Lipoprotein Metabolism Flashcards
What is the precursor for all steroid hormones?
cholesterol
What are some important steroid hormones?
glucocorticoids, mineralcorticoids, and sex hormones (androgens and estrogens)
Where are glucocorticoids made?
(e.g. cortisol) made in the adrenal cortex (zona fasciculata and zona reticularis)
Where are mineralcorticoids made?
(e.g. aldosterone) made in the adrenal cortex (zona glomerulosa)
What is the most potent glucocorticoid?
cortisol
When is cortisol released and what is its release regulated by?
released in response to stress and regulated by pituitary ACTH
What are the main effects of cortisol?
Stimulates gluconeogenesis, glycogen synthesis (can lead to hyperglycemia- can lead to diabetes)
Promotes protein catabolism (patients get muscle wasting over a long term)
Anti-inflammatory
Inhibits leukocyte migration (immuno-supression- patients can be susceptible to infection)
Promotes sodium retention (some mineralocorticoid activity)- high doses may lead to anemia
How is aldosterone made/released?
When the juxtamedullary apparatus in the kidney senses low blood volume in the circulation, renin is released. Renin converts angiostensinogen to angiotensin I. Angiotenson I is then converted to angiotensin II by angiotensin-converting enzyme. Angiotensin II then stimulates the adrenal cortex to release aldosterone
How do ACE inhibitors work?
they inhibit the release of aldosterone by inhibiting the action of angiotensin converting enzyme
What does aldosterone do?
It decreases Na+ and water excretion to replenish extracellular fluid volume. Increased BP then provides feedback inhibition to the process
Patients with cirrhosis typically have what? What is the treatment?
lots of water retention and high levels of aldosterone leading to edema. treatment is Aldactone that inhibits aldosterone to help sodium excretion
Where is testosterone made?
leydig cells in the testes and regulated by pituitary LH
What does testosterone do?
stimulates spermatogenesis and induces male sex differentiation, protein synthesis, and increased muscle mass
Where is estradiol made?
made in ovarian granulosa cells and regulated by FSH
What does estradiol do?
Regulates follicular maturation and ovulation with progesterone
Induces feminization
Role in bone turnover
What is Congenital Adrenal Hyperplasia?
Genetic defect in steroidogenic enzymes
21-hydroxylase deficiency is the most common
Failure to produce cortisol (which provides feedback inhibition on ACTH) and aldosterone
Overproduction of ACTH stimulates increased production of 17-hydroxyprogesterone upstream of the block that is converted to testosterone, leading to masculinization of female infants
Mineralocorticoid deficiency leads to severe salt loss and electrolyte abnormalities
Routine newborn screening now includes this disease
The major form of vitamin D is what?
Vitamin D3 or cholecalciferol
T or F. Most of our vitamin D is provided by diet
F. Most is produced endogenously
Where is endogenous vitamin D synthesized?
in the Malpighian layer of the epidermis by sunlight
What happens to newly synthesized vitamin D to convert it to its most active form?
C-25 hydroxylation in the liver (first) and then C-1 hydroxylation in the kidney yields 1,25-dihydroxycholecalciferol (the most metabolically active form of vitamin D)
What is the main effect of vitamin D?
Exerts effects via nuclear vitamin D receptor (VDR)- so it binds and then goes to the nucleus to influence the transcription of other genes
What genes/functions does vitamin D promote/regulate?
Stimulates expression of several genes (such as calbindin) involved in the intestinal absorption of calcium
Recruits stem cells to mature to osteoclasts, which mobilize calcium from bone
Major effect on bone is to provide the proper balance of calcium and phosphorus to support mineralization
decreases parathormone secretion
Most of the benefits of vitamin D are related to skeletal maintenance. What are some of the non-skeletal benefits?
Lower mortality rate Lower CV mortality Reduced diabetes risk Reduced cancer risk Reduced risk of allergy and asthma Reduced risk of infection Reduced risk of mental illness
NOT confirmed (excessive vitamin D can be toxic)
Which part of vitamin D synthesis is tightly regulated?
Hepatic hydroxylation (of C25) is loosely regulated
Renal hydroxylation (of C1 by 1a-hydroylase) is tightly regulated and is the major control point for production of the active hormone
What is the major inducer of kidney hydroxylation of vitamin D by 1a-hydroxylase ?
parathyroid hormone, which is induced by low serum levels of calcium
can also be stimulated by low calcium and phosphate levels
What is 1a-hydroxylase inhibited by?
Fibroblast Growth Factor 23 from osteocytes
vitamin D deficiency can lead to what?
rickets in children and osteomalacia in adults
What are some causes of vitamin D deficiency?
Insufficient exposure to sunlight (e.g. northern climates)
Liver or kidney disease (can’t hydroxylate vitamin D)
Genetic defects of the vitamin D receptor
What is genu varum?
bow-legging of children with rickets
What is the purpose of lipoproteins?
Provide a thermodynamically stable particle to transport lipid (water insoluble) through the aqueous environment of the bloodstream
Where are lipoproteins primarily made?
liver and intestines
What kinds of lipoproteins does the liver make?
Very low density lipoproteins (VLDL)
Low density lipoproteins (LDL) derived from VLDL
High density lipoproteins (HDL)
What kinds of lipoproteins do the intestines make?
Chylomicrons
Small amounts of VLDL and HDL
LDL and VLDL carry mainly what?
LDL- mainly cholesterol (because the TAG is all gone at the point of formation)
VLDL- mainly triglycerides (also has cholesterol)
What is the structure of lipoproteins?
typically cholesterol esters in the interior, surrounded by free cholesterol and apolipoproteins (that stablize and provide other functions) on the exterior
What is the function of apolipoproteins?
e.g. APO48 and APO100
Surface peptides of lipoprotein particles with lipid binding properties (can dissociate)
(apo48 and apo100 do not dissociate)
Play important roles in the assembly, secretion, peripheral metabolism and clearance of lipoproteins
Produced in liver and small intestine
What are the two forms of Apo B and how are they formed?
Apo48 (intestine) and Apo100 (liver) derived from same mRNA transcript by mRNA editing. A single BP change creates a stop codon for Apo48
editing accomplished by APOBEC (ApoB editing complex)-1. So this is only active in the gut
What does Apo48 do?
essential for chylomicron packaging and secretion, lacks the LDL receptor binding domain
What does Apo100 do?
essential for VLDL packaging and secretion, contains the LDL receptor binding domain
Where is ApoA1 produced?
liver and intestines
What are the functions of ApoA1?
Major apolipoprotein of plasma HDL
Co-factor for lecithin:cholesterol transferase (LCAT), which esterifies free cholesterol in HDL
Where is ApoA4 produced?
Produced by intestine and secreted with chylomicrons
a large portion is not bound to lipoproteins in plasma
What does ApoA4 do?
May activate LCAT, facilitate reverse cholesterol transport through HDL, function as a lipoprotein lipid antioxidant, serve as a post-prandial satiety signal (to decrease appetite), can be overexpressed to prevent atherosclerosis and allow packaging of absorbed lipid into larger chylomicrons
What is ApoCII found in? What does it do?
Found in VLDL, HDL, and chylomicrons
Activates lipoprotein lipase (LPL), which hydrolyzes triglyceride in VLDL and chylomicrons
What is ApoE found in/on?
Found in VLDL and chylomicrons and their remnants, as well as HDL
Ligand for hepatic chylomicron remnant receptor and LDL receptor
What is ApoE produced by?
produced by astrocytes in CNS and transports cholesterol to neurons via apo E receptors and may help clear amyloid protein (high amyloid protein is found in alzheimer’s)
What are the three isoforms of ApoE?
E2, E3, and E4 with E3 being the most common
Increased levels of E4 can lead to what?
atherosclerosis and alzheimers
What does hepatic lipase do?
Attached to heparan sulfate proteoglycans on hepatocytes
Role in remnant lipoprotein uptake
What is Lecithin:cholesterol acyltransferase (LCAT) activated by?
ApoA1
What does LCAT do?
Catalyzes transfer of fatty acid from lecithin (phosphatidylcholine) to free cholesterol in HDL
What do ABCA1 and ABCG1 do?
ABCA1 mediates phospholipid/cholesterol efflux from cells to lipid-poor apo A-I to form nascent HDL in reverse cholesterol transport
ABCG1 mediates transfer to more mature HDL particles
What does B-hydroxy-B-methylglutaryl coenzyme-A reductase (HMG-CoA reductase)
do?
Rate-limiting enzyme in cholesterol synthesis
What does Acyl-CoA:cholesterol acyltransferase (ACAT) do?
Catalyzes conversion of free cholesterol to cholesteryl ester in cells for storage
What does LDL receptor do?
Binds apo B-100 and E
Role in cellular uptake of LDL and remnant lipoproteins
What does LDL receptor-related protein (LRP)
do?
Role in hepatic uptake of remnant lipoproteins
What does Scavenger receptor-BI (SR-BI) do?
Mediates hepatic uptake of cholesteryl ester from HDL in reverse cholesterol transport
Describe the steps of exogenous lipoprotein transfer.
absorbed TAGs are packaged into chylomicrons and transferred to the bloodstream where they receive ApoCII and ApoE from HDL. LPL receptors hydrolyze the release of triglycerides from the chylomicron core until the chylomicron is small enough to be characterized as a ‘remnant’. Then the remnant is taken up by the liver via an LRP receptor and ApoE
Describe the steps of endogenous lipoprotein transfer.
the liver synthesizes TAG which are packaged into VLDL with Apo 100. The VLDL circulates until it interacts with LPL, where it is hydrolyzed. Most VLDL remnants become IDL particles and then cholesterol rich LDL particles. LDL can be taken up via LDL receptors (~50% located in liver) or it can interact with artery walls and build up plaque
What is the major end product of VLDL metabolism?
LDL
Describe the steps of HDL lipoprotein transfer.
Cholesterol for peripheral cells effluxes and is packaged into HDL, HDL is taken up by SR-B1 receptors in the liver
In the intestine, where are monoacyglycerol and FAs re-esterifed to TAG?
ER
What enzyme promotes the attachment of Apo48 to TAG in the intestinal ER?
microsomal triglyceride transfer protein
