RT Journal Article SR Electronic T1 Paradoxical activation of SREBP1c and de novo lipogenesis by hepatocyte-selective ACLY depletion in obese mice JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.03.21.485183 DO 10.1101/2022.03.21.485183 A1 Batuhan Yenilmez A1 Mark Kelly A1 Guofang Zhang A1 Nicole Wetoska A1 Olga R. Ilkayeva A1 Kyounghee Min A1 Leslie Rowland A1 Chloe DiMarzio A1 Wentao He A1 Naideline Raymond A1 Lawrence Lifshitz A1 Meixia Pan A1 Xianlin Han A1 Jun Xie A1 Randall H. Friedline A1 Jason K. Kim A1 Guangping Gao A1 Mark A. Herman A1 Christopher B. Newgard A1 Michael P. Czech YR 2022 UL http://biorxiv.org/content/early/2022/03/21/2022.03.21.485183.abstract AB Hepatic steatosis associated with high fat diets, obesity and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl-coenzyme A (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 is 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 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, while 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 (SREBP1c) 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 due to its increased conversion to Malonyl CoA (MalCoA) and palmitate. Together, these data indicate that in HFD fed obese mice, hepatic DNL is not limited by its immediate substrates AcCoA or MalCoA, but rather by activities of DNL enzymes.Competing Interest StatementThe authors have declared no competing interest.