Module 1: Deck 4/Cards 21-33 Flashcards
What is the role of liver X receptor (LXR) in cholesterol homeostasis?
It enhances cellular cholesterol reflux via induction of ABCG 5 and ABCG 8
What is the liver X receptor (LXR)?
Is an activated nuclear receptor that, after binding with the heterodimer, retinoid X receptor, acts in concert with coactivators and co-repressors like fatty acids, oxysterols and bile acids to maintain cholesterol homeostasis
Liver X receptor (LXR) acts as ?
ligand activated nuclear recpetors that act as cholesterol sensors
SREBP are activated by what?
LXR are activated by what?
- low cellular cholesterol levels
2. high cholesterol levels
While the (1) is the target of the SREBP2 pathway, resulting in clearance of LDL particles from the circulation, LXR negatively regulates the (2), thus providing a second mechanism for feedback regulation of intracellular cholesterol levels.
As an adaptive mechanism to lower intracellular cholesterol levels, LXR’s do what? 3 for 3
L XR does have multiple other metabolic effects, some of which include? 3 for 4
- LDL receptor
- LDL receptor pathway
- increase the conversion of cholesterol to bile acids,
- enhance reverse cholesterol transport and
- decrease small intestinal cholesterol absorption
- increased lipogenesis
- increase adipose tissue glucose uptake and
- increased adipose tissue fatty acid oxidation
What are ABCG5/ABCG8? and where are they expressed?
Thus, defects in these genes are associated with what?
B-sitosterolemia (also known as phytosterolemia) is an extremely rare disorder due to homozygous or compound heterozygous mutations in ?
- are proteins expressed in the liver and small intestine and facilitate excretion of absorbed plant sterols and cholesterol into the intestinal lumen and bile.
- markedly elevated plasma levels of plant sterols (e.g. sitosterol and campesterol) and normal to moderately elevated plasma levels of cholesterol.
- either one of these two adenosine triphosphate binding cassette transporter genes.
What is farnesoid X receptor or FXR? Where is it expressed?
It is a nuclear bile acid receptor expressed in the
liver
kidney
intestine
adrenal glands
High levels of bile acids are toxic to cells. What is a nuclear receptor that plays a major role in regulating bile acid synthesis and in its modification before it is released to the gallbladder.
F XR
FXR:
1. It also affects hepatic absorption and uptake of bile acids. FXR reduces conversion of bile to cholesterol acids by what?
- It reduces bile acid toxicity in the liver by what?
- In the intestine, FXR reduces bile acid absorption how? 3 for 3
- FXR reduces hepatic uptake of bile acids how?
- In the liver it reduces what via the down-regulation of phophoenolpyruvate carboxykinase and glucose-6-phosphatase, two key enzymes involved in the glucose synthesis pathway.
- down regulating expression of enzymes involved in bile acid synthesis
- increasing of the bile acid modifying enzymes
- via down-regulation intestinal bile acid transporter,
- promotes bile acid movement across the enterosite via ileal bile acid binding protein and
- promotes recycling of bile acids to the liver.
- by reducing the expression of organic and ion transporting polypeptide and sodium taurocholate co-transporting polypeptide
- gluconeogenesis
FXR reduced lipogensis via inhibition of what?
sterol-regulatory element-binding protein 1C and fatty acid synthase.
FXR reduced gluconeogensis via the down regulation of what two key enzymes involved in the glucose synthesis pathway?
phophoenolpyruvate carboxykinase and glucose-6-phosphatase
- The 2016 American College of cardiology expert consensus decision pathway on the role of non-statin therapies for LDL cholesterol lowering in the management of atherosclerotic cardiovascular disease advises against the use of bile acid sequestrants in which patients?
Bile salts, as FXR ligands, decreased what?
Bile acid sequestrants, by inhibiting what, act as FXR antagonists, a possible explanation further triglyceride raising properties?
- patients who may require additional LDL lowering but have plasma triglycerides over 300.
- circulating triglycerides.
- bile acid reabsorption
- FXR decreases what? 4
2. It increases what? 1
1. gluconeogenesis hepatocyte bile acid synthesis lipogenesis intestinal reabsorption of bile acids.
- increases hepatocyte bile acid modification and secretion
Add graphic
The left hand of a 5-year-old boy referred to lipid clinic as shown. His labs were: Total cholesterol 800, HDL 60, TG 90, and LDL 722. He was followed by lipid specialist and treated with multiple LDL lowering drugs. He developed angina in his mid teens and underwent multivessel PCI at age 19 because of worsening angina. Mutation in the gene encoding for what is the most likely–common cause of his clinical presentation?
LDL-receptor
1-4: Homozygous familial hypercholesterolemia, is an (1) genetic disorder most often caused by mutations in the gene encoding for the (2). The most common mutations of the LDL receptor occur in (3) resulting in the (4) and, therefore, the inability to properly clear LDL particles.
- Other mutations of the LDL receptor include what? 2
- autosomal dominant
- LDL receptor
- the binding domain
- uncoiling of the receptor
- the inability to migrate to the cell surface and
- an abnormality of the epidermal growth factor region, thereby preventing the receptor from functioning at the cell surface.
HoFH: Other genetic disorders that may cause a similar clinical presentation, but occur with lower frequency, include mutations in what? 4
- Apo-B 100,
- gain of function mutations in PCSK9,
- mutations in LDL related protein (autosomal recessive hypercholesterolemia) and
- sitosterolemia
What is sitosterolemia?
an autosomal recessive disorder in either ABCG5 or ABCG8, which impairs the function of the small intestinal sterol efflux transporter.
Patients with homozygous familial hypercholesterolemia accumulate LDL-C where? 3
They are at risk for? when?
The diagnosis is typically based upon the findings of what? 4
- plasma
tendons
skin - premature ASCVD, often within the first 2 decades of life.
- xanthomas in patients under the age of 10 years associated with
- an untreated LDL cholesterol of over 500
- treated LDL cholesterol of over 300 or
- a non-HDL cholesterol of over 330.
What finding is pathognomic for HoFH?
Interdigital xanthomas, particularly between the thumb and index finger
HoFH: Except in parents with autosomal recessive hypercholesterolemia, parents of such patients are often homo or heterozygous?
heterozygous, or rarely homozygous for familial hypercholesterolemia.
Although homozygosity for defective alleles at the LDL receptor is very unlikely, compound genetic states characterized by different defects of the LDL receptor on the 2 receptor genes, or a mixed heterozygous state in which defects of the LDL receptor coexist with other defects such as what may be present? 2
The likelihood that 2 similar mutations are present increases greatly in the presence of consanguinity of the parents. Clustering of homozygous FH patients in certain ethnic groups, including which who is likely related to inter marriage among these ethnic groups? 4
More than 1600 mutations of the LDR receptor have been described in new mutations continue to be identified.
- Apo-B 100 mutation or
PCSK9 gain of function mutation
2. French Canadians Dutch Afrikaners in South Africa Maronite Christians from Lebanon Ashkenazi Jew's from Lithuania
