Mindmap
Cholesterol Homeostasis
Inhalt der Mindmap
Cholesterol Homeostasis
Biomedical importance of cholesterol
- Cholesterol present in
- plasma
- transported in lipoproteins
- LDL supplies cholesterol and cholesteryl ester to tissues
- Free cholesterol removed from tissues by HDL
- transported to the liver
- reverse cholesterol transport
- transported to the liver
- transported in lipoproteins
- tissues
- amphipathic lipid
- structural component of membranes
- maintenance of proper
- permeability
- fluidity
- maintenance of proper
- in outer layer of plasma lipoproteins.
- structural component of membranes
- amphipathic lipid
- synthesized from acetyl-CoA
- plasma
- Forms
- free cholesterol
- with a long-chain fatty acid
- cholesteryl ester
- storage form
- cholesteryl ester
- precursor of all steroids in the body
- corticosteroids
- sex hormones
- bile acids
- vit D
- Found in foods
- egg yolk
- meat
- liver
- brain
- constituent of gallstones
- atherosclerosis
- cerebrovascular disease
- coronary disease
- peripheral vascular disease
- Cholesterol present in
Cholesterol biosynthesis
- all nucleated cells are capable of cholesterol synthesis
- occurs in
- endoplasmic reticulum
- cytosol
- liver 10%
- intestine 10%
- Steps
- 1. Biosynthesis of Mevalonate
- HMG-CoA is formed by the reactions used for ketogenesis
- cytosolic thiolase
- condenses 2 acetyl-CoA molecules
- forms acetoacetyl-CoA
- HMG-CoA synthase
- condenses acetoacetyl-CoA with other acetyl-CoA
- forms HMG-CoA
- HMG-CoA reductase
- reduces it to mevalonate using NADPH
- principal regulatory step
- cholesterol-lowering drugs target
- HMG-CoA reductase
- forms HMG-CoA
- condenses acetoacetyl-CoA with other acetyl-CoA
- HMG-CoA synthase
- forms acetoacetyl-CoA
- condenses 2 acetyl-CoA molecules
- cytosolic thiolase
- HMG-CoA is formed by the reactions used for ketogenesis
- 2. Formation of Isoprenoid Units
- three kinases
- phosphorylate mevalonate using ATP
- decarboxylation of the active isoprenoid unit
- isopentenyl diphosphate is formed
- decarboxylation of the active isoprenoid unit
- phosphorylate mevalonate using ATP
- three kinases
- 3. Six Isoprenoid Units Form Squalene
- Isopentenyl diphosphate is isomerized
- dimethylallyl diphosphate
- condensed with other isopentenyl diphosphate
- form geranyl diphosphate
- further condensation with isopentenyl diphosphate
- farnesyl diphosphate
- 2 farnesyl diphosphate molecules condense at the diphosphate end
- form squalene
- further addition of isopentenyl diphosphate residues
- polyisoprenoids
- dolichol
- ubiquinone
- polyisoprenoids
- Protein prenylation
- protein–protein interactions
- membrane-associated protein trafficking
- proteins anchoring into lipid membranes
- 2 farnesyl diphosphate molecules condense at the diphosphate end
- farnesyl diphosphate
- further condensation with isopentenyl diphosphate
- form geranyl diphosphate
- condensed with other isopentenyl diphosphate
- dimethylallyl diphosphate
- Isopentenyl diphosphate is isomerized
- 4. Formation of Lanosterol
- Squalene can fold into a structure like the steroid nucleus
- squalene epoxidase in endoplasmic reticulum
- forms squalene 2,3-epoxide
- oxidosqualene-lanosterol cyclase
- transfers CH3 on C14 to C13, on C8 to C14 as cyclization occurs
- ring closure
- transfers CH3 on C14 to C13, on C8 to C14 as cyclization occurs
- oxidosqualene-lanosterol cyclase
- forms squalene 2,3-epoxide
- squalene epoxidase in endoplasmic reticulum
- Squalene can fold into a structure like the steroid nucleus
- 5. Formation of Cholesterol
- in endoplasmic reticulum
- methyl groups on C14 and C4 are removed
- form 14-desmethyl lanosterol
- then zymosterol
- double bond at C8—C9 moved to C5—C6
- forming desmosterol
- double bond of the side chain is reduced
- cholesterol
- double bond of the side chain is reduced
- forming desmosterol
- double bond at C8—C9 moved to C5—C6
- then zymosterol
- form 14-desmethyl lanosterol
- methyl groups on C14 and C4 are removed
- in endoplasmic reticulum
- 1. Biosynthesis of Mevalonate
- Regulation
- HMG-CoA reductase step
- inhibited by
- mevalonate
- repress transcription HMG-CoA reductase mRNA
- cholesterol
- repress transcription HMG-CoA reductase mRNA
- by inhibitioning a sterol regulatory element-binding protein (SREBP) transcription factor
- regulate the transcription of genes involved in
- cellular uptake
- lipid metabolism
- inhibited by insulin-induced gene (Insig)
- induced by insulin
- in endoplasmic reticulum
- promotes degradation of HMG-CoA reductase
- regulate the transcription of genes involved in
- by inhibitioning a sterol regulatory element-binding protein (SREBP) transcription factor
- repress transcription HMG-CoA reductase mRNA
- glucagon
- glucocorticoids
- AMPK
- activated by
- allosteric modification by AMP
- AMPKK
- activated by
- mevalonate
- increased by
- Insulin
- thyroid hormone
- Activity modified by
- phosphorylation (inactivation) – dephosphorylation (activation)
- some are cAMP-dependent
- responsive to glucagon
- some are cAMP-dependent
- phosphorylation (inactivation) – dephosphorylation (activation)
- inhibited by
- increased intake of diet cholesterol
- decrease in de novo synthesis in liver
- Mechanisms
- modulation of the synthesis of enzyme protein
- posttranslational modification
- Short-term changes
- HMG-CoA reductase step
- occurs in
- all nucleated cells are capable of cholesterol synthesis
Cholesterol balance in tissues
- uptake of cholesterol-containing lipoproteins by receptors
- Scavenger receptors (LDL) like CD36
- increase in cell cholesterol
- cholesterol synthesis
- cholesteryl esters hydrolysis by cholesteryl ester hydrolase
- efflux of cholesterol from the membrane to HDL
- via the ABCA1, ABCG1, or SR-B1
- esterification of cholesterol by ACAT
- utilization of cholesterol for synthesis of other steroids
- hormones
- bile acids in liver
- utilization of cholesterol for synthesis of other steroids
- ABCA1
- preβ-HDL exogenous acceptor
- SR-B1 & ABCG1
- HDL3 exogenous acceptor
- esterification of cholesterol by ACAT
- via the ABCA1, ABCG1, or SR-B1
- efflux of cholesterol from the membrane to HDL
- cholesteryl esters hydrolysis by cholesteryl ester hydrolase
- cholesterol synthesis
- increase in cell cholesterol
- Scavenger receptors (LDL) like CD36
- LDL (apo B-100, E) receptors occur on the cell surface
- in clathrin coated pits on the cytosolic side
- glycoprotein receptor spans the membrane
- B-100 binding region being at the exposed amino terminal end
- LDL binding
- intact LDL endocytosis
- lysosomes hydrolize
- apoprotein
- cholesteryl ester
- cholesterol into the cell
- inhibits genes transcription encoding
- HMG-CoA synthase
- HMG-CoA reductase
- LDL receptor
- via SREBP pathway
- PCSK9 regulates the recycling of the receptor
- targeting it for degradation
- suppresses cholesterol synthesis and uptake
- increased ACAT activity
- promotes cholesterol esterification
- inhibits genes transcription encoding
- lysosomes hydrolize
- intact LDL endocytosis
- LDL binding
- B-100 binding region being at the exposed amino terminal end
- uptake of cholesterol-containing lipoproteins by receptors
Cholesterol transport
- transported in plasma in lipoproteins
- mostly cholesteryl ester
- LDL highest proportion
- Dietary cholesterol
- Cholesteryl ester
- hydrolyzed to cholesterol
- absorbed by the intestine
- with dietary unesterified cholesterol and other lipids
- cholesterol synthesized in intestine
- incorporated into chylomicrons
- 80-90% esterified with long-chain fatty acids in the intestinal mucosa
- 95% of chylomicron cholesterol goes to the liver in chylomicron remnants
- most of cholesterol secreted by the liver in VLDL is retained during IDL and LDL
- taken up by the LDL receptor in liver and tissues
- most of cholesterol secreted by the liver in VLDL is retained during IDL and LDL
- incorporated into chylomicrons
- cholesterol synthesized in intestine
- with dietary unesterified cholesterol and other lipids
- absorbed by the intestine
- hydrolyzed to cholesterol
- equilibrates with
- plasma cholesterol
- days
- tissue cholesterol
- weeks
- plasma cholesterol
- Cholesteryl ester
- mostly cholesteryl ester
- Plasma LCAT
- Lecithin: cholesterol acyltransferase acctivity
- associated with HDL containing apo A-I
- cholesterol in HDL becomes esterified
- creates a concentration gradient
- draws in cholesterol from tissues and from other lipoproteins
- HDL functions in reverse cholesterol transport
- draws in cholesterol from tissues and from other lipoproteins
- creates a concentration gradient
- cholesterol in HDL becomes esterified
- associated with HDL containing apo A-I
- Lecithin: cholesterol acyltransferase acctivity
- Cholesteryl ester transfer protein in plasma
- enables transfer of HDL cholesteryl ester to
- VLDL
- IDL
- LDL
- in exchange for triacylglycerol,
- relieves product inhibition of
- LCAT activity in HDL
- cholesteryl ester formed by LCAT finds its way to the liver
- triacylglycerol-enriched HDL2
- delivers cholesterol to the liver
- triacylglycerol-enriched HDL2
- cholesteryl ester formed by LCAT finds its way to the liver
- LCAT activity in HDL
- relieves product inhibition of
- enables transfer of HDL cholesteryl ester to
- transported in plasma in lipoproteins
Cholesterol excretion
- via the bile
- unesterified form
- after conversion into bile acids
- liver
- biosynthesis of bile acids
- primary bile acids
- cholic acid
- chenodeoxycholic acid
- enter the bile as
- glycine
- taurine conjugates
- conjugation in liver peroxisomes
- absorbed in ileum
- lithocholic acid is not reabsorbed
- 99% is returned to liver
- via the portal circulation
- enterohepatic circulation
- only small part eliminated in feces
- but constant size of bile acids pool is maintained
- via the portal circulation
- 99% is returned to liver
- lithocholic acid is not reabsorbed
- cholesterol
- 7α-hydroxylation by enzyme:
- cholesterol 7α-hydroxylase (CYP7A1)
- first and principal regulatory step
- monooxygenase
- Requires
- oxygen
- NADPH
- cytochrome P450
- Subsequent hydroxylation steps by monooxygenases
- Requires
- feedback regulated
- nuclear bile acid–binding receptor
- farnesoid X receptor (FXR)
- activated when bile acid pool increases
- especially chenodeoxycholic acid
- CYP7A1 gene is suppressed
- especially chenodeoxycholic acid
- activated when bile acid pool increases
- farnesoid X receptor (FXR)
- enhanced by cholesterol
- endogenous
- regulated by more hormones
- dietary
- regulated by more hormones
- insulin, glucagon, glucocorticoids, thyroid hormone.
- regulated by more hormones
- endogenous
- nuclear bile acid–binding receptor
- cholesterol 7α-hydroxylase (CYP7A1)
- 7α-hydroxylation by enzyme:
- divides into subpathways
- leading to cholyl-CoA
- extra α-OH group on position 12
- leading to chenodeoxycholyl-CoA
- enzyme CYP27A1
- 27-hydroxylation of cholesterol
- big proportion of the primary bile acids
- takes place in the mitochondria
- big proportion of the primary bile acids
- 27-hydroxylation of cholesterol
- enzyme CYP27A1
- leading to cholyl-CoA
- alkaline bile (pH 7.6-8.4)
- salt form
- secondary bile acids
- absorbed in ileum
- primary bile acids
- Coprostanol
- feces
- via the bile
Bilder und Dateien der Mindmap
Informationen
- Beschreibung
- Medicina Mindmap am Cholesterol Homeostasis, erstellt von Valentina Ardila Mora am 28/10/2020.
- Erstellt von
- Valentina Ardila Mora
- Aufrufe
- 5
- Bewertung
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