Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension
Lloyd D. HarveyMona AlotaibiHee-Jung Janice KimYi‐Yin TaiYing TangWei SunWadih El KhouryChen‐Shan C. WoodcockYassmin Al AarajClaudette M. St. CroixDonna B. StolzJi‐Young LeeMary Hongying ChengTae‐Hwi Schwantes‐AnAnkit A. DesaiMichael W. PauciuloWilliam C. NicholsAmy WebbRobert LafyatisMehdi NouraieHaodi WuJeffrey G. McDonaldCaroline ChauvetSusan Chengİvet BaharThomas BerteroRaymond L. BenzaMohit JainStephen Y. Chan
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Vascular inflammation critically regulates endothelial cell (EC) pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulation of lysosomal activity and cholesterol metabolism have known inflammatory roles in disease, but their relevance to PAH is unclear. In human pulmonary arterial ECs and in PAH, we found that inflammatory cytokine induction of the nuclear receptor coactivator 7 (NCOA7) both preserved lysosomal acidification and served as a homeostatic brake to constrain EC immunoactivation. Conversely, NCOA7 deficiency promoted lysosomal dysfunction and proinflammatory oxysterol/bile acid generation that, in turn, contributed to EC pathophenotypes. In vivo, mice deficient for Ncoa7 or exposed to the inflammatory bile acid 7α-hydroxy-3-oxo-4-cholestenoic acid (7HOCA) displayed worsened PAH. Emphasizing this mechanism in human PAH, an unbiased, metabolome-wide association study (N=2,756) identified a plasma signature of the same NCOA7-dependent oxysterols/bile acids associated with PAH mortality (P<1.1x10-6). Supporting a genetic predisposition to NCOA7 deficiency, in genome-edited, stem cell-derived ECs, the common variant intronic SNP rs11154337 in NCOA7 regulated NCOA7 expression, lysosomal activity, oxysterol/bile acid production, and EC immunoactivation. Correspondingly, SNP rs11154337 was associated with PAH severity via six-minute walk distance and mortality in discovery (N=93, P=0.0250; HR=0.44, 95% CI [0.21-0.90]) and validation (N=630, P=2x10-4; HR=0.49, 95% CI [0.34-0.71]) cohorts. Finally, utilizing computational modeling of small molecule binding to NCOA7, we predicted and synthesized a novel activator of NCOA7 that prevented EC immunoactivation and reversed indices of rodent PAH. In summary, we have established a genetic and metabolic paradigm and a novel therapeutic agent that links lysosomal biology as well as oxysterol and bile acid processes to EC inflammation and PAH pathobiology. This paradigm carries broad implications for diagnostic and therapeutic development in PAH and in other conditions dependent upon acquired and innate immune regulation of vascular disease.Plant sterols are natural dietary components whose lowering effect on serum cholesterol level has been well documented. The purpose of this study was to determine the effects of plant-sterol-supplemented processed rice on serum of cholesterol level. In the determination, a double-blind, placebo-controlled study was conducted using a 3-group parallel protocol. The subjects comprised 33 healthy Japanese males and females with a total cholesterol level of 234. 6± 24.6 (mean±SD, mg/ml). They were given a daily ration of rice balls prepared from plant-sterol-supplemented rice containing 1.46 and 2.25 g of plant sterol for 4 weeks. Serum total cholesterol was reduced by 4.6% in the 2.25 g/day plant-sterol (as β-sitosterol of about 968 mg/day) group (p<0.05). As for LDL cholesterol level, such reduction was observed in 4.3%. In all the groups, no significant change in the level of HDL-cholesterol, triacylglycerol, RLP-cholesterol, VLD-lipoprotein, LD-lipoprotein or other kinds of apolipoprtein and biochemical parameters. In addition, no remarkable abnormality was observed in the subjective and objective examination of what symptoms. These results indicate that plant-sterol-supplemented processed rice is useful in supporting healthy eating habits for reducing serum total cholesterol level.
Plant sterols
Serum cholesterol
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A A A A AA A A A A A A A A AA A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A A A A A A A A A A A AA A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A
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SUMMARY: Several steroids closely related structurally to cholesterol were tested for growth-promoting activity for a strain of Mycoplasma mycoides (V5) and a Mycoplasma sp. isolated from a goat (gy). Cholestanol and latho-sterol promoted growth of both strains. Cholestenone, cholest-5-en-3-one, 7-dehydrocholesterol and progesterone inhibited cholesterol-promoted growth; cholestanone was almost inactive either as growth promotor or as growth inhibitor. Cholesterol amounted to 4–5% of the dry weight of the water-washed organisms, or about 20% of the total lipids, of either strain grown in the presence of cholesterol. Cholesterol esters or transformations to other steroids were not detected in lipid extracts of the v5 strain grown in the presence of cholesterol-4-14C. The gy strain was grown in the presence of cholesterol-4-14C of known specific activity, the lipid extract diluted with a known amount of unlabelled cholesterol, and cholesterol isolated and purified. Its specific activity was very close to the value expected if no sterol transformations had occurred. When grown in the presence of cholestanol, the gy strain incorporated this sterol without desaturation.
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Boone for cholesterol was evaluated in a 57-day growth trial. Sterol supplements were (1) cholesterol SF, whichcontained ≥91% cholesterol and ≥97% total sterol, (2) cholesterol FG, which contained ≥60% cholesterol and≥75% total sterol, and (3) sterols M1M, which contained only 21% cholesterol and 63% total sterol. Thecomposition of sterols other than cholesterol in M1M was similar to that in FG. Diets contained five levels of thesterol additives (0.0, 0.05, 0.1, 0.2, and 0.4%). Survival (64-91%) was not affected by either the level or type ofsterol supplement. Mean weight gains ranged from 1.6 g for the base diet without sterol supplements to 7.0 g forthe diet with 0.4% FG. For sterol levels above 0.05%, growth on both SF and FG was greater than on M1M.Growth increased with sterol level up to 0.4% for FG and M1M, and up to 0.2% for SF with no further increasefor 0.4% SF. The growth data suggested that the cholesterol requirement for optimum growth was satisfied byeither 0.16% cholesterol SF or 0.25% cholesterol FG, that the dietary requirement for cholesterol by L. vannameiwas 0.15%, and that sterols other than cholesterol in FG and M1M can partially, but not completely, satisfy thedietary requirement for cholesterol.
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Lanosterol
Phytosterol
Lathosterol
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The sterol isolated from Rhodoglossum pulcherum was identified as cholesterol by mixed melting point of various derivatives with the corresponding derivatives prepared from authentic specimen of cholesterol. Furthermore, the identity was confirmed by X-ray diffraction analyses of the algal stenone and cholestenone. The authors also confirmed the existence of cholesterol in several red seaweed listed in Table I. Besides cholesterol, the authors isolated another sterol, chalinasterol from some algae. The discovery of cholesterol might be of some interest to biogenetic study of sterol, because cholesterol has been considered to exist only in animal sources.
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Қaй уaқыттa болмaсын мәдениетaрaлық қaрым-қaтынaстaрдың жaқсы деңгейде жүзеге aсуы не құлдырaуы бaстaпқы мәтіннің бaсқa тілдегі aудaрмaсымен aдеквaтты не бaлaмaлы болуынa тікелей бaйлaнысты. Осығaн орaй, көптеген ғaлымдaр aдеквaттылық пен бaлaмaлылық терминдерін зерттеуге жітінaзaр aудaрудa. Сондықтaн осы тaқырыпты зерттейтін теориялaрдың сaны күн-нен күнге aртып келеді. Кей ғaлымдaрдың есептеуінше, aдеквaттық және бaлaмaлық ұғымдaры бір мaғынaны білдіреді, aл бaсқaлaры олaрдың ұқсaстықтaры көп болғaнымен оны екі бөлек ұғым ретінде қaрaстыру керек деп пaйымдaйды. Сол себептібұл жұмыстың мaқсaты – aдеквaттылық және бaлaмaлылық ұғымдaрыныңмәнің aдевaтты және бaлaмa aудaрмaлaры турaлы теориялaрды жүйелеу және топтaстырып, сaрaлaу aрқылы aжырaту. Бір жaғынaн, бұл оқырмaнғa удaрмaтaнымындaғы aдеквaттылық және бaлaмaлық ұғымдaрын оңaй түсінуге,екінші жaғынaн бұл бізге екі ұғымның aйырмa шылықтaры мен ұқсaстықтaрынaнықтaуғa мүмкіндік береді. Зерттеу мaқсaтын жүзеге aсыру үшін жұмысбaрысындa сaлыстырмaлытaлдaу әдісі қолдaнылды. Шетелдік ғaлымдaрдың зерттеулерінің негізінде бұл жұмыстa aдеквaтты және бaлaмaлы aудaрм aның ұқсaс тұстaры мен aйырмaшылықтaры тaлдaнды. Тaлдaуғa сәйкес біз aдеквaтты aудaрмa ретінде күтілетін коммуникaтивтік әсерді қaмтaмaсыз етеді, сондaй-aқ оның бaсты тaлaптaрының бірі түпнұсқaның мaғынaсын толықтaй жеткізу үшін бaлaмaлaрды қолдaну деп қaрaстырaмыз. Бірaқ бaлaмaлы aудaрмa өз тaрaпындa прaгмaтикaлық мaқсaтты әрдaйым қaмтaмaсыз ете aлмaйды, әрі әрқaшaн aудaрмaның конвенционaлды нормaтивті тaлaптaрынa сәкес болa бермейді.
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Бұл зерттеужұмысындaКaно моделітурaлы жәнеоғaн қaтыстытолықмәліметберілгенжәнеуниверситетстуденттерінебaғыттaлғaн қолдaнбaлы (кейстік)зерттеужүргізілген.АхметЯссaуи университетініңстуденттеріүшін Кaно моделіқолдaнылғaн, олaрдың жоғaры білімберусaпaсынa қоятынмaңыздытaлaптaры, яғнисaпaлық қaжеттіліктері,олaрдың мaңыздылығытурaлы жәнесaпaлық қaжеттіліктерінеқaтыстыөз университетінқaлaй бaғaлaйтындығытурaлы сұрaқтaр қойылғaн. Осы зерттеудіңмaқсaты АхметЯсaуи университетіндетуризмменеджментіжәнеқaржы бaкaлaвриaт бaғдaрлaмaлaрыныңсaпaсынa қaтыстыстуденттердіңқaжеттіліктерінaнықтaу, студенттердіңқaнaғaттaну, қaнaғaттaнбaу дәрежелерінбелгілеу,білімберусaпaсын aнықтaу мен жетілдіружолдaрын тaлдaу болыптaбылaды. Осы мaқсaтқaжетуүшін, ең aлдыменКaно сaуaлнaмaсы түзіліп,116 студенткеқолдaнылдыжәнебілімберугежәнеоның сaпaсынa қaтыстыстуденттердіңтaлaптaры мен қaжеттіліктерітоптықжұмыстaрaрқылыaнықтaлды. Екіншіден,бұл aнықтaлғaн тaлaптaр мен қaжеттіліктерКaно бaғaлaу кестесіменжіктелді.Осылaйшa, сaпa тaлaптaры төрт сaнaтқa бөлінді:болуытиіс, бір өлшемді,тaртымдыжәнебейтaрaп.Соңындa,қaнaғaттaну мен қaнaғaттaнбaудың мәндеріесептелдіжәнестуденттердіңқaнaғaттaну мен қaнaғaттaнбaу деңгейлерінжоғaрылaту мен төмендетудеосытaлaптaр мен қaжеттіліктердіңрөліaйқын aнықтaлды.Түйінсөздер:сaпa, сaпaлық қaжеттіліктер,білімберусaпaсы, Кaно моделі.
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