Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice

B. Yenilmez, M. Kelly, GF. Zhang, N. Wetoska, OR. Ilkayeva, K. Min, L. Rowland, C. DiMarzio, W. He, N. Raymond, L. Lifshitz, M. Pan, X. Han, J. Xie, RH. Friedline, JK. Kim, G. Gao, MA. Herman, CB. Newgard, MP. Czech

. 2022 ; 298 (10) : 102401. [pub] 20220818

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, N.I.H., Extramural

Perzistentní odkaz   https://www.medvik.cz/link/bmc22033179

Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high-fat feeding are unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to the generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D2O incorporation into palmitate, whereas in contrast, ACSS2 depletion had no effect. The increase in liver DNL upon ACLY depletion was associated with increased expression of nuclear sterol regulatory element-binding protein 1c and of its target DNL enzymes. This upregulated DNL enzyme expression explains the increased rate of palmitate synthesis in ACLY-depleted livers. Furthermore, this increased flux through DNL may also contribute to the observed depletion of AcCoA levels because of its increased conversion to malonyl CoA and palmitate. Together, these data indicate that in fat diet-fed obese mice, hepatic DNL is not limited by its immediate substrates AcCoA or malonyl CoA but rather by activities of DNL enzymes.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22033179
003      
CZ-PrNML
005      
20230131150639.0
007      
ta
008      
230120s2022 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.jbc.2022.102401 $2 doi
035    __
$a (PubMed)35988648
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Yenilmez, Batuhan $u Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
245    10
$a Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice / $c B. Yenilmez, M. Kelly, GF. Zhang, N. Wetoska, OR. Ilkayeva, K. Min, L. Rowland, C. DiMarzio, W. He, N. Raymond, L. Lifshitz, M. Pan, X. Han, J. Xie, RH. Friedline, JK. Kim, G. Gao, MA. Herman, CB. Newgard, MP. Czech
520    9_
$a Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high-fat feeding are unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to the generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D2O incorporation into palmitate, whereas in contrast, ACSS2 depletion had no effect. The increase in liver DNL upon ACLY depletion was associated with increased expression of nuclear sterol regulatory element-binding protein 1c and of its target DNL enzymes. This upregulated DNL enzyme expression explains the increased rate of palmitate synthesis in ACLY-depleted livers. Furthermore, this increased flux through DNL may also contribute to the observed depletion of AcCoA levels because of its increased conversion to malonyl CoA and palmitate. Together, these data indicate that in fat diet-fed obese mice, hepatic DNL is not limited by its immediate substrates AcCoA or malonyl CoA but rather by activities of DNL enzymes.
650    _2
$a zvířata $7 D000818
650    _2
$a myši $7 D051379
650    _2
$a acetylkoenzym A $x metabolismus $7 D000105
650    _2
$a adenosintrifosfát $x metabolismus $7 D000255
650    _2
$a ATP-citrát-(pro-S)-lyasa $x genetika $x metabolismus $7 D001275
650    12
$a diabetes mellitus 2. typu $x metabolismus $7 D003924
650    _2
$a hepatocyty $x metabolismus $7 D022781
650    12
$a lipogeneze $7 D050155
650    12
$a játra $x metabolismus $7 D008099
650    _2
$a malonylkoenzym A $x metabolismus $7 D008316
650    _2
$a myši obézní $7 D008820
650    _2
$a palmitany $x metabolismus $7 D010168
650    12
$a protein SREBP1 $x genetika $x metabolismus $7 D051780
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
655    _2
$a Research Support, N.I.H., Extramural $7 D052061
700    1_
$a Kelly, Mark $u Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
700    1_
$a Zhang, Guo-Fang $u Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA; Department of Pharmacology and Cancer Biology, and Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, North Carolina, USA
700    1_
$a Wetoska, Nicole $u Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
700    1_
$a Ilkayeva, Olga R $u Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA; Department of Pharmacology and Cancer Biology, and Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, North Carolina, USA
700    1_
$a Min, Kyounghee $u Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
700    1_
$a Rowland, Leslie $u Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
700    1_
$a DiMarzio, Chloe $u Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
700    1_
$a He, Wentao $u Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA; Department of Pharmacology and Cancer Biology, and Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, North Carolina, USA
700    1_
$a Raymond, Naideline $u Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
700    1_
$a Lifshitz, Lawrence $u Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
700    1_
$a Pan, Meixia $u Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
700    1_
$a Han, Xianlin $u Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
700    1_
$a Xie, Jun $u Viral Vector Core, University of Massachusetts Medical School, Worcester, Massachusetts, USA
700    1_
$a Friedline, Randall H $u Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
700    1_
$a Kim, Jason K $u Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
700    1_
$a Gao, Guangping $u Viral Vector Core, University of Massachusetts Medical School, Worcester, Massachusetts, USA
700    1_
$a Herman, Mark A $u Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA; Department of Pharmacology and Cancer Biology, and Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, North Carolina, USA
700    1_
$a Newgard, Christopher B $u Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA; Department of Pharmacology and Cancer Biology, and Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, North Carolina, USA. Electronic address: Chris.Newgard@duke.edu
700    1_
$a Czech, Michael P $u Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA. Electronic address: Michael.Czech@umassmed.edu
773    0_
$w MED00002546 $t The Journal of biological chemistry $x 1083-351X $g Roč. 298, č. 10 (2022), s. 102401
856    41
$u https://pubmed.ncbi.nlm.nih.gov/35988648 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20230120 $b ABA008
991    __
$a 20230131150633 $b ABA008
999    __
$a ok $b bmc $g 1891757 $s 1184514
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2022 $b 298 $c 10 $d 102401 $e 20220818 $i 1083-351X $m The Journal of biological chemistry $n J Biol Chem $x MED00002546
LZP    __
$a Pubmed-20230120

Najít záznam

Citační ukazatele

Možnosti archivace