Cholesterol Synthesis Flashcards
Endogenous cholesterol is produced primarily in which organ?
liver
Cholesterol serve as precursors to which bio macromolecules?
Vitamin D, Sterol hormones, Bile acids
What enzyme catalyzes the rate limiting step of bile acid synthesis?
7-hydroxylase
How can a vegetable rich diet manage high cholesterol?
plant sterols in the diet inhibit the absorption of cholesterol in the diet
What are 3 ways in which serum cholesterol levels can be lowered?
Decreased dietary intake of cholesterol; decrease cholesterol synthesis; increase excretion of bile acids
What type of cholesterol comes from extrahepatic tissues
HDL
In what form is cholesterol distributed throughout the blood stream?
VLDL
What extrahepatic organs can also synthesize cholesterol?
adrenals, gonads, intestine, placenta
cholesterol is synthesized in which part of the cell?
cytoplasm
Describe Stage 1 of cholesterol biosynthesis?
Excess acetylCoA from mitochondrial matrix gets converted to mevalonate by HMG CoA reductase
For stage 1 of cholesterol synthesis, what is the role of thiolase?
converts acetylCoA to Acetoacetyl CoA
What is the rate-limiting step for cholesterol synthesis?
HMG CoA reductase; conversion of Acetoacetyl CoA to Mevalonate; requires 2X NADPH; irreversible
what enzyme is involved in the esterification of cholesterol?
ACAT or LCAT (HDL)
Describe the SREBP/SCAP regulation of cholesterol synthesis when serum levels of cholesterol are low.
SCAP-SREBP complex is transported to golgi apparatus; Once in the Golgi, SCAP activates proteases to cleave SREBP to release the SREBP DNA-binding domain; this domain then translocates to the nucleus to bind to SRE which is the gene that encodes for the HMG CoA reductase
Describe the SREBP/SCAP regulation of cholesterol synthesis when serum levels of cholesterol are high.
cholesterol binds to SCAP and inactivates it
How is cholesterol synthesis regulated in post-transcriptional pathways when serum levels of cholesterol are high
proteolysis of HMG CaA reductase; degradation of mRNA carrying genetic code for HMG CoA reductase
how do glucagon & insulin affect cholesterol synthesis respectively?
Glucagon increases cholesterol synthesis by activating AMPK (phosphorylation); Insulin decreases cholesterol synthesis by activating phosphatase (dephosphorylation)
How do high levels of AMP affect cholesterol synthesis?
activates AMPK and increases cholesterol synthesis (phosphorylation)
what determines the density of lipoproteins?
amount of triglycerides; higher triglyceride to protein ratio is associated with Lower density
What type of lipoproteins transport dietary lipids from intestine to the liver & tissues?
Chylomicrons (least dense; biggest diameter)
What lipoproteins transport endogenous lipids from the liver?
VLDL
What lipoproteins transport cholesterol from liver to tissues with high cholesterol demands (adrenal, sex glands)?
LDL
What Lipoproteins transport cholesterol from tissue back to the liver?
HDL
Where are chylomicrons synthesized?
intestinal epithelial cells
What is the Role of ApoB48?
assembly and secretion of chylomicrons in small intestine assisted by MTP
Chylomicrons are secreted from the intestines as lymph and enter the blood stream through which lymphatic outlet?
thoracic duct
ApoB48 is produced via RNA editing of which gene?
ApoB-100; C edited to U creates a stop codon; basically a shorten transcript compared to the traditional Apo100 which is 52 times the size of Apo48
What enzyme is responsible to the hydrolyzation of TGs in chylomicrons and where are these enzymes located?
LPL; located in BM of capillary endothelium
LPL is activated by which enzyme & what peptide hormone upregulates its synthesis?
LPL is activated by ApoCII and upregulated by insulin
Chylomicrons remnants are taken up by which organ and what is the ligand for the hepatocytes to take up these remnants?
liver; ApoE on remnants bind to ApoE receptor in hepatocytes
chylomicron remnants ……… in size & …….. in density as more content is taken up by tissues?
decreases; increases
What is the main metabolic source of VLDLs?
excess carbohydrates
What is the apoprotein for VLDLs & LDL?
ApoB-100
By then end of a chylomicron’s journey, what type of micelle does it become?
HDL: low levels of TGs & fatty acids & higher concentration of proteins
LDL is rich in what?
cholesterol
How can excess LDL cause atherosclerosis?
LDLs are oxidized by macrophages which forms foam cells that can build up to plaques
Esterification prevents cholesterol from doing what?
moving out of the cytoplasmic membrane
ApoA is associated with what apoprotein?
HDL
What is the process by which cells get rid of cholesterol?
Reverse Cholesterol Transport
How is cholesterol transported out of the cell?
ABC1 ATPase
What two proteins are required for HDL to extract cholesterol from extrahepatic tissues?
LCAT (activated by Apo A1) traps cholesterol in the micelle & CETP (exchanges cholesterol ester from HDL to VLDL)
HDLs bind to which receptors on hepatocytes?
SR-B1
Describe the pathogenesis of Hyperlipoproteinemia Type I?
LPL deficiency; insufficient digestion of Triglycerides will decrease the body’s ability to break down VLDL & chylomicrons leading to high levels of these and low levels of HDL & LDL
What are the multiple pathogenesis for Type IIa hyperliporoteinemia?
Defective LDL Receptor, ApoB100, PCSK9
What is the role of PCSK9 in lipid metobolism?
binds to LDL receptors and targets them for lysosomal degradation leading to increased serum levels of LDL
Describe the pathogenesis of Hyperlipoproteinemia Type III
Defective ApoE
What is the pathogenesis of Type IV hyperlipoproteinemia?
overproduction of VLDL due to glucose intolerance
What is the pathogenesis of Tangier disease?
hypolipoproteinemia caused by defects in ABC1 genes
Describe the pathogenesis of Abetalipoproteinemia.
hypolipoproteinemia; MTP gene mutations
Describe the pathogenesis of hypoalphalipoproteinemia.
hypolipoproteinemia; accelerated breakdown of ApoA-1 & ApoA-II
Wolman’s disease is associated w/ defects in what protein?
lysosomal acid lipases
LCAT deficiency leads to what?
low HDL levels and cholesterol accumulation in tissues
Why is Type I Hyperlipoproteinemia not associated with increased risk of CAD?
A defect of LPL will reduce bioavailability of cholesterol in the tissues since less of it is being transported; therefore we would expect to see increased levels of chylomicron, VLDL and decreased levels of LDL & HDL
What would be the physiological consequence of a defective PCSK9 based on your knowledge of what this protein does?
PCK9 defect would increases serum levels of LDL, cholesterol and therefore increase risk of CAD
what would be the physiological consequences of na defective LDL receptor?
Resistant to breakdown by protease; LDL will accumulate leading to hyperlipoproteinemia
What would be the physiological consequence of a defective ApoB100?
increased serum levels of VLDL & LDL
Based on your knowledge of role ApoE plays in cholesterol metabolism, what would you expect to be the physiological consequences of a defect in this protein to be?
ApoE is required for chylomicron uptake into hepatic tissue so it would make sense for serum levels of chylomicrons to be elevated; extrahepatic endogenous VLDL will also be elevated since they cannot be taken up by the liver; xanthomas
Overproduction of VLDL is typically associated with what medical conditions?
glucose intolerance assoc. w/ DM, CHD, obesity
What would we expect to be elevated in serum of pts. with Type IV hyperlipoproteinemia?
TGs & VLDL
Based on your knowledge of the role ABC ATPases play in cholesterol metabolism, what would you expect the physiological consequences to be if these ATPases were defective?
Lipids & cholesterol will not be able to be transported out of the cell which will decrease serum levels of HDL and cause hypolipoproteinemia
Based on your knowledge of the role MTP plays in cholesterol metabolism, what would you expect the physiological consequences to be if this protein was mutated?
decreased assembly of Chylomicrons will decrease serum levels of all micelles leading to hypolipoproteinemia
Based on your knowledge of the role ApoA proteins play in cholesterol & lipid metabolism, what would you predict to be the physiological consequences if degradation of these proteins was increased?
ApoA proteins are assoc. w/ HDL so we would expect serum levels of HDL to be lowered; this will cause hypolipoproteinemia b/c HDL cannot be extracted from extrahepatic tissues
What is the physiological consequence of LCAT deficiency?
LCAT is one of the two required proteins for extrahepatic extraction in the reverse cholesterol process; therefore HDL will be trapped in extrahepatic tissue thus lowering serum HDL levels
What is the pathogenesis of fatty liver disease?
decreased hepatic synthesis of apolipoproteins resulting in decreased production of VLDL which leads to TG accumulation in the liver
What is the precursor for bile salts?
cholesterol
What is the main route of cholesterol elimination from the body?
feces
in what organ are bile acids stored?
gallbladder
Bile salts have poor solubility; how does the body compensate for this?
hydroxylation and carboxylation of bile salts increases their solubility
What are the 2 main primary bile salts and what makes them primary bile salts?
cholic acid & chenodeoxycholic acid; primary b/c they are produced in the liver
what are the 2 main secondary bile salts and what makes them secondary bile salts?
deoxycholic acid & lithocholic acid; secondary b/t they are formed from primary bile acids by bacterial enzymes in the small intestine
why are secondary bile salts more likely to be excreted than primary bile salts?
lost of hydroxyl group decreases solubility and therefore decreases reabsorption
Describe the process of Bile Salt conjugation?
addition of an amino acid to the carbon 24 carboxylate; Usually glycine or taurine
conjugated bile salts have a lower pKa than physiological pH; what form will therefore predominate in small intestinal pH (6)?
higher percentage of the ionized form of conjugated bile acid
The majority of Bile Acid reabsorption takes place in what part of the colon?
Ileum
What is another name for Type I hyperlipoproteinemia?
familial LPL deficiency
what is another name for Type IIa hyperlipoproteinemia?
familial hypercholesterolemia
what is another name for Type IV hyperlipoproteinemia?
familial hypertriacylglycerolemia
List the components of Metabolic Syndrome.
large waistline; high serum levels of TGs & LDL; low serum levels of HDL; HTN; Glucose intolerance
what is the definition of dyslipidemia?
generic umbrella term for abnormal serum levels of lipids
severe hypertriglyceridemia can lead to what?
acute pancreatitis
what are the parameters for diagnosis of metabolic syndrome?
3 of the following:
blood glucose > 100 mg/dL
BP of at least 130/85
TG > 150 mg/dL
HDL < 40 mg/dL for men; <50 mg/dL for women
waist circumference > 102 cm (40 in.) in men; > 88 cm (35 in.) in women
what is a clinical hallmark of familial combined hyperlipidemia?
disproportionately elevated levels of apoB
what is a major clinical hallmark for dyslipidemia induced by defective LDL receptor?
xanthomas; arcus corneae
Of all the drugs you have learned up to this point, composite a list of drugs that can potentially increase serum levels of cholesterol.
Thiazides; BBs, antiretroviral agents; estrogen supplements; glucocorticoids, cyclosporine, tacromilus
What are other systemic diseases that can cause dyslipidemia besides primary dyslipidemia & cholestatic liver disease?
CKD; Nephrotic syndrome; hypothyroidism; cushing disease
what can cause excessive hepatic production of VLDL?
high carbohydrate diet; obesity; insulin resistance; nephrotic syndrome; cushing’s syndrome; alcohol abuse disorder
What is the mechanism of alcohol-induced dyslipidemia?
ethanol inhibits hepatic oxidation of free fatty acids leading to excess production of VLDL; this promotes TG synthesis and VLDL secretion which will subsequently raise plasma levels of HDL
What are common causes of decreased lipolysis of TGs and lab findings?
obesity; insulin resistance; LPL defect; lab findings: elevated TG, Low HDL with no elevation of LDL or apoB
Impaired hepatic uptake of lipoproteins containing ApoB would be indicative of what lab findings and what are common causes?
elevated LDL & TG; common causes include hypothyroidism & CKD
what are common secondary causes of reduced HDL levels?
cigarette smoking, steroids, HIV, nephrotic syndrome
hypercholesterolemia is assoc/ with what condition?
cholestasis
BBs …… levels of HDL & ………. levels of VLDL.
reduce; elevate
Thiazides ……. levels of LDL
elevate
Estrogen …….. levels of HDL, ……… levels of VLDL & TG
elevate; elevate; elevate
What are some of the neurological effects of extremely high triglyceride levels?
paresthesias, dyspnea, confusion
Acute pancreatitis induced by hypertriglyceridemia can be indicated by what clinical symptoms?
eruptive xanthomas when TG > 1000 mg/dL; lipemia retinalis when TG > 2000 mg/dL
high levels of LDL can present with what?
arcus corneae; tendinosus xanthomas; xanthelasma
what tendons are typically affected by hypercholesterolemia?
extensor tendons of upper & lower extremities
what does arcus corneae look like?
extra layer of sclerae in between rim of the cornea and the iris
what does xanthelasmas look like?
yellow cholesterol plaques surrounding canthus of upper eyelid
how can inflammation affect lab values of a lipid panel?
increase levels of TG and decrease levels of cholesterol
what is the equation for calculating LDL?
LDL = TC -[HDL + (TG/5)]; note only valid when TG level < 400 mg/dL
familial hypercholesterolemia is clinically diagnosed based on what lab findings?
elevated LDL in the absence of hypertriglyceridemia
what supplements can be recommended for management of hypertriglyceridemia?
niacin, fibrates, omega-3 fatty acids
heterozygous and homozygous familial hypercholesterolemia are clinically defined by what parameters?
hetero: LDL > 190 or > 160 for ped. pts.; homo: LDL > 500
