Flashcards in Turner's Lipids/Metabolic Integration, and DRANK Deck (61):
Which tissues use fatty acids as fuel?
heart, muscle, kidney, etc.--NOT the brain!
Where do NEFA (separated from glycerol) come from?
1) dietary sources
2) synthesized de novo by liver and adipose tissue cells
What is the C14 fatty acid?
myristic, 0 double bonds
What are the C16 fatty acids?
1) palmitic (0 double bonds)
2) palmitoleic (1 double bond), also called omega-7
What are the C18 fatty acids?
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
What is the C20 fatty acid?
arachidonic (4 double bonds)
What's up with bile?
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
Describe the mechanism of pancreatic lipase (in duodenum and proximal jejunum)
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
What happens when lipase is done?
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?)
What causes steatorrhea (fatty dumps)?
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
What happens to the fatty acids in the enterocytes?
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!
What are the main differences between LCFA and MCFA/SCFA?
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)
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
What happens to chylomicrons?
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
What's up with VLDL?
1) liver/fat cells synthesize fatty acids de novo
2) converted into TGs, packaged into VLDL particles, sent into blood
How does insulin work in all this? *unloading of chylomicrons and VLDL is under hormonal control!*
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
What happens to released NEFA?
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!)
How are TGs remade in fat cells?
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
1) FA released from TG via hydrolytic rxns (de-esterification)
2) TG-->DAG-->MAG via esterases
What does hormone-sensitive lipase (HSL) do?
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
What does adipose triglyceride lipase do?
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)
How is HSL activated and inhibited?
1) activated via phosphorylation (cAMP-dependent kinase, usually due to catecholamines)
2) NEFA inhibit HSL via product inhibition
What are perilipins and why are they important?
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!
Are free fatty acids really free? (not metaphysically...)
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
What are the 5 general steps of fatty acid metabolism?
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
What are the details of the 1st step?
1) fatty acid activated to fatty acyl CoA via acyl-CoA synthetase (thiokinase)
2) rxn requires 2 ATP
How does fatty acyl CoA get into the mitochondria?
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
How does feedback inhibition work with transfer into mitochondria?
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***
What are the next steps in beta ox?
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
How are unsaturated fatty acids oxidized?
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
How are odd-chain fatty acids oxidized?
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
Describe ketone body metabolism
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)
Where are ketones formed and what do they do? (they're water-soluble equivalents of FA)
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)
Explain ketone body metabolism and degradation
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)
How does beta ox interact with other metabolic pathways?
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
Why can't tissues other than the liver make ketone bodies?
they don't have HMG-CoA synthase and HMG-CoA lyase
What happens with ketone bodies and type I DM?
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)
How is alcohol metabolized by the liver?
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**
How does MEOS work?
1) CYP2E1 is a mixed-function oxidase (a cyt P450) that changes ethanol-->acetaldehyde
2) rxn requires NADPH and oxygen
What are the main ADH enzymes?
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
What is the main ALDH enzyme?
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
What happens to the acetate created?
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
How does CYP2E1 work?
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
Why are women able to drink less (allegedly)?
1) gastric ADH has lower activity
2) less water space than men
What are the acute effects of alcohol metabolism on the liver and what causes them?
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)
How does drinking cause hypoglycemia or hyperglycemia?
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
What are the bad effects of long-term drinking?
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
What happens in fibrosis and cirrhosis?
1) too much bad juju causes "wound-healing" rxn
2) inflamm type infiltrates, ECM stuff
3) fibrosis-->cirrhosis, cirrhosis irreversible, can lead to jaundice
Explain fatty acids and the TCA cycle
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
What are the catabolic enzymes and when are they active?
1) active when phosphorylated
2) glycogen phosphorylase
3) phosphorylase kinase
4) hormone-sensitive lipase
What are the anabolic enzymes and when are they active?
1) active when dephosphorylated
2) acetyl-CoA carboxylase
3) glycogen synthase
4) HMG-CoA reductase
What are the things that insulin does?
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)
What are the things that glucagon does?
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***
What are the things that epi does?
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
What happens in adipocytes during fasting?
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)
How does insulin regulate the storage of TGs in fat tissue?
1) insulin stimulates secretion of lipoprotein lipase from adipose cell (apoCII activates LPL)
2) also stimulates glucose transport into fat cells
How does glucagon regulate lipolysis in fat tissue?
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
How does amino acid metabolism work?
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)
How do glucocorticoids work?
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)
How does epi work?
1) stimulates glycogen breakdown in muscle and liver
2) stimulates gluconeogenesis in liver
3) stimulates lipolysis in adipose tissue