Targeted Induction of Ceramide Degradation Leads to Improved Systemic Metabolism and Reduced Hepatic Steatosis

Jonathan Y. Xia, William L. Holland, Christine M. Kusminski, Kai Sun, Ankit X. Sharma, Mackenzie J. Pearson, Angelica J. Sifuentes, Jeffrey G. McDonald, Ruth Gordillo, Philipp E. Scherer

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

Sphingolipids have garnered attention for their role in insulin resistance and lipotoxic cell death. We have developed transgenic mice inducibly expressing acid ceramidase that display a reduction in ceramides in adult mouse tissues. Hepatic overexpression of acid ceramidase prevents hepatic steatosis and prompts improvements in insulin action in liver and adipose tissue upon exposure to high-fat diet. Conversely, overexpression of acid ceramidase within adipose tissue also prevents hepatic steatosis and systemic insulin resistance. Induction of ceramidase activity in either tissue promotes a lowering of hepatic ceramides and reduced activation of the ceramide-activated protein kinase C isoform PKCζ, though the induction of ceramidase activity in the adipocyte prompts more rapid resolution of hepatic steatosis than overexpression of the enzyme directly in the liver. Collectively, our observations suggest the existence of a rapidly acting "cross-talk" between liver and adipose tissue sphingolipids, critically regulating glucose metabolism and hepatic lipid uptake.

Original languageEnglish (US)
Pages (from-to)266-278
Number of pages13
JournalCell Metabolism
Volume22
Issue number2
DOIs
StatePublished - Aug 4 2015

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

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