1. Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice
- Author
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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, and Michael P. Czech
- Subjects
Lipogenesis ,Palmitates ,Mice, Obese ,Cell Biology ,Biochemistry ,Malonyl Coenzyme A ,Mice ,Adenosine Triphosphate ,Diabetes Mellitus, Type 2 ,Liver ,Acetyl Coenzyme A ,ATP Citrate (pro-S)-Lyase ,Hepatocytes ,Animals ,Sterol Regulatory Element Binding Protein 1 ,Molecular Biology - 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 D
- Published
- 2022