Mid 2: Lec 13 Flashcards
main enzyme chol synth reg and two types reg
hmg coa reductase
transcriptional
post transcriptional
Short-term regulation of HMG-CoA reductase and aa#
HMG-CoA reductase can be phosphorylated at Ser872 by AMPK to halt hmg coa reductase activity
Ser872 can be dephosphorylated by Protein phosphatase 2A (PP2A) to reactivate
roles of ampk
acts as an energy sensor
phosphorylate ACC (acetyl-CoA
Carboxylase) leading to an inhibition of the enzyme activity and
consequently, inhibits the synthesis of fatty acids (FAs).
HMG-CoA reductase can be phosphorylated by AMPK to halt hmg coa reductase activity and stop chol synth
roles of pp2a
dephosphorylate ACC (acetyl-CoA
Carboxylase) leading to an activation of the enzyme activity and
consequently, promotes the synthesis of fatty acids (FAs)
hmg coa reductase can be dephosphorylated by Protein phosphatase 2A (PP2A) to reactivate chol synth
regulation of pp2a
can be regulated by insulin and glucagon/epinephrine.
Long-term post transcriptional regulation of HMG-CoA reductase
-regulated by controlled proteolysis:
sterol accumulation
hmg coa reductase senses sterols
Membrane sterol binds to HMG-CoA reductase.
leads to the recruitment of Insigs proteins which are
associated to a ubiquitination complex.
HMG-CoA reductase is ubiquitinated, released from the ER membrane
and degraded by the proteosome
Long-term transcriptional regulation of HMG-CoA reductase
The promoter region of the HMG-CoA reductase gene contains an SRE (sterol-regulatory element or sterol-responsive
element)
Binding of the transcription factor SREBP (SRE binding protein) to SRE
activates transcription of HMG-CoA reductase
Availability of SREBP is governed by cholesterol concentrations within the
cells
SREBP structure and genes
basic helix-loop-helix-leucine-
zipper DNA binding protein
in humans encoded by two genes SREBP1 AND SREBP2
Fate of SREBP-2: low cholesterol levels
INSIG (ER) gets degraded when cholesterol concentration is low
SCAP escorts SREBP from ER to Golgi
SREBP-2 is cleaved by endopeptidases in the Golgi, and the N-
terminal SRE binding domain is released
LDL receptor (and type of protei and ligand)
type-I membrane protein (N-terminus is oriented facing the outside of
plasma membrane)
The ligand for LDLR is the
LDL-bound apoB100
mediates endocytosis of LDL
Endocytosis of LDL inc what are ldls broken into
Binding of LDL to the LDLR results in endocytosis
LDLs are broken down into lipids and amino acids
LDLRs are recycled back to the plasma membrane
PCSK9
SREBP-2 also increases the expression of
PCSK9
binds to the extracellular portion of the LDL receptors (doesn’t affect ldl binding or endocytosis)
causes ldlr to be degraded instead of recycled after endocytosis
Cholesterol 7alpha-hydroxylase
catalyzes the
rate-limiting step in the synthesis of bile acid
The expression of cholesterol 7-hydroxylase gene in the liver
is upregulated when levels of cholesterol are high and downregulated when levels of cholesterol are low
Storage of cholesterol ester under high
cholesterol conditions
An increased level of free cholesterol leads to an increased in
Acyl-CoA cholesterol Acyl Transferase (ACAT) activity
increase in storage of cholesterol in the form of cholesterol esters
(CE)
Familial hypercholesterolemia (FH) and causes
elevated plasma LDL concentrations and premature atherosclerosis
- Loss-of-function mutations within the LDLR gene is the most
prevalent cause of hypercholesterolemia
main cause - ER/Golgi trafficking – mutations causing retention of LDLR
within the ER and not transported to the plasma membrane - Ligand-binding – mutations within the ligand-binding
domain resulting in impaired binding to LDL (apoB100) - Internalization – mutations in the intracellular domain of
LDLR resulting in inability to internalize LDLR/LDL complex - LDLR recycling – mutations preventing dissociation of
LDLR/LDL complex within the “sorting” endosome and not
allowing LDLR recycle back to the plasma membrane
Treatment paths for hypercholesterolemia
Dietary intake of cholesterol
Rate of endogenous synthesis in the liver
Rate of cholesterol use by the cells
statins
Inhibition of HMG-CoA reductase by the competitive inhibitors
Reduction of de novo cholesterol biosynthesis
Low cellular cholesterol leads to an increase in SREBP2
Increase in LDL receptors production
Clearance of extracellular cholesterol from the blood
Why are statins unable to completely remove LDL from the
blood? Also, solution to this mech
Low cholesterol levels also leads to the expression of PCSK9
Degradation of LDL receptors
Inhibitors of PCSK9 can counteract
