Presentation on theme: "Hepatic Glycogenolysis"— Presentation transcript:
1Hepatic Glycogenolysis regulated byhypoglycemicsignalsphosphorylase b
2Contrast: Skeletal Muscle Glycogen Utilization anaerobic glycolysisCoricyclehepaticgluconeogenesisMuscle lacks G6 PTPaseGlycogen conversion to lactate is not regulated byhypoglycemic signals but solely by muscle’s need for ATP
3PFKepinephrineATP synthesis depletes NADH, which can only be replenished by TCA cycleand glycolysis.
4Skeletal Muscle Metabolism and Work Limited levels of adenine nucleotides ensure that ADP and ATP serve as the link between muscle contraction and glycogen conversion to lactateRegulation of skeletal muscle metabolismglycolysis only occurs if ADP is available because ADP is a required substratephosphofructokinase (catalyzes the 1st irreversible step of glycolysis) controls overall glycolytic rate and is allosterically inhibited by ATP, and activated by 5-AMP and ADPphosphorylase b can be activated by AMPphosphorylase b conversion to phosphorylase a is regulated by epinephrine, released in anticipation of muscular activity, and by muscular activity
7Tissue Utilization of Fatty Acids Fatty acid uptakeplasma free (albumin-bound) fatty acid levels can vary considerably depending on lipolysis ratesuptake: free diffusion across the plasma membranerate of uptake is proportional to plasma concentrationFatty acid utilization is governed by demand, ensuring fuel economyFAD and NAD are necessary for b-oxidationthese factors are limiting in cellselectron transport chain can only generate oxidized cofactors when ADP is presentLiver-derived VLDLsfatty acid in excess of liver energetic needs is converted to triglyceride, packaged into VLDLs and released into circulationavailable to tissues via lipoprotein lipaseVLDL during feeding and fasting
9Gluconeogenesis Occurs with fasting or starvation Source of blood glucose after glycogen stores are depletedSite of gluconeogenesis and source of precursors depends on duration of starvationliver is site after brief fastingkidney is site after prolonged fastingCarbon sourcesglycerol – product of adipose triglyceride degradation; relatively minor contribution to gluconeogenesislactate – 10-30% of glucose can come from RBC lactate or pyruvate; more during muscle activityamino acids – major carbon source from muscle proteolysis
13Ketone Body Formation Ketone body production occurs exclusively in liverprominent in starvation and diabetesnot under direct hormonal controlHepatic b-oxidation during fastinghigh glucagon, low insulin; catacholaminebrisk adipocyte lipolysis and fatty acid availability to liverhigh oxidation of fatty acids supports gluconeogenesisHepatic gluconeogenesis during fastinggluconeogenesis results in depletion of oxaloacetate and slowed TCA cyclehigh b-oxidation and low TCA cycle results in accumulation of acetyl CoA and ac-acetyl CoAthese lead to the production of the ketone bodies: acetoacetate and its derivatives b-hydroxybutarate and acetone
15Ketone Body Utilization Ketone bodies are released into the systemic bloodacetone is eliminated in the urine and exhaled by lungsacetoacetate and b-hydroxybutarate can be used as fuels, make a substantial contribution to fuel homeostasis during starvationConversion of ketone bodies to energy:b-hydroxybutarate and acetoacetate converted to acetoacetyl CoA using succinyl CoA generated from the TCA cycleacetoacetyl CoA is cleaved to 2 acetyl CoA: Krebs cycleBroad range of tissues can use ketone bodiesfed brain cannot because it lacks the enzyme that activates acetoacetateenzyme is induced with ~ 4 days of starvation; hungry brain can derive ~ 50% of its energy from ketone body oxidation, lowering need for glucoseExcess ketone bodies lead to acidosis, which is relieved by the elimination of ketone bodies through urine
17Metabolic Homeostasis Balance Sheet 180 gms glucose produced per day from glycogen or gluconeogenesis75% used by the brainremainder used by red and white blood cells36 gms of lactate are returned to the liver for gluconeogenesisThe remainder of gluconeogenesis is supported bythe degradation of 75 gms of protein in musclethe production of 16 gms of glycerol from lipolysis in adipose tissue160 gms of triglyceride are usedglycerol goes to gluconeogenesis¼ fatty acids converted to ketone, rest is used directly by tissues
18Protein Synthesis and Degradation Protein cannot be stored as a fuelSynthesis of a particular protein isgoverned entirely by the need for that proteinoften triggered by a specific signalwill occur if expression signals > than catabolic signalsDegradation of a particular protein can occurif there is no longer a need for its functionin response to specific signalsif the catabolic state of the cell is highAnabolic/catabolic state is dependent on metabolite and amino acid availability, and on hormonal status.
19Disposition of Protein Amino Acids Body Protein(400g/day)Body Protein(400g/day)AA Pool(100 g)Dietary Protein(100 g/day)Energyglucose/glycogenketones, FAsCO2NonessentialAA synthesis(varies)Biosynthesisporphyrinscreatineneurotransmitterspurinespyrimidinesother N compounds
21Nitrogen Balance Dietary protein brings in nitrogen for biosynthesis synthesis of non-essential amino acidssynthesis of nitrogen-containing compounds in response to specific signalsexcess nitrogen is immediately eliminated via urea cycleFeast or fast, nitrogen will always be excreted because of constant turnover of nitrogen-containing compoundsNitrogen Balancepositive balance: more nitrogen intake than eliminationnet gain of nitrogen over timeoccurs in adolescent growth, pregnancy, lactation, trauma recoverynegative balance: less nitrogen intake than elimination; occurs during starvation and agingto avoid negative balance total AA intake must exceed biosynthetic requirements for nitrogen
24Ammonia Toxicity Ammonia is a common metabolic precursor and product High levels of ammonia are toxic to brain functionbrain completely oxidizes glucose using TCA cycle; oxaloacetate recycling is necessary for optimal TCA cycle activityhigh ammonia forces glutamate and glutamine production from a-ketoglutaratea-ketoglutarate is taken away so oxaloacetate is not regeneratedloss of TCA cycle activity means loss of ATPGlutamine and aspartate (readily formed from glutamate) have neurotransmitter function
25Nitrogen TransferRedistribution of nitrogen (from dietary protein or protein degradation) takes two forms1. Amino acidnitrogen transport between peripheral tissues and liver or kidney (gluconeogenesis during starvation).avoids ammonia toxicityUreasynthesized by liver, transported to kidney, filtered into urineammonia also found in urine but it is derived solely from reactions that occur in the kidney