Lecture 9 Flashcards
Why are inborn errors of metabolism useful?
They can be sued to sort how particular nutrients are metabolized.
FH.
Due to loss of LDL receptor function. 4 classes of variations: lack of synthesis of the protein, issue with transport to Golgi, defective binding of LDL receptor, inability to cluster in the coated pit.
NPXY.
Cytoplasmic signalling domain of the LDL protein.
Cell response to increased cellular cholesterol concentration.
Hydrolysis of internal lipoproteins releases amino acids. Amino acids activate the signalling cascades. Cholesteryl esters are hydrolyzed into cholesterol and fatty acids. Cholesterol migrates to the endoplasmic reticulum; cell sense that there is too much cholesterol and activates ACAT to turn the excess into cholesteryl oleate.
What happens when HMG-CoA reductase is reduced?
Prevents endogenous formation of cholesterol.
Statins.
Competitive inhibitors of HMG-CoA reductase.
Reverse cholesterol pathway.
Excess cholesterol in the periphery is loaded onto HDL. LDL receptors int he liver are increases so more lipoproteins can be taken up for disposal. Indirect: deliver cholesterol via low density lipoprotein pathways, which are removed from plasma very rapidly.
ABCA1.
Codes from transporter in the efflux of cholesterol from the cell.
Cyp 7a1.
Codes for the 1st and rate-limiting step of bile acid synthesis.
Stimulating ABCA1 and Apo E…
Stimulates trasnfer of cholesterol from the blood to the liver, which causes transformation of cholesterol into bile acids in rodents, not humans.
In humans, what os the relationship between cholesterol and Apo E?
As cholesterol increases, Apo E also increases.
Why is Apo E important?
It has the LDL receptor binding sites.
Nuclear receptors.
They regulate gene expression by acting as transcription factors. They can bind to DNA with or without a ligand on the hormone response element (HRE) half-site.
Heterodimer nuclear receptors.
2 different nuclear receptors interact and bind to DNA.
Types of repeats for nuclear receptors?
Direct repeat (head-to-tail), everted repeat (tail-to-tail, and inverted repeat (head-to-head).
Type of nuclear receptors.
Steroid hormone receptors, RXR heterodimers (vitamin D is the ligand), dimeric orphan receptor, and monomeric tethered orphan receptors.
Transcription factors are sensitive to…
Nutrients.
Function of nuclear receptors
They either stimulate or inhibit gene translation. They can also recruit co-activators or co-repressors.
LXR.
Nuclear receptor. Alpha and beta forms are activated by oxysterols.
LXR alpha.
Expressed in tissues and cells; they maintain lipid homeostasis.
LXR beta.
Ubiquitous distribution in the body.
Regulation of LXR alpha.
ABCA1, Cyp 7a1 (rodents), ans SREBP-1c.
Does Cyp 7a1 bind to LXR alpha?
Not in humans.
SNPs (single nucleotide polymorphisms).
The reason for individual variations. Generates different versions of the same gene.
