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MBOD Week 13 > Cholesterol Metabolism 1 > Flashcards

Cholesterol Metabolism 1 Flashcards

1
Q

What 3 big classes of biologically active compounds is cholesterol a precursor to?

A
  • Bile Acid
  • Steroid Hormones
  • Vitamin D
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2
Q

T or F: Cholesterol is an essential component of mammilian membranes.

A

True

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3
Q

What are the 3 major sources of cholesterol that is sent to the small intestine?
- What are the relative amounts

A

Food (meat, eggs, dairy)
- 300-500 mg/day

Bililary Cholesterol **Greatest contributor
- 800-1200 mg/day

Intestinal Epithelial Turnover
- 300 mg/day

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4
Q

How much of the cholesterol that’s in the small intestine is actually absorbed?

A

70%

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5
Q

Why does diet have a smaller affect on serum cholesterol than what people might think.

A

~1g (1000mg) of NEW cholesterol is synthesized de novo every day by the LIVER and the amount you ingest is only about 1/6 of total cholesterol

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6
Q

What makes cholesterol polar?

A

Hydroxyl at 3 position

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7
Q

T or F: 40% of circulating cholesterol is esterified to fatty acids.

A

False, its more like 70%

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8
Q

Where are the following located in lipoproteins and why?

  • Free Cholesterol
  • Cholesterol Esters
A

Free cholesterol stays on surface

Cholesterol Esters are more non-polar so they must go to the hydrophobic core

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9
Q

What causes sitosterolemia?

- Symptoms

A
  • ABCG5 and ABCG8 gatekeeper is not there to move sterols out of the cell
  • *this is a heterodimer so mutations in either gene = complete loss of function in protein
  • Patients have elevated levels of STEROL in the blood, a plant cholesterol that is normally transported out by ABCG5/ABCG8
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10
Q

What does ABC in ABCG5 stand for?

A
  • ATP-binding Cassette Transporter
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11
Q

Where is ABCG5/ABCG8 expressed (2 places)?

A
  1. Enterocyte Microvillus Membrane
  2. Hepatocyte Canalicular Membrane
    * This is responsible for making Cholesterol gets in the bile
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12
Q

What does ABCG5/ABCG8 do?

A

SECRETES cholesterol and plant sterols back into the interstinal lumen and excludes plant sterols from absorption (gatekeeper)

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13
Q

What is Niemann-Pick C1-Like Protein 1 (NPC1L1)?

- Location?

A
  • Located on lumenal side of enterocyte to import cholesterol
  • Found in the Highest Density in Brush Border of proximal Jejunum
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14
Q

What drug acts on NPC1L1 and why does it work?

A

Ezetimibe (Zetia)

  • If cholesterol is not reabsorbed (job of NPC1L1) then it must be resynthesized
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15
Q

How can dietary plant sterols and stanols like Benecol inhibit cholesterol absorption and lower plasma cholesterol?

A
  • These cholesterol-like molecules probably displace cholesterol from micelles
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16
Q

What organs do cholesterol synthesis?

- which is the major site of production?

A
  • Liver (Major site)

- Small Intestine, adrenal cortex, gonads

17
Q

T or F: acetyl CoA is the initial substrate and source of all 27 carbons

18
Q

Where can the cell go to get Acetyl coA for all 27 carbons needed in cholesterol Synthesis?

A
  1. Long-Chain Fatty Acid ß-oxidation
  2. Dehydrogenation of Pyruvate
  3. Oxidation of Ketogenic Amino acids
19
Q

What are the requirements to make Cholesterol?

A
  1. 18 moles of acetyl CoA
  2. 36 moles of ATP
  3. 16 mols of NADPH

**Its costly to make Cholesterol

20
Q

What is the enzyme of the rate limiting, COMMITTED step of mevalonic acid production?

A

HMG CoA Reductase

PRINCIPAL SITE OF REGULATION FOR CHOESTEROL SYNTHESIS**

21
Q

T or F: statins act by inhibiting HMG CoA reductase

22
Q

What reaction does HMG CoA Reductase Catalyze?

A

HMG-CoA + 2NADPH + 2H+ —-> 2NADP + CoASH + Mevalonate

23
Q

What transcriptionally regulates HMG CoA?

- factors influencing activity?

A

Transciptional Regulation - SREBP
Factors influencing activity:
- Intracellular Concentration of: HMG CoA, FREE Cholesterol

- Homones: 
(+) insulin
(+) Thyroid Hormone
(-) Glucagon
(-) Cortisol

***Note: Hormones work by Changing Phosphorylation State

24
Q

How does the liver store cholesterol?

A
  • As Cholesterol Esters
25
Q

What are Liver X Receptors (LXRs)?

  • activation
  • what do they bind
  • Cellular effect
A
  • Nuclear Receptors that Heterodimerize with RXR (retinoid X receptor) and bind to RESPONSE ELEMENTS to promote gene transcription
  • These are activated by oxysterols

Modulate Cholesterol Homeostasis at several steps to avoid Cholesterol Overload

26
Q

What are the cellular location of LXR alpha and beta?

- differences in regulation

A
  • LXR-alpha is found in LIVER and INTESTINES and other tissues
  • LXR-beta ubiquitous

** LXR-alpha - has a response element in its gene promoter and can autoregulate its own transcription

27
Q

LXR’s are good in the fact that it helps to clear cholesterol but what are some of its negative effects?

  • liver
  • macrophages
  • monocytes
A

Liver - Promotes FA synthesis:

  • Hypertriglyceridemia
  • Cholesterol Esterfication for Storage

Macrophages - Promotes LPL:
- TAG hydrolysis => Cholesterol Esterfication for storage

TNF-alpha expressed:
- Apoptosis, Inflammation => Atherosclerosis

28
Q

What causes Smith-Lemli-Opitz Syndrome?

  • prevalence
  • how to detect it
  • symptoms
A

Cause:
3-ß-hydroxysterol- ∆ 7-reductase deficiency

  • LOW PLASMA CHOLESTEROL
  • HIGH 7-dehydrocholesterol

Affects 1/20,000:

  • Mental Retardation
  • Congenital malformations (microencephaly etc.)
29
Q

What are 2 treatment options for patients with Smith-Lemli-Opitz Syndrome?
- which would be better

A
  1. Treat by giving excess cholesterol since they can’t make there own
    * *Problem - Cholesterol can’t cross BBB
  2. Treat with statins to inhibit HMG-CoA Reductase to prevent build up 7-dehydrocholesterol
    * *Able to cross BBB - not that effective
30
Q

Where are Bile Acids Synthesized and from what?

A

Made in Liver from:

  1. Cholesterol conjugated to
  2. Taurine and Glycine
31
Q

What do Bile Acids do?

A

Act like a detergent to emulsify Fat products and form a micelle

**Micelles allow fat to cross the unstirred H2O layer to get into enterocyte

32
Q

Where do the majority of Bile Acids go to be reabsorbed (enterohepatic circulation)?

A
  • Absorbed in the ileum
33
Q

What is the Rate Limiting Enzyme in Bile Synthesis?
- Regulation

A

7-alpha-hydroxylase (CYP7A1)

  • Regulated via Farensoid X Receptor (FXR) that:
    1. Binds Bile Acids (indicating they are high)
    2. DOWN regulates CYP7A1 transcription
34
Q

What is Sistosterolemia?

A

High levels of Sterols in the blood

35
Q

What is SREBP?

A
  • Regulates Transcription of HMG-CoA Reductase for Cholesterol Synthesis

**Note: LXR can upregulate SREBP production

36
Q

What is the rate limiting enzyme in bile acid synthesis?

A

7-alpha-hydroxylase

37
Q

T or F: large amounts of bile acid can be toxic to the liver

38
Q

Where is Cholesterol and bile salts absorbed?

A
  • Cholesterol: Jejunum

- Biles Salts: Ileum

MBOD Week 13 (7 decks)

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