Lipoprotein Metabolism (end of cholesterol) Flashcards
What cholesterol importer is located on enterocytes in the ileum and to a lesser extent in the colon and kidney?
ASBT
What cholesterol exporter is located on enterocytes in the ileum and to a lesser extent in the colon and kidney?
OST-alpha/beta
What is phase I bile composition?
-Bile is a micellular liquid
Composition:
- Bile Salts: Moderate amount (40-90%)
- Cholesterol: Low ( 85%)
What is the precursor for all steroid hormones?
Cholesterol
Where are glucocorticoids made (be specific)?
- Adrenal Cortex (zona fasciculata and zona reticularis)
* Cortisol = glucocorticoid
Where are mineralcorticoids made (be specific)?
- Adrenal Cortex (zona glomerulosa)
* Aldosterone = mineralcorticoid
Where are sex hormones made (be specific)?
- Made in testis and ovary
* Androgens and estrogens = sex hormones
When is cortisol released?
- regulation
- effects
- Released in response to stress
- MOST POTENT glucocorticoid
effects:
- Gluconeogenesis, and glycogen synthesis stimulated
- Protein Catabolism
- ANTI-inflammatory
- Inhibits leukocyte migration
- Na+ retention (swelling)
What result does cortisol have on an infection?
Infection may persist because it prevents leukocyte migration
What disease state might result from cortisol stimulating gluconeogenesis and glycogen synthesis?
Diabetes
Estradiol
- Where is it produced?
- What does it do?
- Produced in ovarian granulosa cells
- Has an affect on bone turnover
- This is why post menopausal women are more susceptable to osteoporosis
What is the precursor for estrodiol?
Testosterone
What disease results from a 21-hydroxylase deficiency?
Congenital Adrenal Hyperplasia
What causes the ambiguous genitalia in patients with Congenital Adrenal Hyperplasia?
21-hydroxylase Deficiency leads to build up of 17-hydroxyprogesterone that is converted to testosterone
- This masculinizes female infants
Why is microgenitalia not the biggest issue for patients with Congenital Adrenal Hyperplasia?
- Along with not being able to make estrodiol they also don’t make CORTISOL and ALDOSTERONE
- No aldosterone means you pee all your Na+ (and thus H2O) out and get dehydrated
What needs to happen for Vitamin D to get activated?
- name of activated species
1 C-25 hydroxylation in the liver
2 Hydroxylations
Final METABOLICALLY ACTIVE product = 1,25-dihydroxycholecalciferol
What the sources of Vitamin D?
- biggest contributor
MAJORITY made by Malpighian layer of the epidermis by SUNlight
Small amounts also come from the diet
What does the active form of Vit D. (1,25-dihydroxycholecaliferol) do?
(3 things)
- Stimulates expression of genes involved in intestinal absorption of calcium
- Recruits stem cells to make osteoclasts that mobilize Calcium form bone
- MAJOR EFFECT is to get correct Ca2+ and phosphate balance
Where is Vitamin D synthesis most highly regulated?
- Renal Hydroxylation by 1 alpha-hydroxylation
liver hydroxylation is only loosely regulated
What are the regulators of 1 alpha-hydroxylase in the kidney?
(+) PTH (induced by low Ca2+ in blood)
(+) Hypocalcemia
(+) Hypophosphatemia
(-) Fibroblast Growth Factor 23 from osteocytes
What does vitamin D deficiency lead to in adults and in children?
- causes
Children - Rickets
Adults - Osteomalacia
Causes:
- no sunlight
- Liver or Kidney Disease
- Genetic defects of Vit D receptor
Why would liver or kidney disease cause osteomalacia?
- You can’t complete one of the two hydroxylation steps needed to get to the active form
What is Rachitic Rosary?
- swelling of costochondral junctions resulting from rickets
What is the cause of biliary rickets?
- Lack of bile production
- Vit D. is fat solubule so it can’t be absorbed without bile
- Lack of vitamin D = bad
What is the purpose of lipoproteins?
- They provide a thermodynamically stable particle to transport lipid through the bloodsteam
What type of Lipoproteins are made by the liver?
- VLDLs
- LDL (from VLDL)
- HDL
What type of lipoprotein is important in reverse cholesterol transport?
HDLs
What types of lipoproteins are made by the intestines?
- Chylomicrons
- Small amounts of VLDL and HDL
Why are Apo proteins need in lipoproteins?
- Assembly
- Assembly
- Secretion
- Interaction with the appropriate enzymes
Why do lipoproteins get worse for you as you progress from Chylomicron toward LDL?
- The cholesterol is becoming more concentrated in the particle
If Lipoproteins get worse for you as they get small, then why are HDLs good for you?
- Because they participate in reverse cholesterol transport
What 3 pathways exist for lipoproteins?
- Exogenous Pathway (Chylomicrons)
- Endogenous Pathways (VLDL)
- Reverse Cholesterol Transport back to liver (HDL)
Where are lipoproteins produced?
Liver and Small Intestine
What is the only apoliprotein that stays with the lipoprotein throughout its lifetime?
Apo B
What are the 2 types of Apo B?
- structural difference
- functional difference
- ApoB-100 and ApoB-48 (from same mRNA transcript)
ApoB-100
- VLDL packaging
- LDL RECEPTOR BINDING DOMAIN
Apo-48
- Chylomicron Packaging
- NO LDL RECEPTOR
Apo A-1
- Produced where?
- associated lipoprotein type?
- What does it do?
- Produced in liver and small
- apolipoprotein of plasma HDL
- Its a co-factor for LCAT
What is LCAT and what does it do?
- Lecithin Cholesterol Transferase (LCAT)
- Esterfies Fatty acid from LECITHIN onto free cholesterol to make HDL
How does ApoB mRNA editing happen?
- ApoB 100 and 48 are synthesized from the same gene
- ApoB 48 has a stop codon in the middle inserted by a single basepair change that shortens the protein (excludes LDL binding domain)
What is APOBEC-1?
- ApoB editing complex
How does APOBEC-1 work?
- Binds the ApoB gene at MOORING SEQUENCE
2. Mooring sequence lines it up to change a single residue resulting in ApoB 48 and not 100
Apo A-IV
- Location
- associated lipoprotein
“Jack of all Trades”
- Produced by intestine
- Secreted with Chylomicrons
What does Apo A-IV do?
- Activate LCAT
- Facilitate Reverse Cholesterol transport
- Lipid ANTIOXIDANT
- SATIETY INDICATOR
- Prevent atherosclerosis
- Allow packaging of absorbed lipids into CHYLOMICRONS
When is the packaging of absorbed lipids into chylomicrons most important?
- What protein helps in this packaging?
- In neonates its important to getting more fat into breast milk
- ApoA-IV
Apo C-II
- associated lipoprotein
- job
- VLDL, HDL, chylomicrons
- activates LPL
what links LPL to capillaries in muscle and adipose tissue?
- Heparan Sulfate Proteoglycans
What activates LPL?
Apo CII
What does LPL do?
- Hydrolyzes triglyceride in VLDL and chylomicrons to liberate free fatty acids for OXIDATION (muscle) or STORAGE (fat)
Does does Hepatic Lipase (HL) do?
- helps absorb remnants of chylomicrons into liver
What is Lecithin:Cholesterol Acyltransferase (LCAT)?
- Catalyzes transfer of fatty acid from LECITHIN (phosphatidylcholine) to free cholesterol in HDL
AKA ESTERIFIES IT
What process does LCAT play an important role in?
- Reverse Cholesterol Transport back to the liver
What is the rate limiting enzyme in cholesterol synthesis?
HMG-CoA reductase
What does ACAT do?
- conversion of free cholesterol to cholesterol ester in cells for STORAGE
**Note: similar function as LCAT except LCAT works in reverse cholesterol transport
What type of receptor recognizes apoB-100 and apoE?
LDL Receptor
What plays a role in uptake of remnant lipoproteins?
- hepatic
- cellular
- LDL receptor-related protein in hepatocytes
- LDL receptor in cells
What is the difference between LDL receptors and LDL receptor-related protein (LRP?)
- LDL receptor takes up LDL
What does Scavenger Receptor-BI (SR-BI) job?
- Mediates hepatic uptake of cholesteryl ester from HDL in reverse cholesteol Transport
