Liver Biochemistry-1/21/16

Question 1

List the functions of the liver

Answer 1

Primary receiving, distribution, and recycling center
Lipid biosynthesis and management
Protein biosynthesis (albumin, IgG)
Nitrogen metabolism (Urea cycle)
Waste management (xenobiotic rxns)
Bilirubin metabolism
Fuel management

Question 2

___ acetyl coa are used to generate IPP

___ serves as the building block for the synthesis of all isoprenoids, including steroids and lipid-soluble vitamins

Answer 2

3

Isopentenyl pyrophosphate (IPP)

Question 3

Acetyl CoA is generated in the mitochondria from these various pathways:

How is acetyl coa transported into the cytoplasm?

Answer 3

Oxidative decarboxylation of pyruvate; B-oxidation of FA’s; Breakdown of AA’s

Via citrate shuttle

Question 4

The ___ is the backbone of most steroids

Answer 4

Sterane ring

Question 5

The hydroxyl group on cholesterol is located at ___

The sterane ring has ___ carbons

The double bond in cholesterol is located between ___

Where is the 8-member hydrocarbon chain attached on the cholesterol molecule?

Answer 5

C3

17

C5 and C6

C17

Question 6

Cholesterol is the precursor of these biologically active compounds:

Answer 6

Bile acids and bile salts
Vitamin D
Steroid hormones

Question 7

What is the reaction to generate Cholesterol?

Answer 7

18 ACoA + 18 ATP + 16 NADPH + 16 H+ + 4O2 —–>

1 Cholesterol + 16 NADP+ + 18 ADP + 18 Pi

Question 8

Acetyl CoA ——> Acetoacetyl CoA
acetyl co-a acetyltransferase

Acetoacetyl Coa ———-> HMG CoA
(Name this enzyme)

HMG CoA —————> Mevalonate
(Name this enzyme)

Answer 8

HMG CoA Synthase

HMG CoA Reductase (rate-limiting)

Question 9

What is the rate-limiting enzyme, substrate, and product for cholesterol synthesis?

Answer 9

Enzyme-HMG CoA reductase
Substrate-HMG CoA
Product-Mevalonate

Question 10

What hormones can stimulate the production of Mevalonate from HMG CoA?

What hormones can inhibit the production of Mevalonate from HMG CoA?

Answer 10

+=insulin, thyroxine

-=Glucagon, sterols, high [AMP], vitamin E, statins

Question 11

List 2 compounds derived from intermediates in cholesterol synthesis:

Answer 11

Quinol form of Ubiquinone (CoQ10)
Heme A (in cytochromes)

Question 12

How is cholesterol utilized in ALL TISSUES?

Liver?

Adrenal glands, ovaries, testes?

Skin?

Answer 12

ALL TISSUES–> incorporated into cell membranes

LIVER–> Used to synthesize bile acids

ADRENALS, OVARIES, TESTES –> synthesize steroid hormones

SKIN –> Synthesize vitamin D

Question 13

____ are plasma membrane microdomains enriched in cholesterol, sphingolipids, and gangliosides. They are detergent-insoluble, have low buoyant density, and local centers for signal transduction processes. They are also sites for abnormal processing of proteins in neurodegenerative disorders

Answer 13

Lipid rafts

Question 14

What are the sites of Ubiquitination on HMG CoA Reductase? Where is the site of Insig binding on HMG CoA reductase?

Answer 14

Ubiquitination–> Lys 89 and Lys 248 (cytosol)

Insig binding –> Membrane domain (lumen)

Question 15

____ is inhibited by free FA’s, bile acids, and oxysterols. Can also be inhibited by statins (act as competitive inhibitors)

Answer 15

HMG CoA reductase-Statins compete with HMG CoA for binding to active site

This is a form of DIRECT INHIBITION

Question 16

HMG CoA reductase will be active when ____

HMG CoA reductase will be inactive when ____

Answer 16

Active=DEPHOSPHORYLATED

Inactive=PHOSPHORYLATED

Question 17

____ inhibits HMG COA by preventing dephosphorylation

____ activates HMG COA by promoting dephosphorylation

Answer 17

Glucagon

Insulin

Question 18

___ levels of [cholesterol] triggers translocation of SREBP-SCAP complex to Golgi and SREBP transcription factor dimer binds to SRE on HMG CoA reductase promoter

Answer 18

Low –> Low sterol promote release SREBP-SCAP complex from ER to Golgi where SREBP undergoes proteolysis to release the mature form of SREBP which dimerizes and translocates to nucleus to promote the transcription of the rate-limiting enzyme

High [cholesterol] levels retain SREBP in ER membrane via binding of SCAP to INSIG

Question 19

Translation of HMG CoA Reductase is reduced by ___

Answer 19

Gamma-tocotrienol (Vitamin E family) and oxylanosterols

Question 20

After cholesterol is synthesized in the liver, the liver packages it into ___ and releases it into the blood. It is then metabolized to ___ by peripheral tissues

Answer 20

VLDL

LDL

Question 21

Statins have a ____ action due to increase in SREBP maturation which leads to transcription of LDL receptor and subsequent enhanced clearance of cholesterol via LDL-receptor mediated endocytosis and leads to an overproduction of ___ protein

Answer 21

Hypocholesterolemic

HMG CoA reductase protein

Question 22

What are 2 supplements that should go alongside statin use?

Answer 22

Ubiquinone and prenylated proteins

Question 23

___ enzymes convert linear isoprenoid squalene into cholesterol and detoxifies xenobiotics and pharmacological agents (including statins)

Answer 23

Cytochrome P450

Question 24

Agents that inhibit CYP will cause an ____ in statin levels leading to toxic side effects (myopathy and rhabdomyolysis).

Agents that induce CYP will ___ levels of statin in plasma

Answer 24

Increase–> inhibitors includes itraconozole, clarithromycin, and cyclosporine. Citrus juices and grapefruit juice

Decrease –> inducers include rifampicin, carbamazepine, and st johns wort

Question 25

In the liver, the first step of bile synthesis converts cholesterol to what?

Answer 25

7-alpha-hydroxycholesterol via 7-alpha-hydroxylase

Question 26

The conversion of cholesterol to 7-alpha-hydroxycholesterol in the liver is stimulated by ___ and inhibited by ____

Answer 26

Cholesterol

Bile acids

Question 27

____ are crystals made up of bile supersaturated with cholesterol

____ is an insufficient secretion of bile salts or phospholipids or excess cholesterol secretion

Answer 27

Gallstones

Cholelithiasis

Question 28

Chronic disturbances in bile salt metabolism can lead to what?

Answer 28

Steatorrhea (malabsorption syndrome) and deficiency in fat-soluble vitamins (A,D,E,K)

Question 29

Oral administration of ____ reduces cholesterol secretion into bile. It is used to dissolve small to medium sized gallstones

Answer 29

Ursodeoxycholic acid (secondary bile acid)

Question 30

75% of blood flow to the liver is supplied by the ___ and 25% is supplied by the ___

Answer 30

Portal v.

Hepatic a.