Part 4 Flashcards
Products which fuel gluconeogenesis and which organs they come from
Lactate: derived from lipolysis and beta oxidation (acetyl coA —> pyruvate —> lactate)
Amino acids: AA that can convert to oxaloacetate only (no acetyl coA or acetoacetyl coA AA) coming from muscles
Glycerol: TAG mobilization in white adipose produces glycerol which can enter Krebs cycle as G3P
Pathways and enzymes affected by glucagon in the liver
Upregulated:
Glycogenolysis: glycogen phosphorylase
Gluconeogenesis: pyruvate carboxylase, PEP carboxykinase, FBPase-1, glucose-6-phosphatase
Ketogenesis and beta oxidation (ATP provision for liver)
Down regulated:
Glycogenesis: glycogen synthase
Glycolysis: hexokinase, PFK-1, pyruvate kinase
Lipogenesis
Pathways affected by glucagon in white adipose
Upregulated: lipolysis
Down regulated: lipid and TAG biosynthesis
Pathways and enzymes affected by glucagon in muscle:
Upregulated:
Glycogenolysis: glycogen phosphoylase
Glycolysis (to fuel muscle)
Protein degradation (provide AA for gluconeogenesis in liver)
What type of signalling is glucagon and epinephrine?
Receptor structure and pathway overview
Hydrophilic molecule signalling with second messengers to amplify signal
Hundreds of types of GPCR, similar pathways with slightly different receptors
Trimeric G protein subunit with G protein alpha, beta and gamma cytosolic portion
General amplification pathway
1) Signal binds —> activates enzyme
2) Enzyme activates second messengers
3) Second messengers activate kinases
4) Kinases activate enzymes to produce target change
Each step amplifies signal
When is a GPCR inactive? When is it active?
GEF vs GAP?
When GDP is bound intracellularly it is inactive
When GTP is bound to the alpha subunit and it is independent from beta and gamma subunits GPCR is active
GEF (guanine nucleotide exchange factor) swaps GDP for GTP activating signal transduction
GAP (GTPase activating protein) activates GTPase activity to hydrolyze GTP to GDP inactivating signal transduction
Second messenger examples
cGMP
cAMP
Ca 2+
Inositol 1,4,5 triphosphate
Krebs cycle metabolites sometimes between cells
PKA activation pathway
1) GTP-bound GPCR alpha subunit activates adenyl cyclase
2) adenyl cyclase converts ATP —> cAMP x4
3) 4 cAMP bind the 2 PKA regulatory subunits, releasing the 2 catalytic subunits
4) 5’3’ phosphodiesterase converts cAMP —> AMP to terminate signal
How does caffeine affect epinephrine signalling?
Caffeine is an adenosine analog and inhibits phosphodiesterase conversion of cAMP to AMP, prolonging epinephrine signalling and making us feel more awake
Adenosine build up is what causes us to get sleepy
Function of pancreatic alpha cells
Contain glucagon granules which are stimulated to fuse with plasma membrane and be released into blood stream when blood glucose drops
Glycogenolysis pathway in liver and muscle
Liver:
Glycogen —> G1P by Glycogen phosphorylase (RLS, B6 dependent)
G1P —> G6P by phosphoglucomutase
G6P —> glucose by Glucose-6-phosphatase - fuels body
Muscle:
Glycogen —> G1P by Glycogen phosphorylase (RLS, B6 dependent)
G1P —> G6P by phosphoglucomutase
G6P —> pyruvate via glycolysis (ATP for muscle function) - no G6Phosphatase in muscle
Glucagon/epinephrine pathway leading up to glycogenolysis
1) hormone binds GPCR receptor
2) activation of adenyl cyclase
3) ATP —> cAMP
4) 4x cAMP activates 2 PKA
5) PKA converts phosphorylase kinase b —> phosphorylase kinase a (active)
6) phosphorylase kinase a converts glycogen phosphorylase b —> glycogen phosphorylase a (active)
Enzymes required for glycogenolysis and why
Glycogen debranching enzyme - moves a1,6 linkages to main chain
- initiates glycogenolysis and engaged when GP stalls at a branch point
Glycogen phosphorylase a - separates glucose monomers to form G1P
Glycogen phosphorylase a can’t debranch due to steric hinderance
Enzymes work in tandem with glycogen debranching enzyme
As a product of glycogenolysis G1P can feed into which pathways?
Convert to glucose
Energy metabolism (glycolysis and Krebs)
PPP (after conversion to G6P)
Gluconeogenesis during vigorous exercise vs. starvation
Vigorous exercise: Cori cycle gluconeogenesis of lactate –> glucose in the liver
Starvation: gluconeogenesis from AA and glycerol (from lipolysis)
Which AA cannot be used for gluconeogenesis (aka ketone forming)?
Which can form acetyl coA or acetoacetyl coA
Ile, Leu, Lys, Trp, Phe, Tyr
Acetyl coA: Ile, Leu, Trp
Acetoacetyl coA: Ile, Lys, Trp, Phe, Tyr
How does glucagon affect F-2,6-BP and gluconeogenesis?
Glucagon increases FBPase-2 activity, decreasing [F-2,6-BP] and thus increasing F-1,6-bisphosphatase activity in gluconeogenesis
The 2 signaling pathways and targets of the pathways for glucagon (gluconeogenic and ketogenic)
G(alpha_s) –> AC –> cAMP –> PKA:
1) PKA activates CREB (gluconeogenic)
2) PKA activates FoxA2 (ketogenic, indirect)
3) PKA activates MAPK which activates PPARA2
4) PKA activates FoxO
- 2 ways, via IP3R and indirectly
G(alpha_q) –> PLC –> IP3 –> IP3R –> Ca2+ release
1) Ca2+ release activates FoxO (indirectly)
- PKA helps stimulate too
Lipolysis pathway during starvation
How fatty acids travel in the blood
Fuel for the liver
1) TAG –> DAG, Hormone sensitive lipase
2) DAG –> MAG, Lipoprotein lipase
3) MAG –> glycerol for gluconeogenesis + FAs for beta oxidation, Monoacyl-glycerol lipase
SCFA travel in the blood, whereas long chain FA are escorted by albumin in the blood
Glucagon effect on ACC activity
1) Palmitate from TAGs mobilized from adipose binds ACC to induce depolymerization
2) Glucagon/epinephrine signaled PKA phosphorylates monomeric ACC inactivating it
