Review and Integration of Energy Metabolism (Exam II) Flashcards
Function of liver (metabolism)
- maintains blood glucose level (70-100mg/dL). It has glucose-6-phosphatase so its stored glycogen can contribute to blood glucose. It also makes glucose via glucogneogenesis
- preferentially uses fatty acids and amino acids for its own energy requirements, sparing glucose for glucose-dependent tissues.
- makes ketone bodies, an alternate fuel, BUT does not use them for its own energy requirements. Why? Lacks transferase that moves CoA from succinyl CoA to acetoacetate.
- deaminates amino acids (1° straight chain) and converts the toxic NH3 to non-toxic urea. The C-skeletons can enter the pathways of energy metabolism.
- makes fatty acids using acetyl CoA generated from pyruvate and NADPH from PPP; makes TAG by esterifying fa to glycerol; makes glycerol backbone from glucose.
Function of muscle (metabolism)
- stores glycogen for its own use during exercise
- under anaerobic conditions generates lactate which can be used by liver for gluconeogenesis (Cori Cycle)
- synthesizes and “stores” protein; no dedicated storage form for energy production
- resting muscle preferentially uses faty acids (takes them up from VLDLs in circulation) and amino acids, especially BCAA, (and ketone bodies, if available) for its energy needs
Function of adipose (metabolism)
Stores TAG. It takes up fa from VLDLs in the circulation and esterifies them to make TAG or oxidizes them to acetyl CoA; makes the glycerol 3-P from DHAP.
It degrades TAG to fa + glycerol BUT can’t use the free glycerol to make glucose because it lacks glycerol kinase. The glycerol is sent out and used by the liver (and kidney) to make glucose, as they do have glycerol kinase.
Cytosolic Reactions
- Glycolysis
- Glycogenesis
- Glycogenolysis
- FA synthesis
- PPP (Pentose Phosphate Pathway)
- Urea cycle (partly here, partly in mitochondria)
- Gluconeogenesis (partly here, partly in mitochondria)
Mitochondrial Reactions
- Matrix
a. PDH
b. TCA cycle (except succinate dehydrogenase: associated with mitochondrial
membrane)
c. β oxidation of fa (and ketogenesis in liver) - Inner membrane
a. oxidative phosphorylation
Hepatic Enzymes more active when I/G ratio is HIGH
acetyl CoA carboxylase (acetyl-CoA to produce malonyl-CoA)
fatty acid synthase (synthesis of palmitate from malonyl-CoA & acetyl CoA)
glucose 6-P dehydrogenase (PPP)
glycerol 3-P acyltransferase
glucokinase (glucose to G6P)
PFK1 (F6P to F-1,6-BP)
PK (PEP to pyruvate)
Hepatic Enzymes more active when I/G ratio is LOW
carnitine acyltransferase I (beta oxidation)
glucose 6-phosphatase (gluconeogenesis & glycogenolysis)
phosphoenolpyruvate carboxykinase (gluconeogenesis)
pyruvate carboxylase (pyruvate to OAA)
High energy signals
ATP
citrate
acetyl CoA (in cytosol)
Low energy signals
cAMP
AMP
ADP
P
High glucose signals
fructose-2,6-bisphosphate (in liver)
glucose-6-phosphate
Low glucose signals
cAMP
Acetyl CoA carboxylase: covalent effectors
active when deP; inactive when P
glycogen phosphorylase: covalent effectors
active when deP; active when P
glycogen phosphorylase kinase: covalent effectors
active when P; inactive when deP
glycogen synthase: covalent effectors
active when deP; inactive when P
PDH: covalent effectors
active when deP; inactive when P
PFK2 (kinase domain): covalent effectors
active when deP; inactive when P
PK: covalent effectors
active when deP; inactive when P
Absorptive State
high blood glucose levels; increased I/G ratio
store aa as protein, fat as TAG, glucose as glycogen
synthetic pathways are activated; degradative ones are inhibited
↑I, ↓G, ↓ cAMP, therefore ↓ cAMP-mediated phosphorylation of proteins and activation of phosphatases
Characteristics of blood in the absorptive state.
- Glucose levels will be high, perhaps as high as 8 mM.
- Insulin/glucagon ratio will therefore be high.
- Predominant circulatory lipids are lipoproteins, in particular, chylomicrons.
- Amino acids are present from the digestion of dietary proteins.
Muscle in absorptive state:
Increased
a. glucose uptake; uptake via GLUT4 is I-dependent. Glucose used for glycogen synthesis + for glycolysis
b. uptake and catabolism of BCAA; 1° site of BCAA transaminase
c. protein synthesis
Adipose in absorptive state:
- increased
a. glucose uptake; uptake via GLUT4 is I-dependent
b. glycolysis
c. activity of PPP due to increased glucose-6-phosphate; therefore, increased NADPH
d. NADPH allows for increased fa synthesis. Liver, however, remains primary site of fa synthesis.
e. TAG synthesis - decreased TAG degradation; ↑ I/G; ↓ HSL (de P)
Increased reactions of liver in absorptive state
Uptake of glucose and phosphorylation of glucose. Uptake via GLUT2 is insulin-independent, driven by glucose concentration. Phosphorylation to glc 6-P. Glucokinase is isozyme in liver: high Km, no direct product inhibition. Recall that frc and gal need own kinases.
Synthesis of glycogen via activation (deP) of glycogen synthase and increased availability of glc-6-P, its allosteric activator.
Activity of PPP because of increased glucose-6-phosphate and the use of NADPH in fatty acid synthesis that keeps G6PD active.
Glycolysis because of increased activity (and amount) of key glycolytic enzymes, e.g. activation of PFK1 by fructose 2,6-bisphosphate; pyruvate enters mitochondria, and is oxidized to acetyl CoA by PDH. PDH is active (deP) because its kinase is inhibited by pyruvate.
Fatty acid synthesis via activation of acetyl CoA carboxylase by deP and by increased availability of its ⊕ allosteric effector, citrate; increased availability of NADPH
from the PPP and malic enzyme. Use of NADPH raises NADP+/NADPH and keeps the pentose phosphate pathway active.
TAG synthesis due to increased glycerol from DHAP from glycolysis, and to increased fa. TAG out as VLDL.
Protein synthesis
Degradation of amino acids from food because more aa are present than the liver can use in biosynthesis; their α-ketoacids can be used in synthesis of fatty acids.
Decreased reactions of liver in absorptive state
Free fatty acid availability due to I-mediated decrease in HSL activity (de P) in adipose.
Fatty acid degradation due to increased malonyl CoA and its inhibition of CAT I.
Gluconeogenesis due to inactivation of pyruvate carboxylase because of the low levels of acetyl CoA, its ⊕ allosteric effector. The acetyl CoA is being used in
fa synthesis. Frc 2, 6-bis P from PFK-2 inhibits frc 1,6 bisphosphatase.
Glycogenolysis due to inactivation (deP) of phosphorylase kinase and phosphorylase.