Cholesterol Metabolism Flashcards
Cholesterol is synthesized from ____ ___ in the cytosol or taken up from the diet. Cholesterol is a very ____ structure, who is rigidity plays an important role in regulating the fluidity of membranes.
Acetyl Coa
Insoluble
Cholesterol is the precursor of ___ ___, ___ hormones, and ___ _.
Bile salts
Steroid
Vitamin D
In the body cholesterol can be ___ or ____ to a fatty acid.
Free
Esterified
Cholesterol has one precursor: ___ ___, from the cytosol and is generated primarily from the citrate lyase reaction
Acetyl CoA
Four stages of cholesterol synthesis:
1. Three acetyl CoAs make ____ (6C)
2. Mevalonate is converted to ____ (5C)
3. Six isoprenes condense to form _____ (30 C)
4. Squalene is cyclized and converged to ____(27 C)
Mevalonate
Isoprene
Squalene
Cholesterol
The key regulatory enzyme in cholesterol synthesis:
Beta-hydroxy-beta-methylglutaryl CoA reductase (HMG CoA reductase)
Cholesterol synthesis occurs in the ____ and requires a lot of ____.
Cytosol
Energy
Cholesterol synthesis: first step:
3 acetyl CoAs condense to form ___ ___. Then ___ ___ ____ removes coenzyme A and reduces the aldehyde to an alcohol forming ____.
HMG-CoA
HMG CoA reductase
Mevalonate
HMG CoA reductase is an important drug target for managing ___ ___.
High cholesterol
Transcriptional regulation of HMG CoA reductase:
When cholesterol is abundant, the transcription factor sterile response element binding protein ( _____) is sequestered in intracellular membranes in complex with SREBP cleavage activating protein (______). When cholesterol levels drop, _____ cleaves the DNA binding domain of ____, which then translocate to the nucleus and regulates transcription of HMG CoA reductase
SREBP
SCAP
SCAP
SREBP
High ____ levels promote proteolysis and degradation of HMG CoA reductase
Sterol
In fasted conditions, HMG CoA reductase is phosphorylated and inactivated by ____. AMP-K is activated by ___ and ___.
AMP-K
AMP
sterols
Insulin promotes cholesterol synthesis by activating ____ that dephosphorylates HMG CoA reductase
Phosphatases
Three ____ are added to Mevalonate to form 3-phospho 5-pyrophosphomevalonate, which is dephosphorylated and decarboxylated to form 3-isopentenyl pyrophosphate which can then isomerize to dimethylallyl pyrophosphate.
Phosphates
Three isoprenes condense to form two ___ ____, which join together to form thirty carbon ____.
Farnesyl pyrophosphate
Squalene
Farnesyl pyrophosphate is a common precursor of ____, ____ (coenzyme Q), and ____.
Cholesterol
Ubiquinone
Dolichol
The thirty carbon Squalene is hydroxylated and cyclized to form ____. Subsequent reactions reduce the acyl chain and remove methyl groups to form the 27 carbon ____.
Ianosterol
Cholesterol
The liver can export cholesterol in the form of cholesterol esters in ___ particles into the blood, bile acids, and the lumen of the gut
VLDL
To be effective detergents that emulsify dietary fat, bile acids must be ____. Rate limiting step in bile acid synthesis is ____ of C7 of ____.
Amphipathic
Hydroxylation
Cholesterol
Bile salts act as detergents and make dietary fats ___ and accessible to ____.
Soluble
Lipase
Dietary fat and cholesterol are packaged as ___ ____ by intestinal epithelial cells. The ___ enter the lymphatic circulation first and then are transported to the blood.
Nascent chylomicrons
Chylomicrons
Cholesterol is transported into intestinal epithelial cells through the ___ ___ ___ -like-1 protein (NPC1L1). The cholesterol lowering drug ___ blocks cholesterol transport through NPC1L1.
Niemann Pick C1
Ezetimibe
In the blood, ____ particles transfer ApoCII to nascent ____ to make mature Chylomicrons. ApoCII activates ___ ___ (___).
HDL
chylomicrons
Lipoprotein lipase (LPL)
____ are the largest and least dense of the lipoprotein particles
Chylomicrons
After activation by ApoC, lipoprotein lipase cuts ___ ___ off of triacylglycerol in the capillary beds.
Fatty acids
Esterification of cholesterol to a fatty acid makes cholesterol even less ___. Cholesterol exported by the liver is often esterified to the unsaturated fatty acid ____. Acyl CoA cholesterol acyltransferase (____) catalyses the reaction. Cholesterol esters are then used to make membranes or packaged into ___ for export.
Soluble
Linoleate
ACAT
VLDL
High density lipoprotein (HDL) particles contain ___ ____ acyl tranferases (LCAT) which allows cholesterol picked up by the HDL particle to be ____ within the particle for reverse cholesterol transport to the ____.
Lecithin-cholesterol
Trapped
Liver
Two functions of HDL particles:
1. Give ____ to nascent chylomicrons and immature VLDL particles
2. ____ cholesterol transport
ApoCII
Reverse
VLDL particles contain the proteins ____ and ____ and ____
ApoB100
ApoE
ApoCII
Lipoproteins and nucleotide editing:
In the liver, ____ is expressed from the B-apoprotein gene. In intestinal epithelial cells, the B-apoprotein gene transcript is edited, changing ___ to uridine, introducing a ___ ___. The translated protein is ____, about half the size of ApoB100.
ApoB100
Cytosine
Stop codon
ApoB48
Lipoproteins and gene editing:
The cytosine deaminase _____, expressed in intestinal epithelial cells introduced a stop codon in the ____ ____.
APOBEC-1
ApoB mRNA
VLDL particles have less ____ than chylomicrons
Triacylglycerols
Nascent VLDL from the liver becomes mature VLDL when it receives ____ and ___ from circulating HDL.
ApoCII
ApoE
HDL contains the cholesterol ester transfer protein (____) that swaps cholesterol ester (CE) for _____ with VLDL particles. This route of reverse cholesterol transport is more active in conditions of ____.
CETP
Triacylglycerol
Hyperlipidemia
ApoCII activates ___ ___ (LPL). The VLDL particle gets smaller and smaller as it circulates through the body, ultimately becoming a ___ particle
Lipoprotein lipase
LDL
Lipoprotein particles can be endocytosis in target cells that express the ___ ___. The ligand binding domain binds ___ and ___.
LDL receptor
ApoB100
ApoE
The LDL receptor’s cytoplasmic domain is linked to ___. Binding of a lipoprotein to the ligand binding domain results in ___.
Clathrin
Endocytosis
After endocytosis, fatty acids and cholesterol are ____ into new particles and the LDL receptor is return to the ___ ___.
Recycled
Plasma membrane
Extracellular proprotein convertase subtilisin/kexin type 9 (____) is a protein that modulates LDL receptor activity.
PCSK9
PCSK9 is secreted by hepatocytes and downregulates the ___ ___ by causing its internalization. High levels of PCSK9 contribute to _____ by decreasing the trucking of LDL particles
LDL receptor
Hypercholesterolemia
Loss of function mutations in PCSK9 ____ hypercholesterolemia. Activating mutations ___ hypercholesterolemia. ____ is a medication that inhibits PCSK9 to help treat hypercholesterolemia
Prevent
Increase
Evolucamab
Steroids hormones are derived from cholesterol and are synthesized in the ___ ___ and the ___.
Adrenal cortex
Gonads
Some statins are associated with ____ (muscle pain and weakness) due to inhibition of ____ __ synthesis leading to energy starvation of muscles.
Myopathy
Coenzyme Q (ubiquinone)
Mutations in the LDL receptor are common causes of ___ ____. Symptoms include hyperlipidemia, premature CVD, xanthomas
Familial hypercholesterolemia
Familial hypercholesterolemia:
As LDL circulates, constituents can become oxidized upon exposure to ___ and ___. Oxidized LDL can be taken up by ____ which fill up with cholesterol and become ___ ___.
ROS
Nitrogen
Macrophages
Foam cells
Familial hypercholesterolemia:
Foam cells become lodges below the endothelial layer of blood vessels and from ___ ___. Damage to the plaque can initiate ____ and lead to ___.
Atherosclerotic plaques
Clotting
Thrombus
Picture of xanthomas
Lipoproteins table:
