WEEK 2 cholesterol

citrate

(metabolite control) upstream regulator activates ACC for FA biosynthesis by promoting polymerization

palmitoyl-CoA

(metabolite control) downstream regulator inhibits ACC for FA biosynthesis by promoting filament disassociation, inhibits citrate transporter, inhibits G6P dehydrogenase

glucagon, epinephrine

(hormonal control) hormones downregulate ACC activity via phosphorylation in a fasted state

insulin

(hormonal control) hormone signaling activates PP2A and citrate lyase in a fed state promoting ACC dephosphorylation increasing FA biosynthesis

PP2A

activated by insulin signaling in a fed state dephosphorylating ACC for FA synthesis

insulin

hormone promotes FA synthesis by activating cAMP phosphodiesterase, increasing glucose uptake, increasing flux through glycolysis and PDH, increasing citrate lyase activity, and increasing ACC activity

ketone bodies

synthesized in liver, mobilization of fats during a fast that allows humans to survive long periods of starvation, water soluble

acetyl CoA accumulation in the mitochondria

excess used to synthesize ketone bodies in the liver

liver

makes ketone bodies in the mitochondria, however cannot use them itself

liver

primary site of cholesterol biosynthesis where reactions take place in the cytosol and ER

cytosol, ER

loci of cholesterol biosynthesis in the liver

HMG-CoA reductase

enzyme catalyzes the committed step in cholesterol biosynthesis to make mevalonate

acetyl coA → mevalonate → isopentyl pyrophosphate → squalene → cholesterol

list all 4 IMs of cholesterol biosynthesis starting from acetyl coA down to cholesterol

Low density lipoproteins (LDL)

transport cholesterol to extra hepatic tissues

receptor mediated endocytosis

method in which cells uptake LDLs (containing cholesterol) after binding LDL receptors LDLRs

lysosome

release cholesterol, AAs, and FAs into the cell after being endocytosed

acetyl CoA cholesterol acyl transferase (ACAT)

enzyme catalyzes cholesterol storage and transport

peripheral tissues

loci where the enzyme ACAT promotes storage of cholesterol in lipid droplets

intestine, liver

loci where ACAT activity is important for packaging cholesterol into lipoproteins for transport

excrete in bile

as we cannot break down cholesterol, this is the only way we can remove it from our bodies

HMGR

(cholesterol synthesis) inhibited by glucagon in a fasted state preventing synthesis of the IM Mevalonate

AMPK, glucagon

two hormones/molecules inhibit cholesterol synthesis by promoting phosphorylation of HMGR

insulin

promotes cholesterol synthesis by dephosphorylating HMGR

PP2A

rapid regulation of HMG-CoA reductase, promotes cholesterol synthesis by dephosphorylating HMGR in a fed state

AMPK

rapid regulation of HMG-CoA reductase, turns off cholesterol synthesis and phosphorylates HMGR when sensing low energy

PKA

rapid regulation of HMG-CoA reductase, turns off cholesterol synthesis and phosphorylates HMGR when sensing low blood glucose via glucagon

sterol regulatory element binding protein (SREBP)

used for long term regulation of HMG CoA reductase activity for cholesterol synthesis, membrane bound transcription activator regulates HMGR and LDLR expression

SCAP

used for long term regulation of HMG CoA reductase activity for cholesterol synthesis, sterol sensing domain binds cholesterol, if cholesterol is bound promotes binding by INSIG and retains them in the ER

insulin induced growth response genes INSIG

interacts with SCAP and is stabilized by cholesterol in sterol sensing domain of SCAP retaining it in the ER in high cholesterol conditions

sterol regulatory element binding protein (SREBP)

in low cholesterol conditions these proteins transcription factors are released, translocate to the nucleus, and increase expression of target genes increasing cholesterol biosynthesis

gp78

used for long term regulation of HMG-CoA reductase activity for cholesterol biosynthesis, enzyme brought in by INSIG bound to HMGR bound to cholesterol promoting ubiquitylation and HMGR degradation

statins

competitive inhibitors of HMG-CoA blocking cholesterol biosynthesis decreasing circulating LDL cholesterol levels by binding HMGR stronger with an HMG like group

PCSK9

therapeutic target for treating high cholesterol, when bound by a monoclonal Ab evolocumab prevents interaction with LDLR decreasing abilities of hepatocytes to take up circulating LDL particles decreasing overall LDL clearance