Upregulation of the serine palmitoyltransferase subunit SPTLC2 by endoplasmic reticulum stress inhibits the hepatic insulin response

Goon Tae Kim, Shivani Devi, Amitesh Sharma, Kyung Hee Cho, Su Jung Kim, Bo Rahm Kim, Sang Ho Kwon, Tae Sik Park

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Endoplasmic reticulum (ER) stress is induced by various conditions, such as inflammation and the presence of excess nutrients. Abnormal accumulation of unfolded proteins leads to the activation of a collective signaling cascade, termed the unfolded protein response (UPR). ER stress is reported to perturb hepatic insulin response metabolism while promoting insulin resistance. Here, we report that ER stress regulates the de novo biosynthesis of sphingolipids via the activation of serine palmitoyltransferase (SPT), a rate-limiting enzyme involved in the de novo biosynthesis of ceramides. We found that the expression levels of Sptlc1 and Sptlc2, the major SPT subunits, were upregulated and that the cellular concentrations of ceramide and dihydroceramide were elevated by acute ER stress inducers in primary hepatocytes and HepG2 cells. Sptlc2 was upregulated and ceramide levels were elevated by tunicamycin in the livers of C57BL/6J wild-type mice. Analysis of the Sptlc2 promoter demonstrated that the transcriptional activation of Sptlc2 was mediated by the spliced form of X-box binding protein 1 (sXBP1). Liver-specific Sptlc2 transgenic mice exhibited increased ceramide levels in the liver and elevated fasting glucose levels. The insulin response was reduced by the inhibition of the phosphorylation of insulin receptor β (IRβ). Collectively, these results demonstrate that ER stress induces activation of the de novo biosynthesis of ceramide and contributes to the progression of hepatic insulin resistance via the reduced phosphorylation of IRβ in hepatocytes.

Original languageEnglish (US)
Pages (from-to)573-584
Number of pages12
JournalExperimental and Molecular Medicine
Issue number5
StatePublished - May 2022


  • Animals
  • Ceramides/metabolism
  • Endoplasmic Reticulum Stress
  • Insulin Resistance
  • Insulin/metabolism
  • Liver/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Serine C-Palmitoyltransferase/genetics
  • Transcriptional Activation
  • Up-Regulation


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