Turner's Lipids/Metabolic Integration, and DRANK

Question 1

Which tissues use fatty acids as fuel?

Answer 1

heart, muscle, kidney, etc.–NOT the brain!

Question 2

Where do NEFA (separated from glycerol) come from?

Answer 2

1) dietary sources

2) synthesized de novo by liver and adipose tissue cells

Question 3

What is the C14 fatty acid?

Answer 3

myristic, 0 double bonds

Question 4

What are the C16 fatty acids?

Answer 4

1) palmitic (0 double bonds)

2) palmitoleic (1 double bond), also called omega-7

Question 5

What are the C18 fatty acids?

Answer 5

1) stearic (0 double bonds)
2) oleic (1 double bond), also called omega-9
3) linoleic (2 double bonds), also called omega-6, essential
4) linolenic (3 double bonds), also called omega-3, essential

Question 6

What is the C20 fatty acid?

Answer 6

arachidonic (4 double bonds)

Question 7

What’s up with bile?

Answer 7

1) highly charged cholesterol derivatives
2) bile acids are digestive detergents, they emulsify lipids so lipase, et al can work
3) they also help micelles get into cells…dual role! But they don’t actually enter the enterocytes, they hang out in the lumen and get reabsorbed later on

Question 8

Describe the mechanism of pancreatic lipase (in duodenum and proximal jejunum)

Answer 8

1) activated by forming a complex with colipase
2) lipase is an esterase (hydrolyzes ester bonds), cleaves preferentially at 1&3 positions of TG
3) 2-MAG (monoacylglycerol) and NEFA released

Question 9

What happens when lipase is done?

Answer 9

1) bile acids form mixed micelles with the products (2-MAG and NEFA)
2) micelles enter enterocytes via a member of the fatty acid transport protein family, FATP5 (glycerol has another transport apparently?)

Question 10

What causes steatorrhea (fatty dumps)?

Answer 10

1) bile not produced or backed up
2) pancreas isn’t working right or blocked
3) fat not taken up in gut–can’t be absorbed and/or digested

Question 11

What happens to the fatty acids in the enterocytes?

Answer 11

1) acyl-CoA synthetase forms acyl-CoA derivatives of LCFA (long-chain fatty acids)
2) acyltransferases help 2 LCFA to join 2-MAG
3) TGs remade!

Question 12

What are the main differences between LCFA and MCFA/SCFA?

Answer 12

1) LCFA most abundant, require micelle formation/pancreatic lipase
2) MCFA/SCFA don’t require these, in smaller amounts (lots of SCFA in poop, not easily broken down)

Question 13

Explain chylomicrons

Answer 13

1) it’s a kind of lipoprotein, Apo-B48 is the main component (protein)
2) lipids on inside, proteins on outside
3) they leave the intestinal cells via lymphatics

Question 14

What happens to chylomicrons?

Answer 14

1) interact with lipoprotein lipase in the capillary endothelial walls (mostly muscle/fat tissue)
2) all ester bonds cleaved by this lipase
3) chylomicrons cleared really quickly from the blood
4) released NEFA taken up by nearby tissue and used either as fuel or turned into TG for storage, depending on need and tissue

Question 15

What’s up with VLDL?

Answer 15

1) liver/fat cells synthesize fatty acids de novo

2) converted into TGs, packaged into VLDL particles, sent into blood

Question 16

How does insulin work in all this? unloading of chylomicrons and VLDL is under hormonal control!

Answer 16

1) insulin promotes release of lipoprotein lipase from fat cells/muscle, so VLDL/chylomicrons release NEFA to be taken up as fuel (muscle) or stored (adipocytes)–insulin also facilitates TG entrance into cells (receptors)
3) insulin promotes glucose uptake by adipocytes, promotes GLUT4 receptors
4) inhibits hydrolysis of stored TG

Question 17

What happens to released NEFA?

Answer 17

1) enter fat cells via FA transporters (FATP1), these receptors stimulated by insulin
2) LCFA bind to ALBP (binding protein in cell–if free, they’re toxic!)

Question 18

How are TGs remade in fat cells?

Answer 18

1) NEFA converted to fatty acyl CoA (via acyl CoA synthase)
2) fatty acyl CoA’s acyl groups transferred to glycerol-3-phosphate (via acyl transferases)
3) first 2 acyl transfers yield phosphatidic acid (PA), which is then dephosphorylated to make DAG
4) third acyl group added to make TG

Question 19

What’s lipolysis?

Answer 19

1) FA released from TG via hydrolytic rxns (de-esterification)
2) TG–>DAG–>MAG via esterases

Question 20

What does hormone-sensitive lipase (HSL) do?

Answer 20

1) releases FA from DG/MG; also releases FA more slowly from TG and esters/cholesterol esters (NOT rate-limiting enzyme)
2) activated by glucagon and catecholamines
3) located in fat cells and cells that make steroid hormones from cholesterol

Question 21

What does adipose triglyceride lipase do?

Answer 21

1) catalyzes rate-limiting step of lipolysis, the 1st step (DG formed from TG)
2) can be found in any tissue that can accumulate TGs (not just fat cells)

Question 22

How is HSL activated and inhibited?

Answer 22

1) activated via phosphorylation (cAMP-dependent kinase, usually due to catecholamines)
2) NEFA inhibit HSL via product inhibition

Question 23

What are perilipins and why are they important?

Answer 23

1) they’re proteins that cover fat droplets
2) must be phosphorylated (a hormonal response) to move
3) once they’re out of the way, lipases can get to work!

Question 24

Are free fatty acids really free? (not metaphysically…)

Answer 24

Nope! NEFA have to be bound to albumin or some sort of protein carrier to move around in da blood once they’re freed by HSL or another lipase

Question 25

What are the 5 general steps of fatty acid metabolism?

Answer 25

1) fatty acid activated to fatty acyl-CoA
2) acyl CoA enters mitochondria
3) beta-oxidation produces acetyl CoA, FADH2, NADH
4) acetyl CoA oxidized via TCA cycle
5) e- transport system makes ATP

Question 26

What are the details of the 1st step?

Answer 26

1) fatty acid activated to fatty acyl CoA via acyl-CoA synthetase (thiokinase)
2) rxn requires 2 ATP

Question 27

How does fatty acyl CoA get into the mitochondria?

Answer 27

1) fatty acyl CoA transferred to carnitine via carnitine palmitoyl transferase (CPT1)
2) yields acyl-carnitine, goes across internal mitochondrial membrane
3) acyl goes back to CoA, acyl-CoA enters beta-ox path

Question 28

How does feedback inhibition work with transfer into mitochondria?

Answer 28

CPT-1 inhibitied by malonyl CoA, 1st product of committed step in FA synthesis–means when FA being synthesized, they aren’t being used as fuel

Question 29

What are the next steps in beta ox?

Answer 29

1) acyl CoA oxidized to double bond (alpha, beta) via acyl-CoA dehydrogenase (yields 2 ATP)
2) water added across double bond via hydratase
3) keto acyl CoA generated via dehydration (needs NAD, yields 3 ATP)
4) 3-keto acyl CoA yields acyl CoA (1 fewer C) and acetyl CoA via thiolase–acyl CoA continues cycle, acetyl CoA enters TCA cycle

Question 30

How are unsaturated fatty acids oxidized?

Answer 30

1) gamma, beta double bond changed to alpha, beta double bond via enoyl-CoA isomerase
2) delta 4 double bond has to be reduced to gamma, beta bond, then isomerized–reductase and isomerase needed
3) beta, gamma reduces net energy yield

Question 31

How are odd-chain fatty acids oxidized?

Answer 31

1) normal beta oxidation until propionyl CoA formed at end, not two molecules of acetyl-CoA
2) propionyl CoA carboxylated to methylmalonyl CoA (enzyme requires biotin as cofactor)
3) methylmalonyl CoA converted to succinyl CoA, enters TCA

Question 32

Describe ketone body metabolism

Answer 32

1) 2 acetyl CoA join to form acetoacetyl CoA
2) eventually acetyl CoA regenerated (rejoins cycle), and acetoacetate (ketone body)
3) acetoacetate yields acetone and beta-hydroxybutyrate, both these products ketone bodies
4) beta-hydroxybutyrate converted to acetoacetate, steals CoA from succinyl CoA to form acetoacetyl CoA, then thiolase converts it (succinyl CoA has to be regenerated, requires energy)

Question 33

Where are ketones formed and what do they do? (they’re water-soluble equivalents of FA)

Answer 33

1) ketogenesis in liver mitochondria***
2) acetoacetate and beta-hydroxybutyrate can be used as fuel by lots of tissues, including brain, kidneys and heart prefer these guys to glucose! (go figure…)
3) liver CANNOT use ketone bodies, since it doesn’t have 3-ketoacyl-CoA transferase (needed for metabolism)

Question 34

Explain ketone body metabolism and degradation

Answer 34

1) too much acetyl CoA from beta ox of FA won’t be able to enter the TCA cycle
2) acetyl CoA metabolized into ketone bodies (during fasting, boozing, uncontrolled diabetes, high fat/low carb diets)

Question 35

How does beta ox interact with other metabolic pathways?

Answer 35

1) acetyl CoA from FAs only enters TCA cycle if fat/carb digestion are balanced
2) too much acetyl CoA from beta ox inhibits pyruvate dehydrogenase and activates pyruvate carboxylase (increases OAA)
3) high levels of NADH from beta ox inhibit TCA cycle enzymes–OAA becomes malate, which furthers glucuneogenesis

Question 36

Why can’t tissues other than the liver make ketone bodies?

Answer 36

they don’t have HMG-CoA synthase and HMG-CoA lyase

Question 37

What happens with ketone bodies and type I DM?

Answer 37

1) insulin is gone period
2) if catecholamines elevated, HSL/perilipins active
3) unchecked lipolysis occurs
4) TGs converted by liver into ketone bodies
5) KBs made so quickly they aren’t metabolized
6) ketoacids accumulate in blood, can cause metabolic acidosis (diabetic ketoacidosis)

Question 38

How is alcohol metabolized by the liver?

Answer 38

1) ethanol–>acetoaldehyde via ADH in cytosol
2) acetoaldehyde–>acetate via ALDH in mitochondria
3) acetate enters blood, converted to acetyl CoA in tissues, enters TCA cycle
4) some alcohol oxidized via MEOS of cyt P450
5) both rxns generate NADH

Question 39

How does MEOS work?

Answer 39

1) CYP2E1 is a mixed-function oxidase (a cyt P450) that changes ethanol–>acetaldehyde
2) rxn requires NADPH and oxygen

Question 40

What are the main ADH enzymes?

Answer 40

1) ADH1 in liver, has highest affinity (lowest Km) for ethanol
2) ADH4 in GI tract; lower affinity, may contribute to GI cancer risk of heavy drinkers

Question 41

What is the main ALDH enzyme?

Answer 41

1) ALDH2 has highest affinity for acetaldehyde
2) when ALDH2 inactive, accumulating acetaldehyde causes nausea, vomiting, etc.–ALDH inhibitors (disulfiam) can help drinkers quit, causes these icky symptoms

Question 42

What happens to the acetate created?

Answer 42

1) converted to acetyl CoA via acetyl CoA synthetase (ACS)

2) acetate entry into TCA cycle, etc. regulated by cholesterol, insulin; most acetate enters blood

Question 43

How does CYP2E1 work?

Answer 43

1) CYP2E1 has a much higher Km for ethanol than ALD1, so it’s involved when large amounts of alcohol are drunk
2) products of CYP2E1 alcohol metabolism are acetyaldehyde and ROS
3) chronic alcohol consumption causes much higher expression of CYP2E1, less gastric ADH–clears ethanol from blood but also produces acetaldehyde much quicker than ALDH can clear it

Question 44

Why are women able to drink less (allegedly)?

Answer 44

1) gastric ADH has lower activity

2) less water space than men

Question 45

What are the acute effects of alcohol metabolism on the liver and what causes them?

Answer 45

1) caused by increased NADH/NAD+ ratio
2) fatty acid ox and TCA cycle inhibited (reversible)
3) TG synthesis increases (fatty liver) and VLDL/TG levels go up, reversible)
4) fatty acids ox, converted to acetyl CoA become ketone bodies
5) lactate created (via lactate dehydrogenase)

Question 46

How does drinking cause hypoglycemia or hyperglycemia?

Answer 46

1) caused by NADH/NAD+ ratio
2) lactate formed rather than pyruvate, causes hypoglycemia when fasting
3) glycolysis inhibited at GAP step, hyperglycemia when eating and drinking

Question 47

What are the bad effects of long-term drinking?

Answer 47

1) increased acetaldehyde and ROS in liver, then blood
2) acetaldehyde forms adduct with amino acids/nucleotides/phospholipids
3) adduct causes cessation of protein protein synthesis, then retention, in liver, then portal hypertension
4) Antiox enzymes attach to adduct, inhibited
5) lipid peroxidation causes a whole mess of problems

Question 48

What happens in fibrosis and cirrhosis?

Answer 48

1) too much bad juju causes “wound-healing” rxn
2) inflamm type infiltrates, ECM stuff
3) fibrosis–>cirrhosis, cirrhosis irreversible, can lead to jaundice

Question 49

Explain fatty acids and the TCA cycle

Answer 49

1) fatty acids broken down into acetyl CoA, converted into OAA
2) OAA –>glucose (via PEPCK), but we CANNOT have a net conversion of acetyl-CoA to glucose** (stuck in TCA cycle)
3) however, the carbons in TG can be used to synthesize glucose (3 C of glycerol backbone)
4) also, ox of odd-chain fatty acids make propionyl CoA, which can be converted to glucose

Question 50

What are the catabolic enzymes and when are they active?

Answer 50

1) active when phosphorylated
2) glycogen phosphorylase
3) phosphorylase kinase
4) hormone-sensitive lipase

Question 51

What are the anabolic enzymes and when are they active?

Answer 51

1) active when dephosphorylated
2) acetyl-CoA carboxylase
3) glycogen synthase
4) HMG-CoA reductase

Question 52

What are the things that insulin does?

Answer 52

1) sent out by high blood glucose
2) anabolic: stimulates synthesis of glycogen, fat, protein
3) inhibits breakdown of glycogen, fat, protein
4) increases glucose transport into muscle, fat, liver
5) promotes dephosphorylation (anabolic)

Question 53

What are the things that glucagon does?

Answer 53

1) sent out by low blood glucose levels
2) catabolic: stimulates breakdown of glycogen, fat, proteins
3) inhibits synthesis of glycogen, fat, protein
4) increases phosphorylation of key enzymes via activation of cAMP-dependent protein kinase A***

Question 54

What are the things that epi does?

Answer 54

1) signal that energy is needed right the fuck now!!
2) catabolic: stimulates breakdown of glycogen, fat, protein
3) inhibits synthesis of glycogen, fat, protein

Question 55

What happens in adipocytes during fasting?

Answer 55

1) low blood glucose/insulin
2) cAMP high: lipolysis and phosphorylation (activation) of transcr factor CREB
3) PEPCK transcribed: OAA–>GAP via gluconeogenesis
4) GAP furthers esterification of fatty acids, they’re retained in adipocytes
5) TGs simultaneously broken down and regenerated–futile cycle (ATP wasted)

Question 56

How does insulin regulate the storage of TGs in fat tissue?

Answer 56

1) insulin stimulates secretion of lipoprotein lipase from adipose cell (apoCII activates LPL)
2) also stimulates glucose transport into fat cells

Question 57

How does glucagon regulate lipolysis in fat tissue?

Answer 57

1) cAMP increases, protein kinase A activated, phosphorylates hormone-sensitive lipase (HSL), activates it
2) HSL removes a fatty acids from adipose tissue
3) other lipases create glycerol and fatty acids
4) PKA also phosphorylates perilipins, furthers lipolysis of stored TGs

Question 58

How does amino acid metabolism work?

Answer 58

1) amino acids released from digestion enter liver via portal vein
2) used for synthesis of proteins (especially blood proteins like albumin)
3) excess amino acids converted to glucose of TAG; these are packaged and secreted in VLDL
4) in the fed state, amino acids converted into glucose converted into glycogen, or released into blood
5) during fasting, released amino acids from muscle; nitrogen enters urea cycle, carbons used as glucose or ketone bodies (oxidized by tissues for energy)

Question 59

How do glucocorticoids work?

Answer 59

1) stimulate lipolysis in adipose tissue
2) stimulate release of amino acids from muscle
3) in liver, stimulate gluconeogenesis and synthesis of glycogen (glycogen synthesis effect opposite of epi)

Question 60

How does epi work?

Answer 60

1) stimulates glycogen breakdown in muscle and liver
2) stimulates gluconeogenesis in liver
3) stimulates lipolysis in adipose tissue

Question 61

How does cancer cell metabolism work? (Warburg effect)

Answer 61

1) they use aerobic glycolysis
2) cancer cells take up a lot of glucose, convert it to pyruvate, then convert it to lactate (don’t use TCA cycle)
3) pentose phosphate shunt very active, so lots of NADPH/R5P made for biosynthesis and replication
4) cells also take up a lot of glutamine, which is converted in mitochondria to glutamate (further conversion to other products used in biosynthesis)
5) inactivation of p53 causes promotion of aerobic glycolysis, diminishes TCA cycle for ATP generation