Nutrient Sensing Mechanisms Flashcards
What are some important mechanisms?
-overall energy status (nucleotides)
(AMPK)
-Overal nutrient status (fed/fasting)
(insulin)
-Glucose-regulated gene expression
(ChREBP)
-Fatty-acid regulated gene expression
(PPARs)
-Amino acid-regulated gene expression
(mTOR)
What does AMPK do? General
-regulates many cellular processes
-activated by AMP
-can result from low nutrient supply or increased energy expenditure (exercise)
REGULATES ATP PRODUCTION;
Turns on catabolic processes
Turns off anabolic processes
Why is AMP-activated?
-AMP is a sensitive index of cellular energy status
-ATP changes very little
-When demand for ATP is high or fuel supply is low
-Some ADP converted to AMP by adenylate kinase
-relative change in AMP much greater than ATP
How does AMPK work?
-responds to an increase in [AMP] by phosphorylating key proteins
-activates energy producing processes ON
(increases glucose uptake, activates glycolysis, activates fatty acid oxidation)
-Suppresses energy requiring processes OFF
(fatty acid synthesis, gluconeogensis, cholesterol synthesis)
What metformin?
-important diabetes drug
-activates AMPK
-decreases hepatic glucose output
-decreased gluconeogenesis and glycogenolysis
What are the major effects of insulin?
-insulin promotes fuel storage
-as a result, insulin lowers the circulating concentrations of glucose, fatty acids, ketone bodies, and amino acids
What signals the pancreas to release insulin?
-major signal: glucose
-other signals: amino acids, ketone bodies, vagal stimulation, GLP-1 and other GI hormones, sulfonylureas
What are the biological actions of insulin?
-promotes the synthesis and storage of fuels:
inhibit their breakdown
(glycogen, lipid, protein)
-Target tissues
(muscle, adipose tissue, live)
What are the effects of insulin on muscle?
-increases the rate of glucose uptake and conversion to glycogen
-actiavtes glycogen synthase
-decreases the rate of glycogen breakdown
-decreases activity off glycogen phosphorylase
-increase amino acid uptake and protein synthesis
-decrease protein degradation
What are the effects of insulin on adipocytes?
-increases synthesis and storage of triacylglycerol
(increases fatty acid synthesis, actiavtes pyruvate dehydrogenase and acetyl-CoA carboxylase, increases triacylglycerol esterification by activating lipoprotein lipase)
~most FA synthesis is in the liver in humans, most triacylglycerol comes from the liver)
-decreases triacylglycerol breakdown (lipolysis)
(decreases activity of adipose triacylglycerol lipase and hormone-senstive lipase)
-increases glucose uptake, glycogen and protein synthesis
What can the liver do in regards to insulin?
Liver can take glucose independently of insulin.
When the concentration of glucose is high, the rate of glucose intake in the liver increases with or without insulin
What are the effects of insulin on the liver? (activate/ inhibit)
-inhibits glucose output:
inhibits glycogen breakdown
inhibits gluconeogenesis (decreases concentration of glucoenogenic enzymes)
-promotes glycogen synthesis
actiavtes glycogen synthase
inhibits glycogen phosphorylase
What are the effects of insulin on the liver? (increase/ decrease)
-increase synthesis of fatty acids, VLDL, and cholesterol
activates acetyl-CoA carboxylase
activates HMG-CoA reductase
-decreases ketogenesis
primarily by inhibiting adipocyte lipolysis
-increases protein synthesis
How is insulin regulated by nutrient metabolism?
-secreted when nutrients, primarily glucose, are plentiful
-increases fuel storage
activates glucose transport
actiavtes lipogenesis
activates glycogen synthesis
actiavtes protein synthesis
-decreases fuel breakdown
inhibits lipolysis
inhibits glycogenolysis
inhibits proteolysis
Explain insulins acute effects.
Acutely increase or decreases activity of key enzymes (primarily by phosphorylation)
ex. activation of glycogen synthase
Explain insulins prolonged effects.
prolonged changes in insulin alters transcription of enzymes involved in nutrient metabolism. >150 genes are transcriptionally regulated by insulin. It changes the concentrations of enzymes
What genes are regulated by Insulin?
Increased: unregulated:
Glucokinase
PFK-1
Pyruvate kinase
G6PDH
PDH
ATP-citrate lyase
fatty acid synthase complex
Decreased: down regulated:
PEP carboxykinase
glucose-6-phosphatase
Explain transcription factors in insulin action.
-numerous, some examples: SREBP-1, CREB, and FOXO1.
Many regulated in response to phosphorylation of Act
Explain regulation of gene expression by glucose.
-several mechanisms documented
-best described involves ChREBP
-expressed primarily in liver, adipose tissue, and kidney
-responds to increases pentose phosphate pathway activity
How is ChREBP activated?
When glucose is high, xylulose-5-phosphate allosterically actiavtes PP2A, which dephosphorylates ChREBP. ChREBP translocates to the nucleus, binds together with a “partner” called Mix to the ChoRE, which regulates transcription.
Turns on genes responsible for lipolysis
What are PPARs?
-family of ligand-activated transcription factors (alpha, beta, gamma)
-respond to changes in dietary lipid by altering gene expression
-first recognized as involved in peroxisome synthesis
-act in combination with RXR
Explain PPARa.
-expressed in liver, kidney, skeletal muscle, brown adipose tissue
-turns on genes for uptake and oxidation of fatty acids and ketogenesis
-activated by fibrates and related drugs (used to lower triacylglycerols and raise HDL)
Explain PPARb:
-regulators of fat oxidation
-respond to dietary factors
-stimulate fat depletion, weight loss and thermogenesis (by uncoupling mitochondria)
-no drugs yet, but interesting target
Explain PPARg:
-expressed primarily in adipose tissue, some in liver
-turns on genes for differentiation of preadipocytes into adipocytes and genes for lipogenesis
-activated by the thiazolidinediones
What do thiazolidinediones do?
decrease fat deposition in liver, which increases insulin uptake in the liver, used the treat diabetes
