAG) or triglyceride (TG) Intramuscular TAG or TG (IMTG) Blood-borne Albumin-bound free fatty acids (FFA or FA) from adipose TAGs from chylomicrons (intestinal-derived) or VLDL (liver) Lipids as a Fuel: The body’s main form of stored energy Makes sense to use this if possible to spare carb reserves Can’t use anaerobically … but still contributes to high intensity exercise (e.g. 85% VO2 max) 2  Sites of Regulation 1) Mobilization from adipose tissue 2) Uptake by muscle 3) Mitochondrial uptake and oxidation 3  Mobilization from Adipose Tissue Also ATGL Review: What is the fate of fatty acids in adipose tissue? 1) Release, 2) Re-esterification (storage), 3) Oxidation 4  Lipolysis is More Sensitive to Epi after Training In a rat study, 18 wk of swim training increased amount of HSL and sensitivity of HSL to stimulation by Epi (5 or 20 min) in adipose tissue (differences between fat depots). Black bars = trained rats White bars = sedentary rats Enevoldsen et al. J Physiol. 536(3):871-7, 2001 5  Muscle fatty acid uptake FAT/CD36 FABPpm FATP1-6 6 FAT/CD36, fatty acid translocase; FABP, fatty acid binding protein; FATP, fatty acid transport family  Two separate pools of FAT/CD36 translocate in response to insulin and exercise Translocation to plasma membrane and fatty acid uptake are partially additive Take home point: Insulin and contraction stimulate FA transport in an additive manner. Increase in transport is facilitated by FA transport proteins. Jain et al. FEBS Letters 583(13):2294-2300, 2009 7 7 days of electrical stimulation via sciatic nerve 8  The human data: 2 hrs cycling @ 60% VO2 max What “refinement” has been made in this study in terms of measurements? 9  Think about both carbohydrates and lipids…. Response of fatty acid transporters to exercise is similar to that of GLUT4 Co-ordinated regulation of both GLUT4 and FAT/CD36 ensures adequate uptake of fuel to the working muscles 10  Circulating triglycerides as a fuel source during exercise Morino et al. 2012 Lipoprotein lipase breaks down plasma triglycerides and allows for fatty acids to be taken up by skeletal muscle. Don’t worry about the rest of the schematic 11  Exercise and Lipoprotein Lipase in Skeletal Muscle Greiwe et al. J Appl Physiol 89: 176-181, 2000 dg0700026002 6 subjects, cycled at 65% VO2 max, 1 h Increased total amount of LPL in muscle What does this do? Helps to ensure increased supply of fatty acids to contracting muscle 12  Intramuscular lipid utilization during exercise Van Loon et al. 2004 13  120 minutes of exercise, 60% of VO2 max No lipid breakdown in type II fibers Point of interest: The Danish group shows basically the opposite … break down intramuscular lipids during recovery! J Physiol 553(2): 611-25, 2003 14  Mitochondrial membrane transport FA entry into the mitochondrion is a complex process! Minimally, requires carnitine palmitoyl transferase1 (CPT1), as well as the substrate carnitine FA are activated by acyl CoA-synthetase to form FA acyl-CoA Fatty acyl CoA gets converted to fatty acyl carnitine, which can move across the mitochondrial membrane This was the dogma until only a few years ago i.e. that CPTI was rate limiting for FA entry into mitochondria FAT/CD36 may also be present on inner mitochondrial membrane! Again, some controversy! With the Danish researchers!!! 15  Journal of Human Genetics 64:87-98, 2019 FAT/CD36 ? Lots of “fat burning” supplements contain carnitine … but is it necessary??? Probably not! 16 At a given workload, the contribution from fat oxidation increases in exercise-trained subjects 4 h low-intensity running T UT 1 h recovery T T UT UT 17 Klein et al. Am J Physiol 267:E394, 1994.  What happens to plasma FFA with aerobic training? Does this agree with what we previously showed??? untrained trained Klein et al. Am J Physiol 267:E394, 1994. 18 So, trained individuals use more total fat utilization during aerobic exercise, but they have lower circulating FFA levels - can this be right? Yes! 1. This illustrates a possible shift from where the fat comes from: i.e. less dependency on plasma FFAs, but a greater dependency on intramuscular TGs 2. Is the contribution from plasma FFAs really impaired in the trained state? Plasma levels might be lower in trained individuals, BUT trained muscle has more fatty acid transporters (FAT/CD36!) - thus there is better extraction from the blood! Which might be why the plasma FFA levels are lower! 3. This is low intensity and catecholamine response is not very large. What you see in the plasma could well be different at higher intensities. Or in isolated cells with a fixed concentration of epi. 19  How is Fat Oxidation Increased with Training?  increased sensitivity of adipose HSL to epi  increased lipoprotein lipase content  increased FA transporters at the plasma membrane  increased content of bet-oxidation, Krebs, and ETC enzymes  increased IMTG content (increased local source of FFAs) 20  IMTG associated with insulin resistance: a paradox in endurance trained athletes? M = glucose disposal Lots of IMTG BUT insulin sensitive ! Take home point: TGs must not be interfering with insulin sensitivity. What is? Goodpaster et al. J Clin Endocrinol 86: 5755-5761, 2001 21 Diacylglycerols and ceramides interfere with insulin signaling leading to insulin resistance Insulin LCFA Glucose Ins R FAT/CD36 GLUT4 IRSP P PKCs DAG Akt2 Glucose LCFA ceramides P Glycogen AS160 P IMTG GLUT4 FAT/CD36 GLUT4 z GLUT4 z FAT/CD36 ATP FAT/CD36 ATP 22 Total ceramide, not DAG, reduced in athletes Ceramides DAGs NWA = normal weight athlete NWS = normal weight sedentary OBS = obese sedentary Total DAG was lowest in obese subjects! But, unsaturated FA content in DAG was lowest in normal weight individuals. Muscle ceramide content highest in obese individuals. This is true of total ceramides, as well as saturated and unsaturated FA content. Amati et al. Diabetes 60(10): 2588-97, 2011. 23