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

Batuhan Yenilmez, Mark Kelly, Guo Fang Zhang, Nicole Wetoska, Olga R. Ilkayeva, Kyounghee Min, Leslie Rowland, Chloe DiMarzio, Wentao He, Naideline Raymond, Lawrence Lifshitz, Meixia Pan, Xianlin Han, Jun Xie, Randall H. Friedline, Jason K. Kim, Guangping Gao, Mark A. Herman, Christopher B. Newgard, Michael P. Czech

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number102401
JournalJournal of Biological Chemistry
Volume298
Issue number10
DOIs
StatePublished - Oct 2022

Keywords

  • ACLY
  • de novo lipogenesis
  • lipid metabolism
  • liver metabolism
  • metabolomics
  • NAFLD

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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