Biochem Cholesterol

Front 1

what is the regulated step in cholesterol synthesis?

Back 1

HMG-CoA reductase
(HMG-CoA to Mevalonate, requiring NADPH)

Front 2

what enzyme couples transport of acetyl-CoA with production of NADPH?

Back 2

malic enzyme

Front 3

what are the allosteric inhibitors of HMG-CoA reductase?

Back 3

bile acid
cholesterol
mevalonate

Front 4

what are the two alternative pathways for cholesterol metabolism to start?

Back 4

cytosolic thiolase condensing cytosolic acetyl-CoAs (primary)
mitochondrial acetoacetate from ketogenesis diffusing into cytosol

Front 5

what enzyme converts acetoacetate to acetoacetyl-CoA?

Back 5

acetoacetyl-CoA synthase

Front 6

what is the product of HMG-CoA reductase?

Back 6

mevalonate

Front 7

what is an important intermediate in cholesterol metabolism? what does this intermediate produce?

Back 7

farnesyl-PP

prenylated proteins
geranylgeranyl-PP
heme a and ubiquinone

Front 8

where do statins affect metabolism?

Back 8

inhibit HMGR, thus inhibiting cholesterol metabolism

Front 9

what are the advantages to statin drugs?
what is the disadvantage to long-term statin therapy?

Back 9

A: lowers the amount of cholesterol produced
A: lowers amount of prenylated proteins (many of which are inflammatory proteins)
D: decreases heme a and ubiquinone causing muscle weakness and pain

Front 10

what effect does cholesterol have on HMGR? how?

Back 10

decreased transcription and translation of HMGR
via SREBP activity

Front 11

what is the short term regulation of HMGR?

Back 11

phosphorylation of HMGR via AMPK

Front 12

in what way do sterols regulate HMGR?

Back 12

ubiquitination, leading to proteosomal degradation, of HMGR

Front 13

what enzymes activate AMPK?
how?

Back 13

LKB1=STK11=PJK=AMPKK
CaMKK+Ca2+

phosphorylate AMPK

Front 14

what enzyme inhibits AMPK?
how?

Back 14

protein phosphatase 2C

dephosphorylates AMPK

Front 15

what enzyme inhibits protein phosphatase 2C?
what is the effect of this?

Back 15

PPI-1
inhibition of PP2C decreases inactivation of AMPK, which causes inactivation of HMGR

(inhibition of PP2C inhibits cholesterol synthesis)

Front 16

what enzyme inhibits PPI-1?
how?
what is the overall effect of inhibition of PPI-1?

Back 16

phosphoprotein phosphatase inhibits PPI-1 via dephosphorylation of the enzyme
inhibition of PPI-1 reduces inactivation of HMGR, and reduces inhibition of PP2C, reduced inhibition of PP2C increases inhibition of AMPK, which reduces inactivation of HMGR

(overall effect of inhibition of PPI-1 is to stimulate cholesterol synthesis)

Front 17

what effect does cAMP have on HMGR?

Back 17

cAMP is the result of glucagon or epinephrine binding, and therefore it causes a decrease in cholesterol synthesis

Front 18

what is the effect of AMPK on PFK2?

Back 18

only acts on cardiac's inducible form of PFK2, increasing its kinase activity, increasing glycolysis

Front 19

what is the effect of AMPK on GLUT1 and GLUT4?

Back 19

induces their migration to the surface of cells, allowing more glucose into cells

Front 20

what is the effect of AMPK on FAS and ACC?

Back 20

inhibits FAS and ACC, which activates fatty acid oxidation and inhibits FA synthesis

Front 21

what effect does AMPK have on hormone sensitive lipase?

Back 21

inhibits, thereby inhibiting lipolysis

Front 22

what effect does AMPK have on HMGR?

Back 22

inhibits, thereby inhibiting cholesterol synthesis

Front 23

What effect does AMPK have on GPAT?

Back 23

inhibits, thereby inhibiting triglyceride synthesis

Front 24

what effect does AMPK have on glycogen synthase?

Back 24

inhibits, thereby inhibiting glycogen synthesis

Front 25

what effect does AMPK have on eEF2 and mTOR?

Back 25

inhibits, thereby inhibiting protein synthesis

Front 26

what effect does AMPK have on pancreas?

Back 26

inhibits insulin secreation of beta cells

Front 27

what effect does AMPK have on the liver?

Back 27

inhibits fatty acid synthesis
inhibits cholesterol synthesis

Front 28

what effect does AMPK have on adipose tissue?

Back 28

inhibits fatty acid synthesis
inhibits lipolysis

Front 29

what effect does AMPK have on heart?

Back 29

increases fatty acid oxidation
increases glucose uptake
increases glycolysis

Front 30

what effect does AMPK have on skeletal muscle cells?

Back 30

increases fatty acid oxidation
increases glucose uptake

Front 31

which PPAR is the only one which actually proliferates peroxisomes?

Back 31

PPARalpha

Front 32

what type of drug binds to PPARalpha?

Back 32

fibrates

Front 33

what effect does AMPK activation have on SREBP?

Back 33

reduces levels, so that cholesterol synthesizing enzymes are not transcribed

Front 34

what enzyme helps to control intracellular levels of free cholesterol?

Back 34

Acyl-cholesterol acyl transferase (ACAT)

Front 35

what receptor-mediated uptake mechanism regulates plasma level of cholesterol?

Back 35

LDL receptor mediated uptake which delivers cholesterol to the periphery

Front 36

what is the reverse cholesterol mediated transport regulated by?

Back 36

HDLs which suck cholesterol out of periphery cells and it to liver

Front 37

what is forward cholesterol transport?
what is reverse cholesterol transport?

Back 37

hepatic to non-hepatic transport of cholesterol
non-hepatic back to hepatic transport of cholesterol

Front 38

what is the role of acyl-cholesterol acyl transferase?

Back 38

transfer cholesterol to and from fatty acids, creating and degrading FA esters

Front 39

what binding event controls the expression of more than 30 genes in cholesterol synthesis, TAG synthesis, Phospholipid synthesis and FA synthesis?

Back 39

binding of SREBP to SRE-1

Front 40

what interactions regulate the SCAP protein which controls S1P activity?

Back 40

interaction with INSIG
regulation by sterols (high sterol concentration represses SCAP activity)

Front 41

where is SREBP contained until two cleavage events are able to free it?

Back 41

ER/Golgi membrane

Front 42

what is SCAP?

Back 42

SREBP cleavage activator protein
protein which maintains SREBP in ER/Golgi membrane by inhibiting cleavage of two sites by proteases which would release it

Front 43

what two enzymes are responsible for cleaving the two sites on SREBP which allow it to become active?

Back 43

Site-1-protease (has to be first for second cleavage site to present)
Site-2-protease

Front 44

how does cholesterol turn off its own synthesis?

Back 44

inhibits release of SREBP at SCAP via high concentrations

Front 45

what are the two enzymatic effects of statin drugs?

Back 45

induce S-nitrosylation of COX-2, increasing production of lipoxins

inhibit HMGR preventing protein prenylation and cholesterol biosynthesis

Front 46

how does nicotinic acid inhibit VLDL secretion?

Back 46

suppresses the release of FAs from adipose tissue
(lowers triglycerides and elevates HDLs)

Front 47

what are the problems associated with increasing doses of nicotinic acid?

Back 47

liver problems
hyperglycemia
gout
"flushing"

Front 48

what does nicotinic acid bind to to initiate it's effects on cholesterol metabolism?

Back 48

GPCR which causes a signal cascade to reduce amount of FAs released (GRP109A)

Front 49

how do fibrates change the amount of serum cholesterol?

Back 49

increase beta-oxidation via binding to PPARalpha, decreased TG secretion from liver
increases LPL activity
increases level of HDL

Front 50

what effect do cholestyramine related resins have on cholesterol metabolism?

Back 50

bind bile acids, causing them to be excreted, which leads to diversion of cholesterol into bile acid synthesis
(also increases synthesis of LDL receptor)

Front 51

where is the only place that conatains ALL of the enzymes for synthesizing bile acids?

Back 51

liver

Front 52

where are bile acids modified?

Back 52

intestinal bacteria

Front 53

when do bile acids change from primary to secondary designations?

Back 53

primary - synthesized by liver
secondary - modified by intestines

Front 54

what are the primary bile acids?

Back 54

cholic acid
chenodeoxycholic acid

Front 55

what are the secondary bile acids?

Back 55

deoxycholate
lithocholate

Front 56

which primary bile acid is the precursor for deoxycholate?
for lithocholate?

Back 56

cholic acid -> deoxycholate
chenodeoxycholic acid -> lithocholate

Front 57

what modifications are made to bile acids in the liver, which allow them to stay in aqueous phase (emulsifying fats)?

Back 57

addition of glycine and taurine

Front 58

what hormone stimulates the peristaltic contractions of the gall bladder, causing it to squeeze bile into the large intestine?

Back 58

cholecystokinin (CCK)

Front 59

what is involved in the process of enterohepatic circulation?

Back 59

liver -> gall bladder -> intestine -> liver

Front 60

what are the important functions of bile acids?

Back 60

only way to remove cholesterol from body

emulsify dietary lipids to make them accessible to pancreatic lipases

facilitate absorption of fat-soluble vitamins

prevent precipitation of cholesterol in gallbladder

Front 61

through what mechanisms do bile acids effect expression of numerous genes?

Back 61

activation (by binding to) of FXR and PXR

Front 62

what is LXR? FXR? PXR?

Back 62

Liver X Receptor
Farnesoid X Receptor
Pregnane X Receptor

(all bind retinoids)

Front 63

what is a xenobiotic?
what tissue is good at removing xenobiotics?

Back 63

foreign chemical
liver

Front 64

what step initiates bile acid synthesis?

Back 64

7-hydroxylation of cholesterol

Front 65

what enzyme catalyzes the rate-limiting step in bile acid synthesis?

Back 65

7alpha-hydroxylase
(CYP7A1)
(requires Oxygen and NADPH)

Front 66

what precursor molecule can be converted to either of the two primary bile acids?

Back 66

7-hydroxycholesterol

Front 67

what enzyme's transcription is regulated by bile acids' effects on FXR?

Back 67

sterol 12alpha-hydroxylase
(CYP8B1)

Front 68

what is the advantage to linking primary and secondary bile acids with glycine or taurine?

Back 68

lower pKa values
remain ionized over larger pH range

Front 69

what circulation system returns bile to liver?

Back 69

portal circulation

Front 70

what inhibits CYP7A1?

Back 70

small heterodimer partner (SHP) binding to it

Front 71

what transcription factor (with bile acids attached) activate SHP?

Back 71

FXR (which needs bile acids bound to be a transcriptional regulator)

Front 72

which bile acid is most prominent?

Back 72

cholic acid

Front 73

what enzymes/proteins does FXR repress expression of?

Back 73

SREBP
CYP8B1
SLC10A1 (NTCP)

Front 74

why is NTCP necessary in the liver?

Back 74

required for uptake of bile acids

Front 75

Expression of what proteins/enzymes are induced by FXR?

Back 75

SHP
BSEP (ABCB11)
MDR3 (multidrug resistant protein) (ABCB4)
MRP2 (multidrug resistant related protein)

Front 76

what does BSEP do?

Back 76

helps in export of bile salts out of liver into bile canaliculi

Front 77

what causes familial intrahepatic cholestasis types 2 and 3?

Back 77

BSEP (2)
MDR3 (3)

Front 78

what is cholestasis?

Back 78

blockage of bile flow from liver to intestines

Front 79

what is the receptor for lithocholate and other bile acid precursors?

Back 79

PXR

Front 80

what do Guggul lipids do?

Back 80

antagonize FXR
activate PXR
activate BSEP expression independent of FXR

effectively cause more bile to be exported, which causes conversion of more cholesterol into bile

Front 81

what is HNF-4alpha?

Back 81

hepatocyte nuclear factor 4alpha
(not exclusively in hepatocytes)

Front 82

what effect does PXR have on HNF-4alpha?

Back 82

inhibits

Front 83

what transcription factor does HNF-4alpha function with?

Back 83

PGC-1alpha

Front 84

what does PGC-1alpha activate in bile acid synthesis?

Back 84

CYP7A1