determination-fatty-acid-oxidation-lipogenesis-mouse-primary

Determination of Fatty Acid Oxidation and Lipogenesis in Mouse Primary Hepatocytes

Lipid metabolism in liver is complex. In addition to importing and exporting lipid via lipoproteins, hepatocytes can oxidize lipid via fatty acid ...

University of Massachusetts Medical School

PGC-1alpha is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1alpha are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPbeta is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1alpha-independent manner. Despite having reduced mitochondrial function, PGC-1alpha null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1alpha in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.

Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice.

PGC-1alpha est un co-activateur des r&eacute;cepteurs nucl&eacute;aires et d&#39;autres facteurs de transcription qui r&eacute;glemente plusieurs processus m&eacute;taboliques, y compris la biogen&egrave;se mitochondriale et la respiration, glucon&eacute;ogen&egrave;se h&eacute;patique et des fibres musculaires de type commutation. Nous montrons ici que, tandis que les h&eacute;patocytes manque le PGC-1alpha sont d&eacute;fectueuses dans le programme de la glucon&eacute;og&eacute;n&egrave;se stimul&eacute;e par les hormones, les souris ont activ&eacute;s constitutivement expression de g&egrave;ne glucoformateurs qui est totalement insensible aux contr&ocirc;les alimentation normales. C/EBPbeta sont &eacute;lev&eacute;e dans le foie de ces souris et active les g&egrave;nes glucoformateurs d&#39;une fa&ccedil;on PGC-1alpha-ind&eacute;pendante. Malgr&eacute; avoir r&eacute;duit la fonction mitochondriale, PGC-1alpha souris null sont paradoxalement maigre et r&eacute;siste &agrave; l&#39;ob&eacute;sit&eacute; induite par l&#39;alimentation. Ceci est largement d&ucirc; &agrave; une hyperactivit&eacute; profonde affich&eacute;e par les animaux null et est associ&eacute;e &agrave; des l&eacute;sions dans la r&eacute;gion de striatum du cerveau qui contr&ocirc;le le mouvement. Ces donn&eacute;es illustrent un r&ocirc;le central pour le PGC-1alpha dans le contr&ocirc;le du m&eacute;tabolisme &eacute;nerg&eacute;tique, mais r&eacute;v&egrave;lent aussi les nouveaux m&eacute;canismes compensatoires syst&eacute;miques et les effets pathog&egrave;nes de l&#39;hom&eacute;ostasie &eacute;nerg&eacute;tique avec facult&eacute;s affaiblies.

D&eacute;fauts dans le m&eacute;tabolisme &eacute;nerg&eacute;tique adaptative avec hyperactivit&eacute; li&eacute;e &agrave; la CNS dans le PGC-1alpha souris null.

PGC-1alpha &egrave; un coactivator di recettori nucleari e di altri fattori di trascrizione che regola diversi processi metabolici, tra cui biogenesi mitocondriale e respirazione, gluconeogenesi epatica e la fibra muscolare di tipo switching. Mostriamo qui che, mentre manca PGC-1alpha epatociti sono difettosi nel programma della gluconeogenesi stimolata da ormoni, i topi hanno costitutivamente attivato espressione genica gluconeogenic che &egrave; completamente insensibile ai normali controlli di alimentazione. C/EBPbeta &egrave; elevata nel fegato di questi topi e attiva i geni gluconeogenic in maniera PGC-1alpha-indipendenti. Pur avendo ridotto la funzione mitocondriale, PGC-1alpha null topi sono paradossalmente resistente all&#39;obesit&agrave; indotta da dieta e magra. Questo &egrave; in gran parte a causa di una profonda iperattivit&agrave; visualizzata dagli animali null ed &egrave; associato a lesioni nella regione striatal del cervello che controlla il movimento. Questi dati illustrano un ruolo centrale per PGC-1alpha nel controllo del metabolismo energetico, ma anche rivelano nuovi meccanismi di compensazione sistemiche ed effetti patogeni dell&#39;omeostasi energetica ridotta.

Difetti nel metabolismo energetico adattivo con iperattivit&agrave; CNS-collegato in PGC-1alpha null topi.

Leigh syndrome French Canadian variant (LSFC) is an autosomal recessive neurodegenerative disorder due to mutation in the LRP130 (leucine-rich protein 130 kDa) gene. Unlike classic Leigh syndrome, the French Canadian variant spares the heart, skeletal muscle, and kidneys, but severely affects the liver. The precise role of LRP130 in cytochrome c oxidase deficiency and hepatic lactic acidosis that accompanies this disorder is unknown. We show here that LRP130 is a component of the PGC-1alpha (peroxisome proliferator-activated receptor coactivator 1-alpha) transcriptional coactivator holocomplex and regulates expression of PEPCK (phosphoenolpyruvate carboxykinase), G6P (glucose-6-phosphatase), and certain mitochondrial genes through PGC-1alpha. Reduction of LRP130 in fasted mice via adenoviral RNA interference (RNAi) vector blocks the induction of PEPCK and G6P, and blunts hepatic glucose output. LRP130 is also necessary for PGC-1alpha-dependent transcription of several mitochondrial genes in vivo. These data link LRP130 and PGC-1alpha to defective hepatic energy homeostasis in LSFC, and reveal a novel regulatory mechanism of glucose homeostasis.

Defects in energy homeostasis in Leigh syndrome French Canadian variant through PGC-1alpha/LRP130 complex.

&#x68D5;&#x8272;&#x8102;&#x80AA;&#x662F;&#x4E13;&#x95E8;&#x7684;&#x7EC4;&#x7EC7;&#xFF0C;&#x53EF;&#x4EE5;&#x6D88;&#x6563;&#x80FD;&#x6E90;&#x548C;&#x5BF9;&#x6297;&#x80A5;&#x80D6;&#x901A;&#x8FC7;&#x4E00;&#x79CD;&#x6781;&#x5927;&#x5730;&#x589E;&#x52A0;&#x4E86;&#x7EBF;&#x7C92;&#x4F53;&#x7684;&#x5185;&#x5BB9;&#x548C;&#x88AB;&#x62C6;&#x547C;&#x5438;&#x4F5C;&#x7528;&#x7684;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x6A21;&#x5F0F;&#x3002;PRDM16 &#x662F;&#x4E00;&#x79CD;&#x950C;&#x6307;&#x86CB;&#x767D;&#xFF0C;&#x901A;&#x8FC7;&#x523A;&#x6FC0;&#x68D5;&#x8272;&#x8102;&#x80AA;&#x9009;&#x62E9;&#x6027;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#xFF0C;&#x540C;&#x65F6;&#x6291;&#x5236;&#x767D;&#x8272;&#x8102;&#x80AA;&#x7EC6;&#x80DE;&#x7684;&#x9009;&#x62E9;&#x6027;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x7684;&#x63A7;&#x5236;&#x68D5;&#x8272;&#x8102;&#x80AA;&#x6D4B;&#x5B9A;&#x3002;&#x82E5;&#x8981;&#x786E;&#x5B9A;&#x7BA1;&#x7406;&#x8FD9;&#x79CD;&#x5207;&#x6362;&#x7684;&#x57FA;&#x56E0;&#x7A0B;&#x5E8F;&#x7684;&#x673A;&#x5236;&#xFF0C;&#x6211;&#x4EEC;&#x51C0;&#x5316;&#x672C;&#x673A; PRDM16 &#x86CB;&#x767D;&#x590D;&#x5408;&#x7269;&#x7684;&#x8102;&#x80AA;&#x7EC6;&#x80DE;&#x3002;&#x6211;&#x4EEC;&#x5728;&#x8FD9;&#x91CC;&#x663E;&#x793A; PRDM16 &#x8F6C;&#x5F55; holocompex &#x5305;&#x542B; C-&#x7EC8;&#x7AEF;&#x7ED3;&#x5408;&#x86CB;&#x767D;-1 (CtBP-1) &#x548C; CtBP-2&#xFF0C;&#x548C;&#x8FD9;&#x79CD;&#x76F4;&#x63A5;&#x7684;&#x4E92;&#x52A8;&#x6709;&#x9009;&#x62E9;&#x6027;&#x5730;&#x4ECB;&#x5BFC;&#x767D;&#x80D6;&#x57FA;&#x56E0;&#x7684;&#x9547;&#x538B;&#x3002;&#x8FD9;&#x79CD;&#x538B;&#x5236;&#x901A;&#x8FC7;&#x62DB;&#x8058;&#x7684; PRDM16 CtBP &#x590D;&#x6742;&#x5230;&#x5982;&#x62B5;&#x6297;&#xFF0C;&#x767D;&#x8272;&#x8102;&#x80AA;&#x7279;&#x5B9A;&#x57FA;&#x56E0;&#x7684;&#x542F;&#x52A8;&#x5B50;&#x4E0A;&#x53D1;&#x751F;&#xFF0C;&#x5E76;&#x4E14;&#x5E9F;&#x9664;&#x4E86;&#x5728;&#x9057;&#x4F20;&#x6CA1;&#x6709; CtBP-1 &#x548C; CtBP-2&#x3002;&#x53CD;&#x8FC7;&#x6765;&#xFF0C;&#x62DB;&#x52DF; PPAR-&gamma;-&#x8F85;&#x6FC0;&#x6D3B;&#x56E0;&#x5B50;-1alpha (PGC-1alpha) &#x548C; PGC-&#x56E0;&#x5B50; 1 &beta; &#x5BF9;&#x590D;&#x6742; PRDM16 &#x504F;&#x79FB; CtBP&#xFF0C;&#x5141;&#x8BB8;&#x6B64;&#x590D;&#x6742;&#x8981;&#x6709;&#x529B;&#x5730;&#x6FC0;&#x6D3B;&#x68D5;&#x8272;&#x8102;&#x80AA;&#x7684;&#x57FA;&#x56E0;&#xFF0C;&#x6BD4;&#x5982; PGC-1alpha &#x672C;&#x8EAB;&#x3002;&#x8FD9;&#x4E9B;&#x6570;&#x636E;&#x663E;&#x793A;&#x5728; PRDM16 &#x4E0A;&#x53D7;&#x89C4;&#x7BA1;&#x5BF9;&#x63A5;&#x7684; CtBP &#x86CB;&#x767D;&#x8D28;&#x63A7;&#x5236;&#x7684;&#x68D5;&#x8272;&#x548C;&#x767D;&#x8272;&#x8102;&#x80AA;&#x9009;&#x62E9;&#x6027;&#x57FA;&#x56E0;&#x7A0B;&#x5E8F;&#x3002;

&#x68D5;&#x8272;&#x548C;&#x767D;&#x8272;&#x8102;&#x80AA;&#x57FA;&#x56E0;&#x7A0B;&#x5E8F;&#x901A;&#x8FC7; PRDM16/CtBP &#x8F6C;&#x5F55;&#x590D;&#x5408;&#x7269;&#x7684;&#x8C03;&#x8282;&#x3002;

Brown fat is a specialized tissue that can dissipate energy and counteract obesity through a pattern of gene expression that greatly increases mitochondrial content and uncoupled respiration. PRDM16 is a zinc-finger protein that controls brown fat determination by stimulating brown fat-selective gene expression, while suppressing the expression of genes selective for white fat cells. To determine the mechanisms regulating this switching of gene programs, we purified native PRDM16 protein complexes from fat cells. We show here that the PRDM16 transcriptional holocompex contains C-terminal-binding protein-1 (CtBP-1) and CtBP-2, and this direct interaction selectively mediates the repression of white fat genes. This repression occurs through recruiting a PRDM16/CtBP complex onto the promoters of white fat-specific genes such as resistin, and is abolished in the genetic absence of CtBP-1 and CtBP-2. In turn, recruitment of PPAR-gamma-coactivator-1alpha (PGC-1alpha) and PGC-1beta to the PRDM16 complex displaces CtBP, allowing this complex to powerfully activate brown fat genes, such as PGC-1alpha itself. These data show that the regulated docking of the CtBP proteins on PRDM16 controls the brown and white fat-selective gene programs.

Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex.

La graisse brune est un tissu sp&eacute;cialis&eacute; peut de dissiper l&#39;&eacute;nergie et de lutter contre l&#39;ob&eacute;sit&eacute; par un motif d&#39;expression de g&egrave;ne qui accro&icirc;t consid&eacute;rablement le contenu mitochondrial et d&eacute;bo&icirc;ter la respiration. PRDM16 est une prot&eacute;ine de doigt de zinc qui contr&ocirc;le la d&eacute;termination de la graisse brune en stimulant l&#39;expression g&eacute;nique s&eacute;lectif de graisse brune tout en supprimant l&#39;expression des g&egrave;nes s&eacute;lectifs pour les adipocytes blancs. Pour d&eacute;terminer les m&eacute;canismes qui r&eacute;gissent cette commutation des programmes de g&egrave;ne, nous avons purifi&eacute; natives PRDM16 complexes de prot&eacute;ines par les cellules adipeuses. Nous montrons ici que la holocompex de transcriptional PRDM16 contient C-terminal-binding protein-1 (CtBP-1) et CtBP-2, et cette interaction directe intervient s&eacute;lectivement dans la r&eacute;pression des g&egrave;nes de graisses blanches. Cette r&eacute;pression intervient par le biais de recrutement un complexe sur les promoteurs de g&egrave;nes de graisse sp&eacute;cifique blancs comme la r&eacute;sistine PRDM16/CtBP et est abolie en l&#39;absence de g&eacute;n&eacute;tique de CtBP-1 et CtBP-2. &Agrave; son tour, recrutement de PPAR-gamma-coactivateur-1alpha (PGC-1alpha) et PGC-1beta &agrave; la PRDM16 complexe d&eacute;place CtBP, permettant &agrave; ce complexe activer puissamment les g&egrave;nes de graisse brune, comme le PGC-1alpha lui-m&ecirc;me. Ces donn&eacute;es montrent que l&#39;amarrage r&eacute;glement&eacute; des prot&eacute;ines CtBP sur PRDM16 contr&ocirc;le les programmes g&egrave;ne s&eacute;lective des graisses brunes et blanches.

R&egrave;glement des programmes gr&acirc;ce &agrave; un complexe transcriptionnel PRDM16/CtBP g&egrave;ne fat brun et blanc.

Grasso marrone &egrave; un tessuto specializzato che pu&ograve; dissipare energia e contrastare l&#39;obesit&agrave; attraverso un modello di espressione del gene che aumenta notevolmente contenuto mitocondriale e respirazione disgiunti. PRDM16 &egrave; una proteina zinc-finger che controlla la determinazione del grasso marrone da stimolante espressione genica grasso marrone-selettivo, mentre sopprimendo l&#39;espressione dei geni selettivi per le cellule di grasso bianche. Per determinare i meccanismi che regolano questo passaggio dei programmi di gene, abbiamo purificato nativi PRDM16 complessi di proteine da cellule di grasso. Mostriamo qui il holocompex di transcriptional PRDM16 contiene C-terminale-binding protein-1 (CtBP-1) e CtBP-2, che questa interazione diretta da intermediario in modo selettivo la repressione dei geni di grassi bianchi. Questa repressione avviene attraverso un complesso sui promotori del bianchi grasso specifici geni come resistin PRDM16/CtBP di reclutamento e viene abolita in assenza genetica di CtBP-1 e CtBP-2. A sua volta, reclutamento di PPAR-gamma coactivator 1alpha (PGC-1alpha) e PGC-1beta per il PRDM16 complesso si sposta CtBP, permettendo che questo complesso di attivare potentemente grasso marrone geni, quali PGC-1alpha stessa. Questi dati mostrano che l&#39;attracco regolamentato delle proteine CtBP su PRDM16 controlla i programmi di gene selettivo grasso marrone e bianco.

Regolamento dei programmi attraverso un complesso di transcriptional PRDM16/CtBP gene grasso marrone e bianco.

&#x8910;&#x8272;&#x8102;&#x80AA;&#x306F;&#x30A8;&#x30CD;&#x30EB;&#x30AE;&#x30FC;&#x3092;&#x6D88;&#x8CBB;&#x3057;&#x3001;&#x30DF;&#x30C8;&#x30B3;&#x30F3;&#x30C9;&#x30EA;&#x30A2; &#x30B3;&#x30F3;&#x30C6;&#x30F3;&#x30C4;&#x3068;&#x5171;&#x5F79;&#x547C;&#x5438;&#x304C;&#x5927;&#x5E45;&#x306B;&#x5897;&#x52A0;&#x3059;&#x308B;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x30D1;&#x30BF;&#x30FC;&#x30F3;&#x3092;&#x80A5;&#x6E80;&#x306B;&#x5BFE;&#x6297;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3001;&#x5C02;&#x9580;&#x7684;&#x306A;&#x7D44;&#x7E54;&#x3067;&#x3059;&#x3002;PRDM16 &#x8336;&#x8272;&#x3044;&#x8102;&#x80AA;&#x5B9A;&#x91CF;&#x767D;&#x8272;&#x8102;&#x80AA;&#x7D30;&#x80DE;&#x306E;&#x9078;&#x629E;&#x7684;&#x306A;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x767A;&#x73FE;&#x3092;&#x6291;&#x5236;&#x3057;&#x306A;&#x304C;&#x3089;&#x3001;&#x523A;&#x6FC0;&#x306E;&#x8336;&#x8272;&#x3044;&#x8102;&#x80AA;&#x304C;&#x9078;&#x629E;&#x7684;&#x306A;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x5236;&#x5FA1;&#x4E9C;&#x925B;&#x30D5;&#x30A3;&#x30F3;&#x30AC;&#x30FC;&#x86CB;&#x767D;&#x8CEA;&#x3067;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x3053;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x30D7;&#x30ED;&#x30B0;&#x30E9;&#x30E0;&#x306E;&#x5207;&#x308A;&#x66FF;&#x3048;&#x306E;&#x5236;&#x5FA1;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3092;&#x6C7A;&#x5B9A;&#x3059;&#x308B;&#x306B;&#x306F;&#x3001;&#x30CD;&#x30A4;&#x30C6;&#x30A3;&#x30D6;&#x306E; PRDM16 &#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x8907;&#x5408;&#x4F53;&#x306E;&#x8102;&#x80AA;&#x7D30;&#x80DE;&#x304B;&#x3089;&#x7CBE;&#x88FD;&#x3002;&#x3053;&#x3053;&#x3067; PRDM16 &#x306E;&#x8EE2;&#x5199; holocompex C &#x30BF;&#x30FC;&#x30DF;&#x30CA;&#x30EB;&#x7D50;&#x5408;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;-1 &#xFF08;CtBP 1&#xFF09; &#x3068; CtBP 2 &#x304C;&#x542B;&#x307E;&#x308C;&#x3066;&#x3044;&#x308B;&#x3057;&#x3001;&#x3053;&#x306E;&#x76F4;&#x63A5;&#x7684;&#x306A;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x304C;&#x9078;&#x629E;&#x7684;&#x306B;&#x767D;&#x3044;&#x8102;&#x80AA;&#x8CEA;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x6291;&#x5727;&#x3092;&#x4EF2;&#x4ECB;&#x3059;&#x308B;. &#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x306E;&#x6291;&#x5727;&#x306F;&#x3001;PRDM16/CtBP &#x306A;&#x3069;&#x30EC;&#x30B8;&#x30B9;&#x30C1;&#x30F3;&#x3001;&#x767D;&#x3044;&#x8102;&#x80AA;&#x7279;&#x7570;&#x7684;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x30D7;&#x30ED;&#x30E2;&#x30FC;&#x30BF;&#x30FC;&#x306B;&#x8907;&#x96D1;&#x306A;&#x52DF;&#x96C6;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x767A;&#x751F;&#x3057;&#x3001;CtBP 1&#x3001;CtBP 2 &#x306E;&#x907A;&#x4F1D;&#x7684;&#x3076;&#x308A;&#x3092;&#x5EC3;&#x6B62;&#x3057;&#x307E;&#x3059;&#x3002;&#x30BF;&#x30FC;&#x30F3;&#x3067;&#x306F;&#x3001;-1 PPAR-&#x30AC;&#x30F3;&#x30DE;-&#x30B3;&#x30A2;&#x30AF;&#x30C1;&#x30D9;&#x30FC;&#x30BF;&#x30FC;-&alpha; (PGC-1 &alpha;) &#x306E;&#x8907;&#x96D1;&#x306A; PRDM16 &#x3092; PGC &#xFF0D;1 &beta; &#x52DF;&#x96C6;&#x3053;&#x306E;&#x30B3;&#x30F3;&#x30D7;&#x30EC;&#x30C3;&#x30AF;&#x30B9;&#x3092;&#x529B;&#x5F37;&#x304F; PGC-1 &alpha; &#x81EA;&#x4F53;&#x306A;&#x3069;&#x306E;&#x8336;&#x8272;&#x3044;&#x8102;&#x80AA;&#x907A;&#x4F1D;&#x5B50;&#x3092;&#x6D3B;&#x6027;&#x5316;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059; CtBP &#x3092;&#x5909;&#x4F4D;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x898F;&#x5236; CtBP &#x86CB;&#x767D;&#x8CEA;&#x306E; PRDM16 &#x306B;&#x30C9;&#x30C3;&#x30AD;&#x30F3;&#x30B0;&#x8336;&#x8272;&#x3068;&#x767D;&#x306E;&#x8102;&#x80AA;&#x9078;&#x629E;&#x7684;&#x907A;&#x4F1D;&#x5B50;&#x30D7;&#x30ED;&#x30B0;&#x30E9;&#x30E0;&#x3092;&#x5236;&#x5FA1;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;

PRDM16/CtBP &#x306E;&#x8EE2;&#x5199;&#x8907;&#x5408;&#x4F53;&#x3092;&#x901A;&#x3058;&#x3066;&#x3001;&#x8336;&#x8272;&#x3068;&#x767D;&#x306E;&#x8102;&#x80AA;&#x8CEA;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x30D7;&#x30ED;&#x30B0;&#x30E9;&#x30E0;&#x306E;&#x898F;&#x5236;&#x3002;

&#xAC08;&#xC0C9; &#xC9C0;&#xBC29;&#xC774; &#xC5D0;&#xB108;&#xC9C0;&#xB97C; &#xBC1C;&#xC0B0; &#xD558; &#xACE0; &#xD06C;&#xAC8C; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; &#xB0B4;&#xC6A9;&#xACFC; uncoupled &#xD638;&#xD761;&#xC744; &#xC99D;&#xAC00; &#xC2DC;&#xD0A4;&#xB294; &#xC720;&#xC804;&#xC790; &#xBC1C;&#xD604; &#xD328;&#xD134;&#xC744; &#xD1B5;&#xD574; &#xBE44;&#xB9CC; &#xBC29;&#xD574; &#xC218; &#xC788;&#xB294; &#xC804;&#xBB38;&#xD654; &#xB41C; &#xC870;&#xC9C1; &#xC774;&#xB2E4;. PRDM16 &#xBC31;&#xC0C9; &#xC9C0;&#xBC29; &#xC138;&#xD3EC; &#xC120;&#xD0DD;&#xC801; &#xC720;&#xC804;&#xC790;&#xC758; &#xD45C;&#xD604;&#xC744; &#xC5B5;&#xC81C; &#xD558;&#xB294; &#xB3D9;&#xC548; &#xC790;&#xADF9; &#xAC08;&#xC0C9; &#xC9C0;&#xBC29;&#xC774; &#xC120;&#xD0DD;&#xC801; &#xC720;&#xC804;&#xC790; &#xBC1C;&#xD604;&#xC5D0; &#xC758;&#xD574; &#xAC08;&#xC0C9; &#xC9C0;&#xBC29;&#xC774; &#xACB0;&#xC815;&#xC744; &#xC81C;&#xC5B4; &#xD558;&#xB294; &#xC544;&#xC5F0; &#xD551;&#xAC70; &#xB2E8;&#xBC31;&#xC9C8; &#xC774;&#xB2E4;. &#xC720;&#xC804;&#xC790; &#xD504;&#xB85C;&#xADF8;&#xB7A8;&#xC758; &#xC2A4;&#xC704;&#xCE6D;&#xC774; &#xADDC;&#xC81C; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xD655;&#xC778; &#xD558;&#xB824;&#xBA74; &#xB124;&#xC774;&#xD2F0;&#xBE0C; PRDM16 &#xB2E8;&#xBC31;&#xC9C8; &#xBCF5;&#xD569;&#xBB3C; &#xC9C0;&#xBC29; &#xC138;&#xD3EC;&#xC5D0;&#xC11C; &#xC815;&#xD654; &#xD558; &#xACE0;. &#xC6B0;&#xB9AC;&#xAC00; &#xC5EC;&#xAE30;&#xC5D0; &#xD45C;&#xC2DC; PRDM16 transcriptional holocompex &#xD3EC;&#xD568; C &#xD130;&#xBBF8;&#xB110; &#xBC14;&#xC778;&#xB529; &#xB2E8;&#xBC31;&#xC9C8;-1 (CtBP-1) CtBP-2, &#xADF8;&#xB9AC;&#xACE0;&#xC774; &#xC9C1;&#xC811; &#xC0C1;&#xD638; &#xC120;&#xD0DD;&#xC801;&#xC73C;&#xB85C; &#xC911;&#xC7AC; &#xBC31;&#xC0C9; &#xC9C0;&#xBC29; &#xC720;&#xC804;&#xC790;&#xC758; &#xC5B5;&#xC81C;. &#xC774; &#xC5B5;&#xC555;&#xACFC; PRDM16/CtBP resistin, &#xAC19;&#xC740; &#xD558;&#xC580; &#xC9C0;&#xBC29; &#xAD00;&#xB828; &#xC720;&#xC804;&#xC790;&#xC758; &#xD504;&#xB85C;&#xBAA8;&#xD130;&#xC5D0; &#xBCF5;&#xC7A1; &#xD55C; &#xBAA8;&#xC9D1;&#xC744; &#xD1B5;&#xD574; &#xBC1C;&#xC0DD; CtBP 1, CtBP-2 &#xC720;&#xC804;&#xC790; &#xACB0;&#xD54D;&#xC5D0; &#xD3D0;&#xC9C0; &#xB41C;&#xB2E4;. &#xCC28;&#xB840;&#xB85C; &#xCC44;&#xC6A9; PPAR &#xAC10;&#xB9C8; coactivator 1alpha (PGC-1alpha) &#xBC0F; &#xBCF5;&#xC7A1; &#xD55C; prdm16&#xC5D0; PGC 1beta CtBP &#xC218; &#xC788;&#xB3C4;&#xB85D; &#xAC15;&#xB825; &#xD558; &#xAC8C; &#xC790;&#xCCB4; PGC 1alpha &#xAC19;&#xC740; &#xAC08;&#xC0C9; &#xC9C0;&#xBC29; &#xC720;&#xC804;&#xC790;&#xB97C; &#xD65C;&#xC131;&#xD654; &#xD558;&#xAE30; &#xC704;&#xD574; &#xBCF5;&#xC7A1;&#xC774; &#xD55C; &#xBC30; &#xC218;&#xB7C9;. &#xC774;&#xB7EC;&#xD55C; &#xB370;&#xC774;&#xD130;&#xB294; &#xAC08;&#xC0C9;&#xACFC; &#xD770;&#xC0C9; &#xC9C0;&#xBC29;&#xC774; &#xC120;&#xD0DD;&#xC801; &#xC720;&#xC804;&#xC790; &#xD504;&#xB85C;&#xADF8;&#xB7A8; &#xC81C;&#xC5B4; prdm16&#xC5D0; CtBP &#xB2E8;&#xBC31;&#xC9C8;&#xC758; &#xB808; &#xADE4; &#xB808;&#xC774;&#xD2B8; &#xB41C; &#xB3C4;&#xD0B9; &#xBCF4;&#xAE30;.

PRDM16/CtBP transcriptional &#xBCF5;&#xC7A1; &#xD1B5;&#xD574; &#xAC08;&#xC0C9;&#xACFC; &#xD770;&#xC0C9; &#xC9C0;&#xBC29; &#xC720;&#xC804;&#xC790; &#xD504;&#xB85C;&#xADF8;&#xB7A8;&#xC758; &#xADDC;&#xCE59;.

Grasa parda es un tejido especializado que puede disipar energ&iacute;a y contrarrestar la obesidad a trav&eacute;s de un patr&oacute;n de expresi&oacute;n g&eacute;nica que incrementa el contenido mitocondrial y respiraci&oacute;n desacoplada. PRDM16 es una prote&iacute;na de zinc-finger que controla la determinaci&oacute;n de la grasa parda por estimulante selectivo de grasa parda genes, mientras que la supresi&oacute;n de la expresi&oacute;n de genes selectivas para las c&eacute;lulas de grasa blancas. Para determinar los mecanismos de regulaci&oacute;n de este cambio de programas de gene, nos purifica nativas PRDM16 complejos de la prote&iacute;na de las c&eacute;lulas de grasa. Aqu&iacute; mostramos que la holocompex transcripcional PRDM16 contiene C-terminal-binding protein-1 (CtBP-1) y CtBP-2, y esta interacci&oacute;n directa Media selectivamente la represi&oacute;n de genes de grasas blancas. Esta represi&oacute;n se produce a trav&eacute;s de reclutar un complejo en los promotores de genes de grasa espec&iacute;fica blancos como resistina PRDM16/CtBP y se suprime en la ausencia gen&eacute;tica de CtBP-1 y CtBP-2. A su vez, reclutamiento de PPAR-gamma-coactivator-1alfa (PGC-1 alfa) y PGC-1beta para el PRDM16 complejo desplaza CtBP, permitiendo que este complejo poderosamente activar genes de grasa parda, como PGC-1 alfa s&iacute; mismo. Estos datos demuestran que el regulado de acoplamiento de las prote&iacute;nas CtBP en PRDM16 controla los programas de gene selectiva de grasa marr&oacute;n y blanco.

Regulaci&oacute;n de los programas de gen grasa marr&oacute;n y blanco a trav&eacute;s de un complejo transcripcional PRDM16/CtBP.

PGC-1 &#x5171;&#x6FC0;&#x6D3B;&#x56E0;&#x5B50;&#x7684;&#x6D3B;&#x6027;&#x6C27;&#x4EE3;&#x8C22;&#x7684;&#x91CD;&#x8981;&#x76D1;&#x7BA1;&#x673A;&#x6784;&#x3002;&#x6211;&#x4EEC;&#x4EE5;&#x524D;&#x8868;&#x660E; LRP130 &#x662F; PGC-1alpha&#xFF0C;&#x809D;&#x8461;&#x8404;&#x7CD6;&#x6240;&#x9700;&#x7684;&#x7ED1;&#x5B9A;&#x5408;&#x4F19;&#x4EBA;&#x3002;LRP130 &#x662F; Leigh &#x7EFC;&#x5408;&#x5F81;&#x52A0;&#x62FF;&#x5927;&#x6CD5;&#x8BED;&#x5907;&#x9009;&#x6848;&#x6587;&#xFF0C;&#x4E00;&#x79CD;&#x7F55;&#x89C1;&#x7684;&#x795E;&#x7ECF;&#x9000;&#x884C;&#x6027;&#x75BE;&#x75C5;&#x4E2D;&#x7684;&#x7A81;&#x53D8;&#x7684;&#x57FA;&#x56E0;&#x3002;&#x5728;&#x5176;&#x4ED6;&#x7684; LRP130 &#x91CD;&#x8981;&#x6027;&#xFF0C;&#x975E;&#x809D;&#x7EC6;&#x80DE;&#x751F;&#x7269;&#x5B66;&#x4ECD;&#x7136;&#x4E0D;&#x660E;&#x6717;&#x3002;&#x4E3A;&#x4E86;&#x66F4;&#x597D;&#x5730;&#x7406;&#x89E3; PGC-1 &#x8F85;&#x6FC0;&#x6D3B;&#x56E0;&#x5B50;&#x529F;&#x80FD;&#x7684;&#x68D5;&#x8272;&#x8102;&#x80AA;&#x53D1;&#x5C55;&#xFF0C;&#x6211;&#x4EEC;&#x63A2;&#x8BA8; LRP130 &#x68D5;&#x8272;&#x8102;&#x80AA;&#x7EC6;&#x80DE;&#x5206;&#x5316;&#x8FC7;&#x7A0B;&#x4E2D;&#x7684;&#x4EE3;&#x8C22;&#x4F5C;&#x7528;&#x3002;&#x6211;&#x4EEC;&#x5C55;&#x793A;&#x5728;&#x68D5;&#x8272;&#x8102;&#x80AA;&#x4E0E;&#x767D;&#x8272;&#xFF0C;&#x76F8;&#x6BD4;&#x548C; PGC-1-&#x4F9D;&#x8D56;&#x7684;&#x65B9;&#x5F0F;&#x8BF1;&#x5BFC;&#x5206;&#x5316;&#x8FC7;&#x7A0B;&#x4E2D;&#x4F18;&#x5148;&#x5730;&#x4E30;&#x5BCC;&#x4E86; LRP130&#x3002;&#x5C3D;&#x7BA1;&#x539F;&#x5C01; PGC-1 &#x8F85;&#x6FC0;&#x6D3B;&#x56E0;&#x5B50;&#x7684;&#x8868;&#x8FBE;&#xFF0C;&#x68D5;&#x8272;&#x8102;&#x80AA;&#x7EC6;&#x80DE;&#x7F3A;&#x9677;&#x4E3A; LRP130 &#x9648;&#x5217;&#x51CF;&#x6BD2;&#x7684;&#x51E0;&#x4E2A;&#x57FA;&#x56E0;&#x7279;&#x6027;&#x7684;&#x68D5;&#x8272;&#x8102;&#x80AA;&#xFF0C;&#x5305;&#x62EC;&#x89E3;&#x5076;&#x8054;&#x86CB;&#x767D; 1 &#x8868;&#x8FBE;&#x3002;&#x6C27;&#x6D88;&#x8017;&#x7814;&#x7A76;&#x8D28;&#x5B50;&#x6F0F;&#x7531;&#x4E8E;&#x51CF;&#x6BD2;&#x89E3;&#x5076;&#x8054;&#x86CB;&#x767D; 1 &#x8868;&#x8FBE;&#x652F;&#x6301;&#x7279;&#x5B9A;&#x7684;&#x7F3A;&#x9677;&#x3002;&#x503C;&#x5F97;&#x6CE8;&#x610F;&#x7684;&#x662F;&#xFF0C;&#x4E24;&#x4E2A; PGC-1 &#x5171;&#x6FC0;&#x6D3B;&#x56E0;&#x5B50;&#x7684;&#x5171;&#x540C;&#x7684;&#x68D5;&#x8272;&#x8102;&#x80AA;&#x7EC6;&#x80DE;&#x53D1;&#x5C55;&#x53D7;&#x5236;&#x7EA6; LRP130&#x3002;&#x76F8;&#x53CD;&#xFF0C;&#x7531; PGC-1alpha &#x63A7;&#x5236;&#x7684; cAMP &#x53CD;&#x5E94;&#x4E0D;&#x53D7; LRP130&#x3002;&#x8FD9;&#x4E9B;&#x6570;&#x636E;&#x7275;&#x8FDE; LRP130 &#x68D5;&#x8272;&#x8102;&#x80AA;&#x7EC6;&#x80DE;&#x53D1;&#x80B2;&#x548C;&#x5206;&#x5316;&#x3002;

&#x901A;&#x8FC7; LRP130 &#x68D5;&#x8272;&#x8102;&#x80AA;&#x5206;&#x5316;&#x4E2D;&#x7684; PGC-1 &#x8F85;&#x6FC0;&#x6D3B;&#x56E0;&#x5B50;&#x9014;&#x5F84;&#x7684;&#x8C03;&#x5236;&#x3002;

The PGC-1 coactivators are important regulators of oxidative metabolism. We previously demonstrated that LRP130 is a binding partner of PGC-1alpha, required for hepatic gluconeogenesis. LRP130 is the gene mutated in Leigh syndrome French Canadian variant, a rare neurodegenerative disease. The importance of LRP130 in other, non-hepatocyte biology remains obscure. To better understand PGC-1 coactivator function in brown fat development, we explored the metabolic role of LRP130 in brown adipocyte differentiation. We show that LRP130 is preferentially enriched in brown fat compared with white, and induced in a PGC-1-dependent manner during differentiation. Despite intact PGC-1 coactivator expression, brown fat cells deficient for LRP130 exhibit attenuated expression of several genes characteristic of brown fat, including uncoupling protein 1. Oxygen consumption studies support a specific defect in proton leak due to attenuated uncoupling protein 1 expression. Notably, brown fat cell development common to both PGC-1 coactivators is governed by LRP130. Conversely, the cAMP response controlled by PGC-1alpha is not regulated by LRP130. These data implicate LRP130 in brown fat cell development and differentiation.

Modulation of PGC-1 coactivator pathways in brown fat differentiation through LRP130.

Les PGC-1 coactivateurs sont d&#39;importants r&eacute;gulateurs du m&eacute;tabolisme oxydatif. Nous avons d&eacute;montr&eacute; pr&eacute;c&eacute;demment que le LRP130 est un partenaire de liaison du PGC-1alpha, requis pour la glucon&eacute;ogen&egrave;se h&eacute;patique. LRP130 est le g&egrave;ne mut&eacute; dans la variante canadienne-fran&ccedil;aise du syndrome de Leigh, une maladie neurod&eacute;g&eacute;n&eacute;rative rare. L&#39;importance de la LRP130 dans d&#39;autres, non-h&eacute;patocytes biologie demeure obscure. Pour mieux comprendre le fonction coactivateur PGC-1 dans le d&eacute;veloppement du tissu adipeux brun, nous avons explor&eacute; le r&ocirc;le m&eacute;tabolique de LRP130 dans la diff&eacute;renciation des adipocytes bruns. Nous montrons que LRP130 est pr&eacute;f&eacute;rentiellement enrichis en graisse brune par rapport aux blancs et induit de mani&egrave;re d&eacute;pendante de PGC-1 au cours de la diff&eacute;renciation. Malgr&eacute; l&#39;expression de coactivateur PGC-1 intacte, adipocytes bruns d&eacute;ficients pour LRP130 pi&egrave;ce expression att&eacute;nu&eacute;e de plusieurs caract&eacute;ristique de g&egrave;nes de la graisse brune, y compris la prot&eacute;ine d&eacute;couplante 1. Des &eacute;tudes de consommation d&#39;oxyg&egrave;ne prend en charge un d&eacute;faut sp&eacute;cifique en fuite de protons en raison de l&#39;expression de prot&eacute;ine 1 d&eacute;couplante att&eacute;nu&eacute;e. En particulier, d&eacute;veloppement de cellules de graisse brune commun &agrave; ces deux coactivateurs PGC-1 est r&eacute;gi par LRP130. &Agrave; l&#39;inverse, la r&eacute;ponse de l&#39;AMPc contr&ocirc;l&eacute;e par le PGC-1alpha n&#39;est pas r&eacute;glement&eacute;e par LRP130. Ces donn&eacute;es indiquent que LRP130 dans la diff&eacute;renciation et le d&eacute;veloppement de cellules de graisse brune.

Modulation des voies coactivateur PGC-1 par le biais de LRP130 contrairement &agrave; la graisse brune.

La trascrizione PGC-1 sono importanti regolatori del metabolismo ossidativo. Abbiamo precedentemente dimostrato che LRP130 &egrave; un partner di associazione di PGC-1alpha, necessari per la gluconeogenesi epatica. LRP130 &egrave; il gene mutato in variante francese canadese di sindrome di Leigh, una malattia neurodegenerativa rara. L&#39;importanza di LRP130 in altri, non degli epatociti biologia rimane oscuro. Per comprendere meglio la funzione coactivator PGC-1 nello sviluppo grasso marrone, abbiamo esplorato il ruolo metabolico di LRP130 nella differenziazione degli adipociti marrone. Mostriamo che LRP130 preferenzialmente &egrave; arricchito in grasso marrone rispetto ai bianchi e indotto in modo PGC-1-dipendente durante la differenziazione. Nonostante l&#39;espressione intatta coactivator PGC-1, le cellule di grasso marrone carenti per LRP130 esibiscono attenuato espressione della caratteristica di geni diversi di grasso marrone, tra cui la proteina disgiungente 1. Gli studi di consumo di ossigeno supportano un difetto specifico nella perdita di protoni dovuto attenuato disgiungere espressione della proteina 1. In particolare, lo sviluppo delle cellule grasso marrone comune a entrambi coattivatori PGC-1 &egrave; governato da LRP130. Al contrario, la risposta di campo controllata da PGC-1alpha non &egrave; regolata da LRP130. Questi dati implicano LRP130 nella differenziazione e lo sviluppo delle cellule di grasso marrone.

Modulazione delle vie coactivator PGC-1 nella differenziazione di grasso marrone attraverso LRP130.

PGC 1 &#x30B3;&#x30A2;&#x30AF;&#x30C1;&#x30D9;&#x30FC;&#x30BF;&#x30FC;&#x9178;&#x5316;&#x4EE3;&#x8B1D;&#x306E;&#x91CD;&#x8981;&#x306A;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30BF;&#x3067;&#x3059;&#x3002;&#x79C1;&#x305F;&#x3061;&#x4EE5;&#x524D; LRP130 &#x7D50;&#x5408;&#x30D1;&#x30FC;&#x30C8;&#x30CA;&#x30FC;&#x306E; PGC-1 &alpha;&#x3001;&#x809D;&#x7CD6;&#x65B0;&#x751F;&#x306E;&#x305F;&#x3081;&#x306B;&#x5FC5;&#x8981;&#x306A;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002;LRP130 &#x30EA;&#x30FC;&#x75C7;&#x5019;&#x7FA4;&#x30D5;&#x30E9;&#x30F3;&#x30B9;&#x7CFB;&#x30AB;&#x30CA;&#x30C0;&#x4EBA;&#x30D0;&#x30EA;&#x30A2;&#x30F3;&#x30C8;&#x3067;&#x306F;&#x3001;&#x307E;&#x308C;&#x306A;&#x795E;&#x7D4C;&#x5909;&#x6027;&#x75BE;&#x60A3;&#x5909;&#x7570;&#x907A;&#x4F1D;&#x5B50;&#x3067;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x305D;&#x306E;&#x4ED6;&#x306B;&#x304A;&#x3051;&#x308B; LRP130 &#x306E;&#x91CD;&#x8981;&#x6027;&#x3001;&#x975E;&#x809D;&#x7D30;&#x80DE;&#x751F;&#x7269;&#x5B66;&#x306E;&#x3042;&#x3044;&#x307E;&#x3044;&#x306A;&#x307E;&#x307E;&#x3067;&#x3059;&#x3002;PGC 1 &#x30B3;&#x30A2;&#x30AF;&#x30C1;&#x30D9;&#x30FC;&#x30BF;&#x30FC;&#x95A2;&#x6570;&#x306B;&#x304A;&#x3051;&#x308B;&#x8910;&#x8272;&#x8102;&#x80AA;&#x3092;&#x3088;&#x308A;&#x3088;&#x304F;&#x7406;&#x89E3;&#x3059;&#x308B;&#x306B;&#x306F;&#x3001;&#x8910;&#x8272;&#x8102;&#x80AA;&#x7D30;&#x80DE;&#x5206;&#x5316;&#x306B;&#x304A;&#x3051;&#x308B; LRP130 &#x306E;&#x4EE3;&#x8B1D;&#x306E;&#x5F79;&#x5272;&#x3092;&#x691C;&#x8A0E;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x79C1;&#x9054;&#x306F; LRP130 &#x304C;&#x512A;&#x5148;&#x7684;&#x30D6;&#x30E9;&#x30A6;&#x30F3; &#x30DB;&#x30EF;&#x30A4;&#x30C8;&#x3068;&#x3092;&#x6BD4;&#x8F03;&#x3057;&#x3001;PGC 1 &#x4F9D;&#x5B58;&#x7684;&#x306B;&#x5206;&#x5316;&#x8A98;&#x5C0E;&#x8102;&#x80AA;&#x306B;&#x5BCC;&#x3080;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;&#x305D;&#x306E;&#x307E;&#x307E; PGC - &#x30B3;&#x30A2;&#x30AF;&#x30C1;&#x30D9;&#x30FC;&#x30BF;&#x30FC;&#x767A;&#x73FE;&#x306B;&#x3082;&#x304B;&#x304B;&#x308F;&#x3089;&#x305A;&#x3001;&#x8336;&#x8272;&#x3044;&#x8102;&#x80AA;&#x306E;&#x7D30;&#x80DE; LRP130 &#x306E;&#x6B20;&#x4E4F;&#x6E1B;&#x8870;&#x5F0F;&#x8910;&#x8272;&#x8102;&#x80AA;&#x3001;&#x8131;&#x5171;&#x5F79;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA; 1 &#x3092;&#x542B;&#x3080;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x7279;&#x6027;&#x306E;&#x5C55;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;&#x9178;&#x7D20;&#x6D88;&#x8CBB;&#x7814;&#x7A76;&#x30D7;&#x30ED;&#x30C8;&#x30F3; &#x30EA;&#x30FC;&#x30AF;&#x5F31;&#x6BD2;&#x8131;&#x5171;&#x5F79;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA; 1 &#x306E;&#x767A;&#x73FE;&#x306E;&#x305F;&#x3081;&#x306E;&#x7279;&#x5B9A;&#x306E;&#x6B20;&#x9665;&#x3092;&#x30B5;&#x30DD;&#x30FC;&#x30C8;&#x3057;&#x307E;&#x3059;&#x3002;&#x7279;&#x306B;&#x3001;&#x8910;&#x8272;&#x8102;&#x80AA;&#x7D30;&#x80DE;&#x306E;&#x958B;&#x767A;&#x306E;&#x4E21;&#x65B9; PGC 1 &#x30B3;&#x30A2;&#x30AF;&#x30C1;&#x30D9;&#x30FC;&#x30BF;&#x30FC;&#x306B;&#x4E00;&#x822C;&#x7684;&#x306A; LRP130 &#x306B;&#x3088;&#x3063;&#x3066;&#x652F;&#x914D;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x9006;&#x306B;&#x3001;PGC--1 &alpha; &#x306B;&#x3088;&#x3063;&#x3066;&#x5236;&#x5FA1;&#x3055;&#x308C;&#x308B; cAMP &#x53CD;&#x5FDC; LRP130 &#x306B;&#x3088;&#x3063;&#x3066;&#x898F;&#x5236;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x306F;&#x3001;&#x8910;&#x8272;&#x8102;&#x80AA;&#x7D30;&#x80DE;&#x3068;&#x5206;&#x5316;&#x306B; LRP130 &#x3092;&#x5DFB;&#x304D;&#x8FBC;&#x307F;&#x307E;&#x3059;&#x3002;

LRP130 &#x3092;&#x4ECB;&#x3057;&#x3066;&#x8910;&#x8272;&#x8102;&#x80AA;&#x5206;&#x5316;&#x306B;&#x304A;&#x3051;&#x308B; PGC 1 &#x30B3;&#x30A2;&#x30AF;&#x30C1;&#x30D9;&#x30FC;&#x30BF;&#x30FC;&#x7D4C;&#x8DEF;&#x306E;&#x5909;&#x8ABF;&#x3002;

PGC-1 coactivators&#xB294; &#xC0B0;&#xD654; &#xB300;&#xC0AC;&#xC758; &#xC911;&#xC694; &#xD55C; &#xADDC;&#xC81C;. &#xC6B0;&#xB9AC;&#xB294; &#xC774;&#xC804; LRP130 PGC-1alpha, &#xAC04; gluconeogenesis&#xC5D0; &#xD544;&#xC694;&#xD55C;&#xC758; &#xBC14;&#xC778;&#xB529; &#xD30C;&#xD2B8;&#xB108; &#xC784;&#xC744; &#xC99D;&#xBA85;. LRP130 &#xB808;&#xC774; &#xC99D;&#xD6C4;&#xAD70; &#xD504;&#xB791;&#xC2A4; &#xCE90;&#xB098;&#xB2E4; &#xBCC0;&#xC885;, &#xD76C;&#xADC0; &#xC2E0;&#xACBD; &#xC9C8;&#xD658;&#xC5D0;&#xC11C;&#xC5D0;&#xC11C; &#xBCC0;&#xC774; &#xB41C; &#xC720;&#xC804;&#xC790;&#xC785;&#xB2C8;&#xB2E4;. &#xB2E4;&#xB978; lrp130&#xC758; &#xC911;&#xC694;&#xC131;, &#xBE44; hepatocyte &#xC0DD;&#xBB3C;&#xD559; &#xBB34;&#xBA85; &#xB0A8;&#xC544; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB354; &#xB098;&#xC740; &#xAC08;&#xC0C9; &#xC9C0;&#xBC29; &#xAC1C;&#xBC1C;&#xC5D0; PGC 1 coactivator &#xAE30;&#xB2A5; &#xC774;&#xD574;, &#xAC08;&#xC0C9; &#xCCB4;&#xD615; &#xCC28;&#xBCC4;&#xD654;&#xC5D0; lrp130&#xC758; &#xB300;&#xC0AC; &#xC5ED;&#xD560; &#xD0D0;&#xD5D8;. &#xC6B0;&#xB9AC;&#xB294; LRP130 &#xAC08;&#xC0C9; &#xC9C0;&#xBC29;&#xC774; &#xD770;&#xC0C9;, &#xBE44;&#xAD50; &#xBC0F; &#xCC28;&#xBCC4;&#xD654; &#xC911; PGC 1 &#xC758;&#xC874; &#xBC29;&#xC2DD;&#xC5D0;&#xC11C; &#xC720;&#xB3C4; &#xB18D;&#xCD95; &#xC6B0;&#xC120;&#xC801;&#xC73C;&#xB85C; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;. &#xADF8;&#xB300;&#xB85C; PGC 1 coactivator &#xC2DD;&#xC5D0;&#xB3C4; &#xBD88;&#xAD6C; &#xD558; &#xACE0; lrp130&#xC5D0; &#xB300; &#xD55C; &#xBD88;&#xCDA9;&#xBD84; &#xD55C; &#xAC08;&#xC0C9; &#xC9C0;&#xBC29; &#xC138;&#xD3EC; &#xC5F0;&#xACB0;&#xC744; &#xD478;&#xB294; &#xB2E8;&#xBC31;&#xC9C8; 1&#xC744; &#xD3EC;&#xD568; &#xD558; &#xC5EC; &#xAC08;&#xC0C9; &#xC9C0;&#xBC29;&#xC758; &#xC5EC;&#xB7EC; &#xC720;&#xC804;&#xC790; &#xD2B9;&#xC131;&#xC758; &#xAC10;&#xC1E0; &#xC2DD; &#xC804;&#xC2DC;. &#xC0B0;&#xC18C; &#xC18C;&#xBE44; &#xC5F0;&#xAD6C; &#xC591;&#xC131;&#xC790; &#xB204;&#xCD9C; &#xAC10;&#xC1E0; &#xC5F0;&#xACB0;&#xC744; &#xD478;&#xB294; &#xB2E8;&#xBC31;&#xC9C8; 1 &#xC2DD; &#xB54C;&#xBB38;&#xC5D0; &#xD2B9;&#xC815; &#xACB0;&#xD568;&#xC744; &#xC9C0;&#xC6D0;&#xD569;&#xB2C8;&#xB2E4;. &#xD2B9;&#xD788;, &#xAC08;&#xC0C9; &#xC9C0;&#xBC29; &#xC138;&#xD3EC; &#xAC1C;&#xBC1C; &#xC77C;&#xBC18;&#xC801;&#xC778; &#xB450; PGC-1 coactivators lrp130&#xC5D0; &#xC758;&#xD574; &#xADDC;&#xC728; &#xB429;&#xB2C8;&#xB2E4;. &#xBC18;&#xB300;&#xB85C;, PGC 1alpha&#xC5D0; &#xC758;&#xD574; &#xC81C;&#xC5B4; &#xCEA0;&#xD504; &#xC751;&#xB2F5; &#xD558;&#xC9C0; lrp130&#xC5D0; &#xC758;&#xD574; &#xADDC;&#xC81C; &#xB429;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xB370;&#xC774;&#xD130;&#xB294; &#xAC08;&#xC0C9; &#xC9C0;&#xBC29; &#xC138;&#xD3EC; &#xAC1C;&#xBC1C; &#xBC0F; &#xCC28;&#xBCC4;&#xD654; LRP130 &#xC5F0;&#xB8E8;.

LRP130 &#xD1B5;&#xD574; &#xAC08;&#xC0C9; &#xC9C0;&#xBC29;&#xC774; &#xCC28;&#xBCC4;&#xD654;&#xC5D0;&#xC11C; PGC 1 coactivator &#xACBD;&#xB85C;&#xC758; &#xBCC0;&#xC870;.

La activaci&oacute;n de PGC-1 es importantes reguladores del metabolismo oxidativo. Hemos demostrado previamente que LRP130 es un socio de la Uni&oacute;n de PGC-1 alfa, necesarios para la gluconeog&eacute;nesis hep&aacute;tica. LRP130 es el gen mutado en la variante francocanadiense del s&iacute;ndrome de Leigh, una enfermedad neurodegenerativa rara. La importancia de LRP130 en otro, no hepatocito biolog&iacute;a sigue siendo obscura. Para comprender mejor la funci&oacute;n de coactivator PGC-1 en el desarrollo de la grasa parda, exploramos la funci&oacute;n metab&oacute;lica de LRP130 en la diferenciaci&oacute;n del adipocito marr&oacute;n. Mostramos que LRP130 preferencial se enriquece en la grasa marr&oacute;n con blanco e inducida en una forma dependiente de PGC-1 durante la diferenciaci&oacute;n. A pesar de la expresi&oacute;n de coactivator PGC-1 intacto, las c&eacute;lulas de grasa marr&oacute;n deficientes para LRP130 exhiben expresi&oacute;n atenuada de varias caracter&iacute;sticas de genes de grasa parda, incluyendo prote&iacute;na desacoplar 1. Estudios de consumo de ox&iacute;geno apoyan un defecto espec&iacute;fico en fuga de protones debido a la expresi&oacute;n de la prote&iacute;na 1 desacoplar atenuada. En particular, com&uacute;n a ambos PGC-1 activaci&oacute;n del desarrollo de la c&eacute;lula de la grasa marr&oacute;n se rige por LRP130. Por el contrario, la respuesta de campo controlada por PGC-1 alfa no est&aacute; regulada por LRP130. Estos datos implican LRP130 en la diferenciaci&oacute;n y el desarrollo de la c&eacute;lula de grasa parda.

Modulaci&oacute;n de las v&iacute;as de coactivator PGC-1 grasa parda en la diferenciaci&oacute;n a trav&eacute;s de LRP130.

The peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 family of transcriptional coactivators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1alpha show that this coactivator is important for activating the programs of gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, and lipid secretion during times of nutrient deprivation. However, how moderate changes in PGC-1alpha activity affect metabolism and energy homeostasis has yet to be determined.

Sensitivity of lipid metabolism and insulin signaling to genetic alterations in hepatic peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression.

Mechanisms underlying synergistic liver injury caused by alcohol and obesity are not clear. We have produced a mouse model of synergistic steatohepatitis by recapitulating the natural history of the synergism seen in patients for mechanistic studies.

Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK.

Epigenetic control of angiogenesis via DNA methylation.

Impaired oxidative phosphorylation (OXPHOS) is implicated in several metabolic disorders. Even though mitochondrial DNA encodes several subunits critical for OXPHOS, the metabolic consequence of activating mitochondrial transcription remains unclear. We show here that LRP130, a protein involved in Leigh syndrome, increases hepatic β-fatty acid oxidation. Using convergent genetic and biochemical approaches, we demonstrate LRP130 complexes with the mitochondrial RNA polymerase to activate mitochondrial transcription. Activation of mitochondrial transcription is associated with increased OXPHOS activity, increased supercomplexes, and denser cristae, independent of mitochondrial biogenesis. Consistent with increased oxidative phosphorylation, ATP levels are increased in both cells and mouse liver, whereas coupled respiration is increased in cells. We propose activation of mitochondrial transcription remodels mitochondria and enhances oxidative metabolism.

LRP130 protein remodels mitochondria and stimulates fatty acid oxidation.

TRPM2 Ca(2+)-permeable cation channel is widely expressed and activated by markers of cellular stress. Since inflammation and stress play a major role in insulin resistance, we examined the role of TRPM2 Ca(2+) channel in glucose metabolism. A 2-h hyperinsulinemic euglycemic clamp was performed in TRPM2-deficient (KO) and wild-type mice to assess insulin sensitivity. To examine the effects of diet-induced obesity, mice were fed a high-fat diet for 4-10 mo, and metabolic cage and clamp studies were conducted in conscious mice. TRPM2-KO mice were more insulin sensitive partly because of increased glucose metabolism in peripheral organs. After 4 mo of high-fat feeding, TRPM2-KO mice were resistant to diet-induced obesity, and this was associated with increased energy expenditure and elevated expressions of PGC-1α, PGC-1β, PPARα, ERRα, TFAM, and MCAD in white adipose tissue. Hyperinsulinemic euglycemic clamps showed that TRPM2-KO mice were more insulin sensitive, with increased Akt and GSK-3β phosphorylation in heart. Obesity-mediated inflammation in adipose tissue and liver was attenuated in TRPM2-KO mice. Overall, TRPM2 deletion protected mice from developing diet-induced obesity and insulin resistance. Our findings identify a novel role of TRPM2 Ca(2+) channel in the regulation of energy expenditure, inflammation, and insulin resistance.

TRPM2 Ca2+ channel regulates energy balance and glucose metabolism.

Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes.

The histone demethylase Jhdm1a regulates hepatic gluconeogenesis.

Interplay of mitochondrial biogenesis and oxidative stress in heart failure.

Mitochondria, although required for cellular ATP production, are also known to have other important functions that may include modulating cellular responses to environmental stimuli. However, the mechanisms whereby mitochondria impact cellular phenotype are not yet clear.

Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics.

Obesity places major demands on the protein folding capacity of the endoplasmic reticulum (ER), resulting in ER stress, a condition that promotes hepatic insulin resistance and steatosis. Here we identify the transcription factor, Kruppel-like factor 15 (KLF15), as an essential mediator of ER stress-induced insulin resistance in the liver. Mice with a targeted deletion of KLF15 exhibit increased hepatic ER stress, inflammation, and JNK activation compared to WT mice; however, KLF15 (-/-) mice are protected against hepatic insulin resistance and fatty liver under high-fat feeding conditions and in response to pharmacological induction of ER stress. The mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cellular energy homeostasis, has been shown to cooperate with ER stress signaling pathways to promote hepatic insulin resistance and lipid accumulation. We find that the uncoupling of ER stress and insulin resistance in KLF15 (-/-) liver is associated with the maintenance of a low energy state characterized by decreased mTORC1 activity, increased AMPK phosphorylation and PGC-1α expression and activation of autophagy, an intracellular degradation process that enhances hepatic insulin sensitivity. Furthermore, in primary hepatocytes, KLF15 deficiency markedly inhibits activation of mTORC1 by amino acids and insulin, suggesting a mechanism by which KLF15 controls mTORC1-mediated insulin resistance. This study establishes KLF15 as an important molecular link between ER stress and insulin action.

KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistance.

Sirtuin 3 (SIRT3), an important regulator of energy metabolism and lipid oxidation, is induced in fasted liver mitochondria and implicated in metabolic syndrome. In fasted liver, SIRT3-mediated increases in substrate flux depend on oxidative phosphorylation (OXPHOS), but precisely how OXPHOS meets the challenge of increased substrate oxidation in fasted liver remains unclear. Here, we show that liver mitochondria in fasting mice adapt to the demand of increased substrate oxidation by increasing their OXPHOS efficiency. In response to cAMP signaling, SIRT3 deacetylated and activated leucine-rich protein 130 (LRP130; official symbol, LRPPRC), promoting a mitochondrial transcriptional program that enhanced hepatic OXPHOS. Using mass spectrometry, we identified SIRT3-regulated lysine residues in LRP130 that generated a lysine-to-arginine (KR) mutant of LRP130 that mimics deacetylated protein. Compared with wild-type LRP130 protein, expression of the KR mutant increased mitochondrial transcription and OXPHOS in vitro. Indeed, even when SIRT3 activity was abolished, activation of mitochondrial transcription and OXPHOS by the KR mutant remained robust, further highlighting the contribution of LRP130 deacetylation to increased OXPHOS in fasted liver. These data establish a link between nutrient sensing and mitochondrial transcription that regulates OXPHOS in fasted liver and may explain how fasted liver adapts to increased substrate oxidation.

Nutrient sensing by the mitochondrial transcription machinery dictates oxidative phosphorylation.

OXPHOS is believed to play an important role in non-alcoholic fatty liver disease (NAFLD), however, precise mechanisms whereby OXPHOS influences lipid homeostasis are incompletely understood. We previously reported that ectopic expression of LRPPRC, a protein that increases cristae density and OXPHOS, promoted fatty acid oxidation in cultured primary hepatocytes. To determine the biological significance of that observation and define underlying mechanisms, we have ectopically expressed LRPPRC in mouse liver in the setting of NAFLD. Interestingly, ectopic expression of LRPPRC in mouse liver completely interdicted NAFLD, including inflammation. Consistent with mitigation of NAFLD, two markers of hepatic insulin resistance--ROS and PKCε activity--were both modestly reduced. As reported by others, improvement of NAFLD was associated with improved whole-body insulin sensitivity. Regarding hepatic lipid homeostasis, the ratio of NAD+ to NADH was dramatically increased in mouse liver replete with LRPPRC. Pharmacological activators and inhibitors of the cellular respiration respectively increased and decreased the [NAD+]/[NADH] ratio, indicating respiration-mediated control of the [NAD+]/[NADH] ratio. Supporting a prominent role for NAD+, increasing the concentration of NAD+ stimulated complete oxidation of fatty acids. Importantly, NAD+ rescued impaired fatty acid oxidation in hepatocytes deficient for either OXPHOS or SIRT3. These data are consistent with a model whereby augmented hepatic OXPHOS increases NAD+, which in turn promotes complete oxidation of fatty acids and protects against NAFLD.

OXPHOS-Mediated Induction of NAD+ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease.

In murine and human brown adipose tissue (BAT), mitochondria are powerful generators of heat that safely metabolize fat, a feature that has great promise in the fight against obesity and diabetes. Recent studies suggest that the actions of mitochondria extend beyond their conventional role as generators of heat. There is mounting evidence that impaired mitochondrial respiratory capacity is accompanied by attenuated expression of Ucp1 and other BAT-selective genes, implying that mitochondria exert transcriptional control over the brown fat gene program. In this review, we discuss the current understanding of brown fat mitochondria, their potential role in transcriptional control of the brown fat gene program, and potential strategies to treat obesity in humans by leveraging thermogenesis in brown adipocytes.

Marcus P. Cooper

Division of Cardiovascular Medicine,
Department of Medicine,
Division of Cardiovascular Medicine, Department of Medicine

University of Massachusetts Medical School

Determination of Fatty Acid Oxidation and Lipogenesis in Mouse Primary Hepatocytes

Marcus P. Cooper

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Division of Cardiovascular Medicine,Department of Medicine,Division of Cardiovascular Medicine, Department of Medicine

University of Massachusetts Medical School

Determination of Fatty Acid Oxidation and Lipogenesis in Mouse Primary Hepatocytes

Division of Cardiovascular Medicine,
Department of Medicine,
Division of Cardiovascular Medicine, Department of Medicine