MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

leky-latky/cholesterol/pcsk9

PCSK9

  • Binds the low-density lipoprotein receptor and targets it for degradation
  • PCSK9 mRNA and protein in Caco-2/15 cells were associated to the regulation of 3-hydroxy-3-methylglutaryl-CoA reductase and
  • PCSK9 is ubiquitously expressed in many tissues and cell types
  • PCSK9 binds to the receptor for low-density lipoprotein particles (LDL)
    • Typically transport 3,000 to 6,000 fat molecules (including cholesterol) per particle, within extracellular fluid
  • The LDL receptor (LDLR), on liver and other cell membranes, binds and initiates ingestion of LDL-particles from extracellular fluid into cells
    • Reducing LDL particle concentrations
  • If PCSK9 is blocked, more LDLRs are recycled and are present on the surface of cells to remove LDL-particles from the extracellular fluid
  • Agents which block PCSK9 can lower LDL particle concentrations
  • First two PCSK9 inhibitors, alirocumab and evolocumab
    • Lowering LDL-particle concentrations when statins and other drugs were not sufficiently effective or poorly tolerated [2]
  • Binds the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR [2]
  • When LDL binds to LDLR, it induces internalization of LDLR-LDL complex within an endosome.
    • The acidity of the endosomal environment induces LDLR to adopt a hairpin conformation.
    • The conformational change causes LDLR to release its LDL ligand, and the receptor is recycled back to the plasma membrane.
    • When PCSK9 binds to the LDLR (through the EGF-A domain), PCSK9 prevents the conformational change of the receptor-ligand complex.
      • This inhibition redirects the LDLR to the lysosome instead [2]
  • PCSK9 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum.
  • The protein may function as a proprotein convertase.
  • PCSK9 is expressed mainly in the
    • Liver
    • Intestine
    • Kidney
    • Central nervous system [2]
  • PCSK9 is highly expressed in arterial walls such as endothelium, smooth muscle cells, and macrophages, with a local effect that can regulate vascular homeostasis and atherosclerosis. [2]
    • Tkáně si tak mohou říkat o více cholesterolu pro svoji obnovu - třeba pokud vlivem oxidačního stresu mají více poškozené lipidové membrány aj.
  • Important role in intestinal triglyceride-rich apoB lipoprotein production in small intestine and postprandial lipemia. [2]
  • After being processed in the ER, PCSK9 co-localizes with the protein sortilin on its way through the Golgi and trans-Golgi complex
  • A PCSK9-sortilin interaction is proposed to be required for cellular secretion of PCSK9 [2]
  • Healthy humans
    • Plasma PCSK9 levels directly correlate with plasma sortilin levels
      • Following a diurnal rhythm similar to cholesterol synthesis [2]
  • PCSK9 may also have a role in the differentiation of cortical neurons [2]
    • Still controversial and may be either pro-apoptotic or protective in the development of the nervous system [2]
    • PCSK9 levels have been detected in the cerebrospinal fluid at a 50-60 times lower level than in serum [2]
  • PCSK9 is involved in glucose metabolism and obesity [2]
  • Regulation of re-absorption of sodium in the kidney which is relevant in hypertension [2]
  • May be involved in bacterial or viral infections and sepsis [2]
  • Binds to low-density lipid receptor family members:
  • Promotes their degradation in intracellular acidic compartments [3]
  • Acts via a non-proteolytic mechanism
    • Enhance the degradation of the hepatic LDLR
    • Through a clathrin LDLRAP1/ARH-mediated pathway [3]
  • May prevent the recycling of LDLR from endosomes to the cell surface
    • Or direct it to lysosomes for degradation
  • Can induce ubiquitination of LDLR leading to its subsequent degradation. [3]
  • Inhibits intracellular degradation of APOB
    • Via the autophagosome/lysosome pathway in a LDLR-independent manner. [3]
  • Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway.
  • Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption
    • By reducing ENaC surface expression
      • Primarily by increasing its proteasomal degradation. [3]
  • Regulates neuronal apoptosis
    • Via modulation of LRP8/APOER2 levels
    • Related anti-apoptotic signaling pathways [3]
  • Defects in PCSK9 are the cause of
    • Hypercholesterolemia autosomal dominant type 3 (HCHOLA3)
      • A familial condition
      • Elevated circulating cholesterol contained in either
        • Low-density lipoproteins alone
        • Or also in very-low-density lipoproteins [3]
  • Belongs to the peptidase S8 family
  • 2 isoforms of the human protein are produced by alternative splicing. [3]

    • Inhibice


    Fasting

    • Was able to reduce PCSK9 expression by 80% even in mice that lack hepatic insulin signaling !!! [1]
    • 24-h fasting in mice dramatically decreased hepatic PCSK9 mRNA and protein levels
      • Progressively restored by carbohydrate refeeding [6]

    Estrogeny

    • The plasma PCSK9 concentration is higher in women compared to men
      • estrogen = snižuje PCSK9 méně než testosteron
    • PCSK9 concentrations decrease with age in men but increase in women
      • Estrogen level most likely plays a role [2]
      • pokles estrogenu = další nárůst PCSK9

    Loss-of-function mutations in the PCSK9 gene

    • Result in lower levels of LDL and protection against cardiovascular disease [2]

    Annexin A2

    • Endogenous protein, is a natural inhibitor of PCSK9 activity [2]
    • Sensors for Ca2+, pH, and lipid second messengers, and regulate various signalling pathways. Recently, annexins were reported to participate in feedback loops, suppressing miRNA synthesis and attenuating stress-induced dysregulation of gene expression.
    • Play a role in many neovascularization diseases

    Berberine (BBR)

    • Inhibits the transcription of the PCSK9 gene in immortalized human hepatocytes in vitro [2]
    • Lowers serum PCSK9 in mice and hamsters in vivo [2]
    • Major isoquinoline alkaloid in Chinese herb Rhizoma coptidis
      • Significant lipid-lowering effect by upregulating hepatic low-density lipoprotein receptor (LDLR) expression [11]

    25-hydroxycholesterol

    • Displayed significant reduction in PCSK9 gene (37%,P 0.01) and protein (75% P 0.001) expression
    • Whereas LDLr showed a decrease at the gene (30%, P 0.05) and protein (57%, P 0.01) levels, respectively [6]

    ANP

    • Reduced insulin-induced PCSK9,
      • Especially in the context of a medium simulating hyperglycemia. [7]
    • ANP indirectly blocked the LDLR degradation, reducing the positive effect of LDL on PCSK9. [7]

    Cholesterol

    • Supplementation with 2% cholesterol in the diet
      • Prevented the increase in Pcsk9.
    • The amounts of Pcsk9 mRNA in livers of refed mice showed correlated regulation by the changes in the nuclear form of Srebp-2. [12]

    Hydrogen sulfide - H2S

    • Endogenous gaseous signaling molecule
    • Inhibits PCSK9 expression
    • Through the PI3K/Akt-SREBP-2 signaling pathway
      • To influence lipid metabolism in HepG2 cells [9]
    • Treatment of the HepG2 cells with H2S
      • Inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9)
      • Increased the level of low-density lipoprotein receptor (LDLR) in a time- and dose-dependent manner. [9]
    • H2S regulates lipid metabolism + reduces atherosclerosis
    • H2S increased lipid uptake, but caused no increase in lipid accumulation. [9]
    • Exogenous H2S can
      • Mitigate fatty liver
      • Reduce triglyceride and total cholesterol levels in obese mice [9]
    • Patients with atherosclerosis exhibit reduced serum H2S concentrations

    Cytathiohine betha synthase

    • Key enzyme for the biosynthesis of H2S [9]

    LDL

    • LDL inhibits binding of PCSK9 to the LDLR in vitro
      • Inhibits PCSK9 uptake in cells
    • Cell-surface heparin-like molecules (HLMs) can partly explain this difference
      • Heparan sulfate proteoglycans (HSPGs) acting as coreceptors for PCSK9
    • HLMs can interact with either PCSK9 or LDL
      • Modulate the inhibitory activity of LDL on PCSK9 uptake
      • Competition with the entire PCSK9 prodomain, but not its truncated variants
    • Gain-of-function PCSK9 variant, S127R, located in the prodomain near the HSPG binding site
      • Exhibits increased affinity for HLMs
        • Potentially explaining its phenotype
    • LDL acts as a negative regulator of PCSK9 function
      • By decreasing its uptake via direct interactions with either the LDLR or HLMs [10]

    Mutace

    • Individuals with genetically determined reduced PCSK9 function
      • Clinical trials of PCSK9 inhibitors
    • Have not revealed clinically meaningful adverse consequences of almost completely eradicating PCSK9 from the circulation [3]
    • PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance:
      • The role of the low-density lipoprotein receptor. [5]
    • PCSK9 loss of function genetic variants are associated with
      • Lower low-density lipoprotein cholesterol
      • Higher plasma glucose levels
      • Increased risk of Type 2 diabetes mellitus. [5]
    • PCSK9 critically controls LDLR expression in pancreas
      • Perhaps contributing to the maintenance of a proper physiological balance to limit cholesterol overload in beta cells.
      • Independent of circulating PCSK9
        • Probably related to locally produced PCSK9.[5]




    Stimulace

    Insulin

    • Increased PCSK9 expression and increased low-density lipoprotein receptor degradation in a PCSK9-dependent manner
    • Hepatic Pcsk9 mRNA and plasma PCSK9 protein levels were reduced by 55% to 75% in mice with liver-specific knockout of the insulin receptor
      • 75% to 88% in mice made insulin-deficient with streptozotocin
      • And 65% in ob/ob mice treated with antisense oligonucleotides against the insulin receptor [1]
    • Antisense oligonucleotide-mediated knockdown of insulin receptor in lean, wild-type mice had little effect
    • Insulin induced
      • PCSK9,
      • LDLR,
      • Sterol-regulatory element-binding protein-1c (SREBP-1c)
      • 2 expression (SREBP-2) [8]

    Obezita

    • PCSK9 was expressed in VAT and its expression was positively correlated with body mass index (BMI). Both intracellular mature and secreted PCSK9 were abundant in cultured human adipocytes. [8]

    Human LDL

    • Induced both mature and secreted PCSK9 and reduced LDLR. [8]

    Sterol regulatory element binding protein-2 (SREBP-2)

    • Can transcriptionally activate PCSK9
      • Via sterol-regulatory elements located in its proximal promoter region [1]
    • PCSK9 gene expression can be regulated by sterol-response element binding proteins (SREBP-1/2)
      • Also controls LDLR expression [2]
    • The amounts of PCSK9 mRNA and protein in Caco- 2/15 cells
      • Associated to the regulation of:
        • 3-hydroxy-3-methylglutaryl-CoA reductase
        • Sterol regulatory element binding protein-2 (SREBP-2)
          • Can transcriptionally activate PCSK9 via sterol-regulatory elements located in its proximal promoter region [6]
    • Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9. [11]

    Depletion of cholesterol content

    • By hydroxypropyl-beta-cyclodextrin upregulated PCSK9 transcripts (20%, P<0.05) and protein mass (540%, P<0.001) in parallel with SREBP-2 protein levels

    Bile acids (BA) to the apical culture medium

    • Taurocholate + deoxycholate
      • Lowered PCSK9 gene expression (25%, P<0.01)
      • Raised PCSK9 protein expression (30%, P<0.01)
      • Probably via the modulation of farnesoid X receptor [6]








    Literatura

    [1] www.ncbi.nlm.nih.gov/pubmed/26023080
    [2] en.wikipedia.org/wiki/PCSK9
    [3] www.mybiosource.com/pcsk9-human-elisa-kits/proprotein-convertase-subtilisin-kexin-type-9/920252
    [4] www.ncbi.nlm.nih.gov/pubmed/30367179
    [5] www.ncbi.nlm.nih.gov/pubmed/29982592
    [6] www.researchgate.net/publication/23959678_Regulation_of_the_proprotein_convertase_subtilisinkexin_type_9_in_intestinal_epithelial_cells www.researchgate.net/publication/23959678_Regulation_of_the_proprotein_convertase_subtilisinkexin_type_9_in_intestinal_epithelial_cells [accessed Jun 16 2019].
    [7] www.researchgate.net/publication/265295961_Quercetin-3-glucoside_increases_low-density_lipoprotein_receptor_LDLR_expression_attenuates_proprotein_convertase_subtilisinkexin_9_PCSK9_secretion_and_stimulates_LDL_uptake_by_Huh7_human_hepatocytes_
    [8] www.researchgate.net/publication/330285740_PCSK9_is_Expressed_in_Human_Visceral_Adipose_Tissue_and_Regulated_by_Insulin_and_Cardiac_Natriuretic_Peptides
    [9] www.researchgate.net/publication/331456936_Hydrogen_sulfide_inhibits_PCSK9_expression_through_the_PI3KAkt-SREBP-2_signaling_pathway_to_influence_lipid_metabolism_in_HepG2_cells
    [10] https://www.researchgate.net/publication/329122912_Cell-associated_Heparin-like_Molecules_Modulate_the_Ability_of_LDL_to_Regulate_PCSK9_Uptake
    [11] www.researchgate.net/publication/328372028_Berberrubine_and_its_analog_hydroxypropyl-berberrubine_regulate_LDLR_and_PCSK9_expression_via_the_ERK_signal_pathway_to_exert_cholesterol-lowering_effects_in_human_hepatoma_HepG2_cells
    [12] www.jlr.org/content/49/2/399
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Poslední aktualizace: 17. 6. 2019 0:16:09