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Scientific Foundations > Lecture 50 > Flashcards

Lecture 50 Flashcards

Energy Storage and Release II

1
Q

metabolic homeostasis

A

regulation achieved at 3 levels: hormones, nervous system, availability of circulating substrates
also balanced by fuel availability and tissue needs

pg 1287

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2
Q

liver ketogenesis: substrates

A
  • substrate for ketone body production is acetyl CoA
  • all ketone body production carried out in mitochondria in liver
  • 1st metabolite is acetoacetyl CoA; ketone bodies produced are acetoactate and 3-hydroxybutyrate

pg 1290

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3
Q

acetyl-CoA formation

A
  • glycolysis
  • fatty acid oxidation
  • ketogenic amino acid catabolism

pg 1290

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4
Q

liver ketogenesis: steps 1 and 2

A
  • step 1: thiolase expressed in liver combines 2 acetyl CoA to acetoacetyl CoA
  • step 2: HMG CoA synthase
  • activators of ketogenesis: fasting and high AMP (high glucagon), increased lipolysis in adipose tissue
  • inhibitors of ketogenesis: food intake, insulin

pg 1291

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5
Q

HMG CoA synthase

A
  • rate-limiting and regulated step
  • expressed ONLY in the liver
  • therefore only liver cells are capable to produce ketone bodies
  • converts acetoacetyl CoA and acetyl CoA to 3-hydroxy-3-methyl glutaryl CoA (HMG CoA) -> metabolite also produced in de novo synthesis of cholesterol

pg 1291

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6
Q

liver ketogenesis: steps 3 and 4

A
  • 3rd step: HMG CoA converted to acetoacetate (1st ketone body) by HMG CoA lyase -> releases an acetyl CoA
  • 4th step: acetoacetate converted to D-β-hydroxybutyrate (2nd ketone body) OR acetone (spontaneous decarboxylation)

pg 1292

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7
Q

liver ketogenesis: products

A
  • physiological ketone bodies: acetoacetate and D-β-hydroxybutyrate
  • non-physiological ketone body: acetone -> volatile, exhaled if not used, fruity breath (ketoacidosis -> occurs in pts w/ increased production of ketone bodies)

pg 1293

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8
Q

liver ketogenesis: summary

A
  • ketone bodies always produced at a low rate
  • always some ketone bodies in the bloodstream

pg 1294

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9
Q

diabetic ketoacidosis (DKA)

A
  • in untreated T1D, the absolute lack of insulin leads to inability to suppress ketogenesis
  • happens very quickly, leads to high levels of ketone bodies

pg 1295

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10
Q

disorders of fatty acid oxidation

A
  • all present with the general picture of…
  • hypoketosis (because of decreased availability of acetyl CoA -> not produced by FAs)
  • hypoglycemia (because of increased reliance on glucose for energy)

pg 1295

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11
Q

during prolonged fasting…

A

ketone bodies are produced at a higher rate in the liver and become a significant source of energy for peripheral tissues, and brain

pg 1295

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12
Q

thioporase

A
  • allows peripheral tissues to utilize ketone bodies for energy (inside the mitochondria)
  • expressed ONLY in peripheral tissues
  • liver DOES NOT express this enzyme, therefore it is unable to utilize ketone bodies for energy

pg 1296

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13
Q

energy yield for oxidation of ketone bodies

A
  • 3-hydroxybutyrate yields 27 ATP
  • acetoacetate yields 24 ATP
  • small molecules but yield lots of energy

pg 1297

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14
Q

ketone bodies in prolonged fasting

A
  • produce ketone bodies at higher rates in the first 10 days of fasting -> ketone bodies also lower pH in the bloodstream
  • post-absorptive state: 6-12 hours between meals -> overnight fast
  • prolonged fasting: several days (3-4)
  • starvation: several weeks

pg 1298

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15
Q

liver in absorptive state

A
  1. glucose uptake by insulin-independent GLUT2 is driven by rise in blood glucose
  2. rise in glucose allows phosphorylation by glucokinase which has a high Km for glucose
  3. glycogen synthase is activated by dephosphorylation and glucose-6-P
  4. glucose-6-P availability stimulates PPP, providing NADPH for FA synthesis
  5. dephosphorylation of pyruvate dehydrogenase favors acetyl CoA production
  6. TCA cycle inhibition at isocitrate dehydrogenase allows use of acetyl CoA in FA synthesis; acetyl CoA carboxylase activated by dephosphorylation and citrate
  7. glycolysis provides glycerol backbone for TAG synthesis

pg 1300

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16
Q

adipose tissue in absorptive state

A
  • glucose enters via insulin-sensitive GLUT 4
  • glucose converted to acetyl-CoA, forms the backbone to store TAG molecules, and produces NADPH
  • NADPH and acetyl CoA can be used for FA synthesis in adipose tissue if needed
  • adipocytes designed to store TAGs for a long time
  • VLDL go to adipose tissue from liver
  • chylomicrons from gut go to adipose tissue (reach peripheral tissues before liver via lymph)
  • fat stored in adipose tissue is derived from dietary FAs packaged as TAG in chylomicrons and endogenous FAs made in the liver and packaged as TAG in VLDL

pg 1301

17
Q

resting skeletal muscle in absorptive state: amino acids

A
  • ⇧ synthesis of proteins (reproduce enzymes and other tissue proteins)
  • ⇧ uptake and metabolism of branched-chain AAs (1st couple steps occur here, rest in liver)
  • ⇧ degradation of excess AAs and the carbon skeleton used for other pathways (we cannot store AAs)

pg 1302

18
Q

resting skeletal muscle in absorptive state: glucose

A
  • ⇧ GLUT4 mediated transport (regulated by insulin)
  • ⇧ glucose phosphorylation
  • ⇧ glycogen synthesis (replenish glycogen)
  • ↓ glycogen degradation
  • ⇧ glycolysis, TCA cycle (respond to energy need)

pg 1303

19
Q

resting skeletal muscle in absorptive state: fatty acids

A
  • ⇧ flux of dietary FAs
  • ⇧ FA oxidation to satisfy ATP need

pg 1304

20
Q

cardiac muscle metabolic preferences

A
  • canNOT store large amounts of glycogen or lipid
  • always aerobic - high O2 demand (98% of ATP derived aerobically)
  • utilizes: 60% fatty acids (preferred substrate), 35% glucose (uptake via GLUT1 and GLUT4), 5% ketone bodies (not preferred, spared for brain)

pg 1305

21
Q

ischemic conditions changes…

A
  • interruption of the blood flow to the heart that results in switch to anaerobic metabolism
  • rate of glycolysis increases, but the accumulation of protons (via lactate formation) is detrimental to the heart

pg 1305

22
Q

brain in absorptive state: glucose

A
  • ⇧ GLUT1 mediated transport
  • ⇧ glycolysis, TCA cycle and ATP production via oxidative phosphorylation
  • glucose preferred for energy at any given time
  • glucose readily transported across blood-brain barrier by GLUT1 which is NOT sensitive to insulin

pg 1306

23
Q

brain in absorptive state: fatty acids

A
  • LCFA canNOT cross the blood-brain barrier due to lack of transporters and therefore canNOT be used for energy in neuronal cells
  • NEVER use FAs for energy in brain
  • neuronal cells produce lipids endogenously

pg 1307

24
Q

intertissue relationships in absorptive state

A
  • insulin is an anabolic signal that promotes synthesis of glycogen, protein, and triacylglycerol
  • dietary carbs, proteins, and fats can be converted to body fat -> when caloric intake exceeds energy expenditure

pg 1308

25
Q

adipose tissue in fasting state: fatty acids

A
  • ↓ fatty acid uptake (NO FAs to uptake)
  • ⇧ TAG lipolysis (NO insulin to deactivate hormone-sensitive lipase)
  • ⇧ fatty acid release
  • also releases glycerol and sends to liver for activation

pg 1311

26
Q

adipose tissue in fasting state: glucose

A
  • ↓ GLUT4 mediated transport (no insulin)
  • ↓ glycolysis, TCA cycle
  • NO glucose used by adipose tissue in fasting state

pg 1311

27
Q

liver during fasting

A
  1. glycogen phosphorylase and phosphorylase kinase are phosphorylated and activated
  2. glucose-6-phosphatase generates free glucose
  3. activation of fructose-2,6-bisphosphatase favors gluconeogenesis
  4. low malonyl CoA allows β-oxidation, acetyl CoA product activates pyruvate carboxylase and inhibits pyruvate dehydrogenase, thereby pushing pyruvate to gluconeogenesis
  5. NADH from β-oxidation inhibits TCA cycle, pushing acetyl CoA to ketogenesis
  6. liver lacks thiophorase, preventing use of ketone bodies

pg 1312

28
Q

liver during fasting pt 2

A
  • liver is most important for maintaining blood glucose levels
  • substrates for gluconeogenesis: amino acids, lactate, glycerol
29
Q

resting skeletal muscle in fasting: fatty acids

A
  • ⇧ flux of FA from adipose tissue lipolysis
  • ⇧ FA oxidation -> primary fuel source during first 2 weeks, exclusively used during prolonged starvation
  • during fasting, skeletal muscle energy switches preference from glucose (needs GLUT4) to fatty acids

pg 1313

30
Q

resting skeletal muscle in fasting: ketone bodies

A

⇧ flux from the liver during the first 2 weeks

pg 1314

31
Q

resting skeletal muscle in fasting: amino acids

A

no glucose to be used (no insulin, no GLUT4)

  • ⇧ degradation of protein first few days
  • ⇧ release of AA to provide liver with GNG substrates
  • ↓ degradation of AAs after several weeks (no AA in circulation and protein needs to be preserved)

pg 1315

32
Q

brain during fasting

A
  • brain uses glucose for energy exclusively during well-fed state
  • during fasting, brain mostly uses ketone bodies for energy (acetoacetate, 3-hydroxy-butyrate), but still uses a little glucose and some amino acids

pg 1316

33
Q

intertissue relationships in fasting state

A
  • cortisol, epinephrine, and glucagon are catabolic signals that promote degradation of protein, triacylglycerol, and glycogen
  • priority 1: feed the glucose-requiring tissues (blood glucose maintained by degradation of liver glycogen and hepatic gluconeogenesis)
  • priority 2: feed the non-glucose-requiring tissues (mobilization of TAGs from adipose tissue provides FAs and precursors for ketone bodies)

pg 1317

Scientific Foundations (46 decks)

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