Hepatic Expression of the Serine Palmitoyltransferase Subunit Sptlc2 Reduces Lipid Droplets in the Liver by Activating VLDL Secretion

Abstract

Objective: Ceramide is a signaling molecule that contributes to insulin resistance and hepatosteatosis. In the present study, we activated de novo ceramide synthesis by inducing the hepatic expression of Sptlc2 to investigate the role of ceramide in glucose and lipid metabolism. Methods: We first constructed an adenovirus containing Sptlc2 (AdSptlc2), which encodes a major catalytic subunit of serine palmitoyltransferase (SPT). We then infected hepatocytes and mice fed a regular diet with AdSptlc2 to activate de novo ceramide biosynthesis. The liverspecific effects of ceramide biosynthesis on glucose and lipid metabolism were investigated by measuring changes in insulin signaling, lipid droplet formation, and very low-density lipoprotein (VLDL) secretion. Results: In HepG2 hepatocytes, adenoviral Sptlc2 expression inhibited insulin signaling and increased ceramide levels via activation of c-Jun N-terminal kinase and serine phosphorylation of insulin receptor substrate 1. In contrast, in mice, AdSptlc2 infection decreased plasma glucose levels by downregulating gluconeogenic genes and increased plasma triglyceride levels by increasing VLDL secretion. In mice infected with AdSptlc2, glucose intolerance and insulin sensitivity improved, while pyruvate utilization via gluconeogenesis decreased. Conclusion: Hepatic ceramide was found to modulate hepatosteatosis and the insulin response via increased VLDL secretion and inhibition of gluconeogenesis in vivo. Although inhibition of the insulin response was observed in vitro, the compensatory mechanism of relieving ceramide-induced stress and reducing ceramide levels resulted in improvements of glucose and lipid metabolic profiles in vivo. This discrepancy between in vitro and in vivo regulation mechanisms suggests that ceramide plays a role in non-alcoholic fatty liver disease and insulin resistance.

Novel Insight into the Serum Sphingolipid Fingerprint Characterizing Longevity

“…It has been demonstrated that the adenoviral expression of Sptlc2 increases ceramide levels in vitro, activating the stress-activated c-Jun N-terminal kinase (JNK) inhibiting insulin signal. However, the same paper indicated that SPTLC2 increased insulin sensitivity in vivo [ 53 ], suggesting that a subtle protective mechanism could be activated in C to maintain glucose homeostasis through the activation of SPTLC2 . Further investigations are ongoing to clarify this issue.…”

Intravital Two-photon Imaging of Dynamic Alteration of Hepatic Lipid Droplets in Fasted and Refed State

“…In the lipid research field, various pathways involved in lipid metabolism or lipidomic analysis in pre-pathological and pathological conditions such as obesity, metabolic syndrome, diabetes, and NAFLD have been actively studied. 5 24 25 26 The newly established intravital imaging methods of LDs in in vivo physiological and pathological microenvironments demonstrated in our study will provide a highly useful tool for future investigations to explore novel molecular and cellular mechanisms involving lipid in physiological and various pathological conditions or to assess novel treatment strategies to alleviate deposition of lipids in preclinical animal models.…”

Hypolipidemic Effects of Beetroot Juice in SHR-CRP and HHTg Rat Models of Metabolic Syndrome: Analysis of Hepatic Proteome

“…SPT catalyses the rate-limiting step in the de novo ceramide biosynthesis pathway. In mice with adenovirus-induced overexpression of the Sptlc2 gene in the liver, hepatic ceramide was found to modulate hepatosteatosis and the insulin response via increased VLDL secretion and inhibition of gluconeogenesis in vivo [ 35 ].…”