本期主要介紹外周組織脂質(zhì)代謝相關(guān)內(nèi)容下期則會(huì)集中介紹中樞代謝相關(guān)內(nèi)容在？ 都知道ACC2被AMPK磷酸化可以促進(jìn)脂肪酸氧化本期CM發(fā)現(xiàn)了另一個(gè)ACC2關(guān)鍵修飾酶--PHD3相應(yīng)的，缺失PHD3提高脂肪酸氧化能力并增強(qiáng)小鼠肌肉代謝和運(yùn)動(dòng)耐力脂肪看似圓滾滾一坨  其實(shí)是一個(gè)成分復(fù)雜的大家庭高大上的單細(xì)胞測序把它們分為兩個(gè)細(xì)胞簇一些習(xí)以為常的事物  向來被認(rèn)為是激活棕色脂肪產(chǎn)熱的經(jīng)典通路新研究卻發(fā)現(xiàn)人類棕色脂肪與眾不同通過血液運(yùn)輸?shù)饺砀髌鞴?/span>“停靠”到靶細(xì)胞的呢？  線粒體ATP，而不是細(xì)胞內(nèi)的總ATP
1. PHD3缺失可以增強(qiáng)骨骼肌的運(yùn)動(dòng)能力和脂肪氧化小編一句話：PHD3，失去你，我會(huì)更強(qiáng)壯！
細(xì)胞代謝的快速變化使組織在面臨可利用能量波動(dòng)時(shí)能夠維持自穩(wěn)態(tài)。在面臨細(xì)胞能量壓力時(shí)，關(guān)鍵代謝調(diào)節(jié)因子ACC2（乙酰輔酶A羧化酶2）被AMPK （AMP激活的蛋白激酶）顯著磷酸化，從而關(guān)閉其對(duì)脂肪氧化的抑制作用。ACC2也可以被PHD3（脯氨酰羥化酶3）羥基化，但其生理后果尚不清楚。我們發(fā)現(xiàn)ACC2的磷酸化和羥基化是反向發(fā)生的兩個(gè)過程。在能量充足情況下，ACC2發(fā)生羥基化并抑制脂肪酸氧化。PHD3基因缺失的小鼠表現(xiàn)出心臟和骨骼肌中ACC2羥基化的缺失，并顯示出脂肪酸氧化升高。在耐力訓(xùn)練挑戰(zhàn)中，全身或骨骼肌特異性PHD3基因缺失的小鼠的運(yùn)動(dòng)能力得到了增強(qiáng)?？傊?，這些數(shù)據(jù)確定了AMPK和PHD3之間的令人意外的聯(lián)系，以及PHD3在急性運(yùn)動(dòng)耐力水平和骨骼肌代謝中的作用。
ACC（乙酰輔酶Ａ羧化酶）是一種生物素酶，在生物體內(nèi)的脂肪酸合成過程中起限速作用。ACC有兩種亞型，即ACC1和ACC2。其中，ACC2在心臟和肌肉中高表達(dá)，具有催化脂肪酸氧化的能力。ACC1/2將乙酰輔酶A（Acetyl-CoA）轉(zhuǎn)化為丙二酰輔酶A（malonyl-CoA），丙二酰輔酶A則會(huì)抑制CPT1（肉堿棕櫚酰轉(zhuǎn)移酶1）活性，而CPT1是控制底物進(jìn)入線粒體進(jìn)行脂肪酸氧化的關(guān)鍵轉(zhuǎn)運(yùn)蛋白，因此，ACC2通過影響CPT1的活性，抑制脂肪酸氧化，并進(jìn)而把底物留在胞漿中，用于脂質(zhì)合成。AMPK （AMP激活的蛋白激酶）則能夠磷酸化ACC1/2，降低其活性，促進(jìn)脂肪酸的氧化作用。因此，AMPK-ACC通路在脂質(zhì)代謝過程和能量平衡中發(fā)揮了重要作用。參考文獻(xiàn)：Yoon H, et al. Cell Metab. 2020;32(2):215-228.e7.
PHD3 Loss Promotes Exercise Capacity and Fat Oxidation in Skeletal Muscle
發(fā)表單位：Department of Cell Biology, Blavatnik Institute, Harvard Medical School
PI：Marcia C. Haigis，一作：Haejin YoonAbstract
Rapid alterations in cellular metabolism allow tissues to maintain homeostasis during changes in energy availability. The central metabolic regulator acetyl-CoA carboxylase 2 (ACC2) is robustly phosphorylated during cellular energy stress by AMP-activated protein kinase (AMPK) to relieve its suppression of fat oxidation. While ACC2 can also behydroxylated by prolyl hydroxylase 3 (PHD3), the physiological consequence thereof is poorly understood. We find that ACC2 phosphorylation and hydroxylation occur in an inverse fashion. ACC2 hydroxylation occurs in conditions of high energy and represses fatty acid oxidation. PHD3-null mice demonstrate loss of ACC2 hydroxylation in heart and skeletal muscle and display elevated fatty acid oxidation. Whole body or skeletal muscle-specific PHD3 loss enhances exercise capacity during an endurance exercise challenge. In sum, these data identify an unexpected link between AMPK and PHD3, and a role for PHD3 in acute exercise endurance capacity and skeletal muscle metabolism.
原文鏈接：https://www./cell-metabolism/fulltext/S1550-4131(20)30318-1 2. 不同iNKT細(xì)胞群利用IFNγ或內(nèi)質(zhì)網(wǎng)應(yīng)激誘導(dǎo)的IL-10來控制脂肪組織穩(wěn)態(tài)小編一句話：脂肪里的“殺手”—iNKT細(xì)胞群維穩(wěn)有一套。中文摘要 脂肪組織iNKT（不變性自然殺傷T細(xì)胞）不同于其他的iNKT細(xì)胞，因?yàn)樗鼈兡軌虍a(chǎn)生IL-10并控制代謝穩(wěn)態(tài)。但原因尚不清楚。本研究中，我們利用單細(xì)胞RNA測序，發(fā)現(xiàn)了幾個(gè)脂肪iNKT簇，可根據(jù)NK1.1的表達(dá)將其分為兩個(gè)功能群。NK1.1NEG iNKT細(xì)胞（即NK1.1陰性細(xì)胞）幾乎只產(chǎn)生IL-10及其他調(diào)節(jié)性細(xì)胞因子，而NK1.1POS iNKT細(xì)胞（即NK1.1陽性細(xì)胞）主要產(chǎn)生IFNγ。從機(jī)理上講，生化分級(jí)揭示了FFA（游離脂肪酸）主要通過未折疊蛋白反應(yīng)的IRE1α-XBP1s臂在NK1.1NEG iNKT細(xì)胞中驅(qū)動(dòng)IL-10的產(chǎn)生。相應(yīng)地，在肥胖小鼠中接種脂肪NK1.1NEG iNKT細(xì)胞可選擇性地恢復(fù)其代謝功能。此外，我們還發(fā)現(xiàn)NK1.1POS iNKT細(xì)胞在瘦的（即非肥胖狀態(tài)）脂肪組織中起到了意想不到的作用，它能夠通過分泌IFNγ介導(dǎo)自然殺傷細(xì)胞的巨噬細(xì)胞殺傷作用，從而限制了巨噬細(xì)胞的病理性擴(kuò)增?？傮w而言，這兩種iNKT細(xì)胞群共同利用非冗余途徑來保持代謝的完整性。 代謝小課堂 抵抗局部炎癥對(duì)于維持脂肪組織的正常功能至關(guān)重要，瘦的動(dòng)物的脂肪組織中含有多種抗炎的免疫細(xì)胞，如巨噬細(xì)胞、Tregc (T調(diào)節(jié)性細(xì)胞)、ILCs（先天淋巴樣細(xì)胞）、嗜酸性粒細(xì)胞、MAIT細(xì)胞、中心粒細(xì)胞、B細(xì)胞、CD8+T Cells等等。巨噬細(xì)胞在瘦的脂肪組織中多向M2型極化，并參與調(diào)節(jié)脂肪的代謝穩(wěn)態(tài)。而在肥胖的情況下，巨噬細(xì)胞多從M2型轉(zhuǎn)變?yōu)榻?jīng)典的M1促炎表型。本文介紹的iNKT細(xì)胞（不變性自然殺傷T細(xì)胞）是其他免疫細(xì)胞的強(qiáng)激活因子，可以作為先天免疫和適應(yīng)性免疫之間的橋梁。多項(xiàng)研究發(fā)現(xiàn)缺乏iNKT細(xì)胞的小鼠的代謝紊亂會(huì)加重，更肥胖。此外還有類似于iNKT細(xì)胞的MAIT細(xì)胞（黏液相關(guān)不變性T細(xì)胞），在脂肪組織中也可產(chǎn)生IL-10發(fā)揮調(diào)節(jié)作用。Treg細(xì)胞（T調(diào)節(jié)性細(xì)胞）是一種自適應(yīng)的αβ T細(xì)胞，在維持機(jī)體免疫的耐受性中起重要作用。脂肪Treg細(xì)胞是脂肪組織中重要的抗炎免疫細(xì)胞，而在肥胖的脂肪組織中其數(shù)量會(huì)減少，加重了炎癥誘發(fā)的胰島素抵抗。ILCs（先天淋巴樣細(xì)胞）是免疫系統(tǒng)的關(guān)鍵調(diào)節(jié)因子，有報(bào)道稱其可維持嗜酸性粒細(xì)胞，交替激活大量的巨噬細(xì)胞促進(jìn)葡萄糖穩(wěn)態(tài)；此外激活脂肪ILC2s可促進(jìn)米色脂肪細(xì)胞的分化和產(chǎn)熱，有助于抵抗肥胖。嗜酸性粒細(xì)胞是一類在骨髓中發(fā)育的粒細(xì)胞，在機(jī)體代謝平衡的狀態(tài)下，通過從脂肪組織ILC2s接收IL-5信號(hào)維持其正常代謝功能，是脂肪組織的重要守護(hù)者。這些免疫細(xì)胞在脂肪微環(huán)境中相互作用，共同維持組織內(nèi)的免疫代謝的動(dòng)態(tài)平衡。參考文獻(xiàn)：KohlgruberA, Lynch L. Curr Diab Rep. 2015;15(11):92.
Distinct iNKT Cell Populations Use IFNγ or ER Stress-Induced IL-10 to Control Adipose Tissue Homeostasis 發(fā)表單位：Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital
PI：Michael B. Brenner，一作：Nelson M. LaMarcheAbstract
Adipose tissue invariant natural killer T (iNKT) cells are phenotypically different from other iNKT cells because they produce IL-10 and control metabolic homeostasis. Why that is the case is unclear. Here, using single-cell RNA sequencing, we found several adipose iNKT clusters, which we grouped into two functional populations based on NK1.1 expression. NK1.1NEG cells almost exclusively produced IL-10 and other regulatory cytokines, while NK1.1POS iNKT cells predominantly produced IFNγ. Mechanistically, biochemical fractionation revealed that free fatty acids drive IL-10 production primarilyin NK1.1NEG iNKT cells via the IRE1α-XBP1s arm of the unfolded protein response. Correspondingly, adoptive transfer of adipose tissue NK1.1NEG iNKT cells selectively restored metabolic function in obese mice. Further, we found an unexpected role for NK1.1POS iNKT cells in lean adipose tissue, as IFNγ licenses natural killer cell-mediated macrophage killing to limit pathological macrophage expansion. Together, these two iNKT cell populations utilize non-redundant pathways to preserve metabolic integrity.
原文鏈接：https://www./cell-metabolism/fulltext/S1550-4131(20)30256-4 3. β2-AR刺激促進(jìn)人棕色脂肪細(xì)胞產(chǎn)熱小編一句話：做道連線題，你和小鼠的BAT分別是由β2-還是β3-AR來刺激？中文摘要 靶向刺激人BAT（棕色脂肪組織）產(chǎn)熱來改善新陳代謝極具吸引力。β3-AR（β3腎上腺素能受體）被認(rèn)為是介導(dǎo)BAT產(chǎn)熱的受體，但是靶向β3-AR的藥物在人類臨床試驗(yàn)中歷來效果不佳。本研究中，我們發(fā)現(xiàn)與嚙齒動(dòng)物不同的是，人BAT的產(chǎn)熱不是通過β3-AR所介導(dǎo)的。口服β3-AR激動(dòng)劑mirabegron（米拉貝隆)僅在最大允許攝入劑量下才能引起B(yǎng)AT產(chǎn)熱增加。這導(dǎo)致藥物脫靶，并與β1-AR和β2-AR結(jié)合，從而分別增加了心血管反應(yīng)和白色脂肪組織脂解。ADRB2（β2腎上腺素能受體）與UCP1在人棕色脂肪細(xì)胞中共表達(dá)。通過對(duì)人棕色脂肪細(xì)胞中β2-AR的藥物刺激和抑制，以及敲低ADRB1、ADRB2或ADRB3基因，均證實(shí)了人體中BAT的脂解和產(chǎn)熱是通過β2-AR信號(hào)所介導(dǎo)的（臨床試驗(yàn). gov NCT02811289）。 β腎上腺素能受體是一類 G蛋白耦聯(lián)受體，根據(jù)其對(duì)去甲腎上腺素的不同反應(yīng)，分為腎上腺素能α和β受體。β受體包括1，2和3三種亞型，β1受體主要分布于心臟和大腦，在激動(dòng)作用下，導(dǎo)致心肌興奮產(chǎn)生一系列反應(yīng)，如心肌收縮加劇，心臟射血速度加快，心率上升等。β2受體主要分布于平滑肌與腺體細(xì)胞，該受體激動(dòng)后能夠松弛平滑肌。β3受體主要分布于白色及棕色脂肪組織，該受體激動(dòng)后可以通過刺激白色脂肪組織的脂解作用和棕色脂肪組織的非顫栗性產(chǎn)熱，消耗貯存的脂肪，起到抵抗肥胖的作用，同時(shí)也介導(dǎo)心臟負(fù)性肌力及血管平滑肌舒張作用。有趣的是，本文發(fā)現(xiàn)人BAT的產(chǎn)熱并不是由通常認(rèn)為的β3-AR所介導(dǎo)，而是通過β2-AR信號(hào)來刺激的。 β腎上腺素受體激動(dòng)劑和阻滯劑種類多樣，有選擇性針對(duì)某一（或某幾種）亞型的，也有非選擇性的。β腎上腺素受體激動(dòng)劑包括非選擇性的β腎上腺素受體激動(dòng)劑如腎上腺素、麻黃堿和異丙腎上腺素以及選擇性β2腎上腺素受體激動(dòng)劑如沙丁胺醇、叔丁喘寧等。β腎上腺素能受體阻滯劑的基本藥理作用為阻斷神經(jīng)遞質(zhì)和兒茶酚膠對(duì)β腎上腺素受體的興奮作用，包括非選擇性的β受體阻滯劑，可同時(shí)阻斷β1和β2受體，如普萘洛爾等；也有選擇性的β受體阻滯劑，對(duì)β2受體影響小或幾乎無影響，如比索洛爾等；也有可同時(shí)阻斷α1和β受體的類型，如卡維地洛。 參考文獻(xiàn)：deLucia C, Eguchi A, Koch WJ. Front Pharmacol. 2018;9:904；OliverE, Mayor F Jr, D'Ocon P. Rev Esp Cardiol (Engl Ed). 2019;72(10):853；MateraMG, Calzetta L, Cazzola M. Drugs. 2013;73(15):1653-1663.
Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation 發(fā)表單位：Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke
PI：André C. Carpentier，一作：Denis P. BlondinAbstract
Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β3-adrenergicreceptor (β3-AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of β3-AR. Oral administration of the β3-AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to β1-AR and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. ADRB2 was co-expressed with UCP1 in human brown adipocytes. Pharmacological stimulation and inhibition of the β2-AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through β2-AR signaling in humans (ClinicalTrials.gov NCT02811289).
原文鏈接：https://www./cell-metabolism/fulltext/S1550-4131(20)30363-6 Clinical and Translational Reports 小編一句話：老藥新用不止二甲雙胍，雙硫侖治療肥胖再出奇招
中文摘要 肥胖是一個(gè)頭等的公共健康問題，開發(fā)一種安全治療肥胖的小分子迫在眉睫。雙硫侖（商品名為安塔布司）是一種已獲得FDA批準(zhǔn)的用于治療慢性酒精成癮的藥物，具有抗炎功效并有助于預(yù)防某些類型的癌癥。本研究中，我們發(fā)現(xiàn)雙硫侖治療可以防止促肥胖飲食引起的小鼠體重增加和胰島素抵抗，同時(shí)減輕肝臟脂肪變性和胰島肥大。此外，雙硫侖治療逆轉(zhuǎn)了中年小鼠因飲食引起的肥胖和代謝功能障礙。長期服用雙硫侖通過減少攝食和增加能量消耗調(diào)節(jié)體重。同時(shí)，在使用雙硫侖治療的大鼠中也觀察到脂肪組織減少和肝臟窗孔結(jié)構(gòu)的增加。鑒于在嚙齒類動(dòng)物中雙硫侖治療具有抵抗肥胖的作用，提示雙硫侖在臨床中可能成為治療肥胖及其代謝共存病的一種新策略。
人飲酒后，酒的主要成分—乙醇會(huì)被乙醇脫氫酶氧化成乙醛，乙醛很快再被乙醛脫氫酶氧化分解。本文的研究對(duì)象—雙硫侖，又稱為“戒酒硫”，常被用于治療酒精成癮性。雙硫侖是乙醛脫氫酶抑制劑, 可抑制胞質(zhì)內(nèi)和線粒體內(nèi)的乙醛脫氫酶，使飲酒者血液中乙醇被氧化為乙醛后不能被進(jìn)一步氧化分解，導(dǎo)致體內(nèi)乙醛蓄積并產(chǎn)生強(qiáng)烈的不適感（如面部潮紅、發(fā)熱、頭痛、惡心和嘔吐等），讓嗜酒者轉(zhuǎn)而對(duì)飲酒產(chǎn)生厭惡和恐懼心理，從而放棄酗酒而達(dá)到戒酒目的。 網(wǎng)絡(luò)上有“頭孢加酒，說走就走”說法。這是因?yàn)榕R床上很多藥物的化學(xué)結(jié)構(gòu)中含有與雙硫侖類似的N-甲硫四氮唑側(cè)鏈, 可抑制肝臟線粒體內(nèi)的乙醛脫氫酶, 用藥后若飲酒可導(dǎo)致體內(nèi)乙醛蓄積而產(chǎn)生雙硫侖反應(yīng)，臨床表現(xiàn)為面色潮紅、頭暈、嘔吐、腹痛、心率加快、血壓異常、呼吸困難、心肌梗死等癥狀，導(dǎo)致嚴(yán)重的后果。常見的引起雙硫侖反應(yīng)的藥物有: (1) 頭孢菌素類藥物藥物，其中以頭孢哌酮致雙硫侖反應(yīng)的報(bào)道最多；（2）硝咪唑類藥物，如甲硝唑等；（3）其他抗菌類藥物，如氯霉素、磺胺類等；（4）降糖藥物，如磺酰脲類口服降糖藥。所以吃藥后，千萬不能喝酒哦！
肝血竇內(nèi)皮細(xì)胞具有發(fā)達(dá)的窗孔結(jié)構(gòu)，大多聚集形成篩板狀，窗孔相當(dāng)于可選擇超濾系統(tǒng)，是維持肝細(xì)胞內(nèi)環(huán)境穩(wěn)定的重要結(jié)構(gòu)。在各種病理狀態(tài)下，窗孔數(shù)量減少、直徑變小，削弱了脂蛋白和膽固醇等物質(zhì)在肝臟的代謝效率，從而引起高脂血癥和肝脂肪變性。參考文獻(xiàn)：Haass-Koffler CL, et al. J Psychopharmacol.2017;31(7):812-818；Mergenhagen KA, et al. Antimicrob Agents Chemother.2020;64(3):e02167-19；S?rensen KK, et al. Compr Physiol. 2015;5(4):1751-1774；Cogger VC, et al.Atherosclerosis. 2006;189(2):273-281.
Disulfiram Treatment Normalizes Body Weight in Obese Mice 發(fā)表單位：Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health
PI：Rafaelde Cabo，一作：Michel Bernier
Abstract
Obesity is a top public health concern, and a molecule that safely treats obesity is urgently needed. Disulfiram (known commercially as Antabuse), an FDA-approved treatment for chronic alcohol addiction, exhibits anti-inflammatory properties and helps protect against certain types of cancer. Here, we show that in mice disulfiram treatment prevented body weight gain and abrogated the adverse impact of an obesogenic diet on insulin responsiveness while mitigating liver steatosis and pancreatic islet hypertrophy. Additionally, disulfiram treatment reversed established diet-induced obesity and metabolic dysfunctions in middle-aged mice. Reductions in feeding efficiency and increases in energy expenditure were associated with body weight regulation in response to long-term disulfiram treatment. Loss of fat tissue and an increase in liver fenestrations were also observed in rats on disulfiram. Given the potent anti-obesogenic effects in rodents, repurposing disulfiram in the clinic could represent a new strategy to treat obesity and its metabolic comorbidities.
原文鏈接：https://www./cell-metabolism/fulltext/S1550-4131(20)30236-9 1. 局部線粒體的ATP產(chǎn)生可調(diào)節(jié)內(nèi)皮細(xì)胞脂肪酸的攝取和運(yùn)輸小編一句話：ATP只能用來供能？看看線粒體ATP與脂肪酸攝取的二三事。中文摘要 大多數(shù)器官將FAs（脂肪酸）作為一種關(guān)鍵的營養(yǎng)物質(zhì)，但血中運(yùn)輸?shù)腇As是如何穿過內(nèi)皮到達(dá)下層組織的，仍不清楚。我們通過小分子篩選，發(fā)現(xiàn)氯硝柳胺（niclosamide）是內(nèi)皮細(xì)胞FA攝取和運(yùn)輸?shù)囊种苿?/strong>其構(gòu)效關(guān)系研究顯示，氯硝柳胺通過線粒體的解偶聯(lián)發(fā)揮作用。氧化磷酸化和ATP/ADP轉(zhuǎn)位酶的抑制劑也能夠抑制FA的攝取，提示ATP產(chǎn)生對(duì)FA攝取的重要性。通過阻斷糖酵解而減少細(xì)胞內(nèi)的總ATP水平并不會(huì)減少FA攝取，提示FA的攝取特異性依賴線粒體ATP。FATP4（脂肪酸轉(zhuǎn)運(yùn)蛋白4）通過其ATP依賴的乙酰輔酶a合成酶活性促進(jìn)內(nèi)皮細(xì)胞FA的攝取。共聚焦顯微分析顯示FATP4位于ER（內(nèi)質(zhì)網(wǎng)）中，且內(nèi)皮細(xì)胞的ER與線粒體緊密排列?？傮w而言，這些數(shù)據(jù)表明在線粒體/內(nèi)質(zhì)網(wǎng)微區(qū)中，線粒體ATP的產(chǎn)生（而非總的ATP水平）可通過?；o酶a的形成來促進(jìn)內(nèi)皮FA的攝取和運(yùn)輸。 脂肪酸轉(zhuǎn)運(yùn)小能手FATP4
FATP4是FABPs家族的一員，更為我們所熟知的名字是FABP4（adipocyte fatty-acid binding protein），或aP2（adipocyte protein 2），又稱為adipocyte lipid binding protein (ALBP）。FABP4主要表達(dá)于脂肪細(xì)胞和巨噬細(xì)胞，在機(jī)體能量代謝和炎癥反應(yīng)中起重要調(diào)控作用，與糖脂代謝障礙及胰島素抵抗有密切關(guān)系，被認(rèn)為是T2DM發(fā)生發(fā)展的危險(xiǎn)因子，成為T2MD藥物預(yù)防和治療的潛在靶點(diǎn)。隨著研究深入，發(fā)現(xiàn)其還可表達(dá)在其他細(xì)胞和組織，如肌纖維細(xì)胞，內(nèi)皮細(xì)胞，胎盤等等。FABP4主要通過兩種形式發(fā)揮作用：胞內(nèi)FABP4通過結(jié)合和轉(zhuǎn)運(yùn)游離脂肪酸等疏水性配體，參與調(diào)控脂質(zhì)代謝和炎癥反應(yīng)，功能異常時(shí)可能誘發(fā)糖尿病和動(dòng)脈粥樣硬化。同時(shí)，脂肪細(xì)胞分泌FABP4入血，對(duì)肝臟肝糖生成和脂質(zhì)代謝、胰島素分泌、心臟心肌收縮、肌肉糖脂代謝等進(jìn)行調(diào)節(jié)。在肥胖和胰島素抵抗?fàn)顟B(tài)下血清FABP4水平明顯升高，F(xiàn)ABP4與胰島素抵抗、糖尿病、動(dòng)脈粥樣硬化等免疫代謝性疾病密切相關(guān)，是連接代謝、炎癥和天然免疫的關(guān)鍵分子。 參考文獻(xiàn)：Furuhashi M, et al. Nature.2007;447(7147):959-965；See?le J, et, al. Biochim Biophys Acta.2015;1851(5):549-565.
Local Mitochondrial ATP Production Regulates Endthelial Fatty Acid Uptake and Transport 發(fā)表單位：Cardiovascular Institute, Perelman School ofMedicine, University of Pennsylvania
PI：Zoltan Arany，一作：Ayon IbrahimAbstract
Most organs use fatty acids (FAs) as a key nutrient, but little is known of how blood-borne FAs traverse the endothelium to reach underlying tissues. We conducted a small-molecule screen and identified niclosamide as a suppressor of endothelial FA uptake and transport. Structure/activity relationship studies demonstrated that niclosamide acts through mitochondrial uncoupling. Inhibitors of oxidative phosphorylation and the ATP/ADP translocase also suppressed FA uptake, pointing principally to ATP production. Decreasing total cellular ATP by blocking glycolysis did not decrease uptake, indicating that specifically mitochondrial ATP is required. Endothelial FA uptake is promoted by fatty acid transport protein 4 (FATP4) via its ATP-dependent acyl-CoA synthetase activity. Confocal microscopy revealed that FATP4 resides in the endoplasmic reticulum (ER), and that endothelial ER is intimately juxtaposed with mitochondria. Together, these data indicate that mitochondrial ATP production, but not total ATP levels, drives endothelial FA uptake and transport via acyl-CoA formation in mitochondrial/ER microdomains.
原文鏈接：https://www./cell-metabolism/fulltext/S1550-4131(20)30257-6
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