1 2 CoA-SH ADP ATP + Pi sintesi del colesterolo acetil-CoA citrato liasi citrato ossalacetato citosol trasp. citrato mitocondrio citrato sintasi citrato ossalacetato CoA-SH acetil-CoA aminoacidi glucoso piruvato piruvato acidi grassi acetato acetaldeide etanolo 3 citosol: 4 citrato trasp. citrato citrato 5 ret. endopl.: 6 perossisomi: 7 perossisomi: 8 isopentenyl pyrophosphate isomerase tail head 9 10 perossisomi: 11 ret. endopl.: 12 ret. endopl.: 13 ret. endopl.: zymosterol 19 steps 7-dehydrocolesterol desmosterol cholesterol 14 mevalonato Bilancio: 18 acetil-CoA 18 ATP 16 NADPH isopentenil-PP isopentenil-PP farnesil-PP dimetilallil-PP unità isoprenoidi attivate geranil-PP monoterpene farnesil-PP sesquiterpene squalene triterpene lanosterolo dieta: 300-500 mg/die sintesi: 800 mg/die colesterolo 15 O C S-CoA + HO acil-CoA colesterolo acil-CoA colesterolo aciltransferasi (ACAT) HS-CoA + colesterolo O C O estere del colesterolo 16 O O C H2 C O C C H O H 2C O P O O CH2 CH2 CH3 N CH3 + HO CH3 O colesterolo fosfatidilcolina (lecitina) lecitina colesterolo aciltransferasi (LCAT) O H2 C HO C H 2C O C H O O P O lisolecitina O CH2 CH2 CH3 N CH3 CH3 + O C O estere del colesterolo 17 AMP AMPK PP1 PKA allosteric inhibition covalent inhibition increased proteolysis decreased expression decreased expression 18 S1P, S2P = proteases SRE = sterol regulatory element SREBPs = sterol regulatory element-binding proteins SCAP = SREBP cleavage-activating protein INSIG = insulin induced gene 19 • • • • • • • • • • HMGCoA synthase HMGCoA reductase farnesylPP synthase squalene synthase fatty acids synthase acetylCoA carboxylase stearoylCoA desaturase glycerol 3-phosphate acyltransferase LDL-R lipoproteinlipase 20 21 statine: 22 23 400 mg are converted into bile acids, 50 mg into steroid hormones and the remaining part is eliminated as cholesterol through the intestine colestanolo (colestan-3-olo): HO H coprostanolo (coprostan-3-olo): HO 24 H Acidi biliari primari: O C OH OH acido colico (acido 3, 7, 12-triidrossicolanico): OH H OH O C OH acido chenodesossicolico o antropodesossicolico (acido 3, 7-diidrossicolanico): OH H OH 25 Acidi biliari secondari: O OH C OH acido desossicolico (acido 3, 12-diidrossicolanico): OH H O C OH acido litocolico (acido 3-idrossicolanico): OH H 26 CH 2 OH C O OH HO O cortisolo CH 3 C CH 2 OH H O O C C O HO HO O colesterolo O progesterone aldosterone OH OH HO O testosterone 27 estradiolo acidi biliari ormoni steroidei vitamina D colesterolo dolicoli fitolo (clorofilla) gomma, olii essenziali isopentenil-PP ubichinone isoprenilazione di proteine vitamina K vitamina E carotenoidi vitamina A 28