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

Abstract

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 beta (IR beta). 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 IR beta in hepatocytes. Diabetes: Linking a lipid to insulin resistance A lipid molecule called ceramide is key to regulating the body's insulin response, which controls blood sugar, and thus may hold keys to new treatments for metabolic diseases such as diabetes. Although ceramide levels were known to be raised in obesity and diabetes, the mechanism remained unclear. Tae-Sik Park at Gachon University, Sungnam, South Korea, and Sang-Ho Kwon at Augusta University, USA, and co-workers investigated how excess ceramide production is triggered and the blood sugar regulation consequences. They found that the liver-specific SPTLC2 transgenic mice fed a high-fat diet had increased levels of an enzyme activity of serine palmitoyltransferase which led to synthesis of high levels of ceramide in the liver. The high ceramide levels suppressed insulin signaling, imbalancing blood sugar levels and causing liver toxicity. Therapies that inhibit ceramide synthesis show promise for treatment of metabolic diseases.