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

Abstract

Sphingolipids have garnered attention for their role in insulin resistance and lipotoxic cell death. Aberrant accumulation of ceramides correlates with hepatic insulin resistance and steatosis. To further investigate the tissue-specific effects of local changes in ceramidase activity, we have developed transgenic mice inducibly expressing acid ceramidase, to trigger the deacylation of ceramides. This represents the first inducible genetic model that acutely manipulates ceramides in adult mouse tissues. Hepatic overexpression of acid ceramidase prevents hepatic steatosis and prompts improvements in insulin action in liver and adipose tissue. Conversely, overexpression of acid ceramidase within adipose tissue prevents hepatic steatosis and 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 PKC-zeta. These observations suggest the existence of a rapidly acting "crosstalk" between liver and adipose tissue sphingolipids, critically regulating glucose metabolism and hepatic lipid uptake.

Ceramide Synthase 5 Is Essential to Maintain C16:0-Ceramide Pools and Contributes to the Development of Diet-induced Obesity

“…Also ceramide-activated protein kinases or phosphatases could directly influence insulin signaling (52). Lowering ceramide levels, especially C 16:0 -and C 18:0 -ceramide, in liver and WAT by increasing ceramide degradation leads to improved insulin signaling and reduced steatosis after HFD feeding (39). We also found decreased autophagy after HFD feeding in eWAT of CerS5 KO mice.…”

“…Real time PCR primer sequences are shown in Table 1. Primers to assess lipid uptake were taken from Xia et al (39).…”

Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54–96 years from the Baltimore Longitudinal Study of Aging

“…Furthermore, in a previous study, the levels of C18:0, C20:0, C24:1, and total ceramides were found to be elevated in type 2 diabetic subjects compared to controls and were inversely correlated with insulin sensitivity, concluding that these species may contribute to insulin resistance through the activation of inflammatory mediators, such as TNF‐alpha (Haus et al, 2009). In addition, C16:0 and C18:0 ceramides have been mechanistically linked to systemic metabolic health in genetic models (Xia et al ., 2015) and with insulin resistance in the muscle in obesity (Coen et al ., 2010). A challenge in interpreting human profiling studies is that ceramides are biosynthetic intermediates that do not exist at a steady‐state concentration.…”

Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars

“…These percentages were twofold higher than in the CARB group (24% [20][21][22][23][24][25][26]) (Supplementary Table 1). Saturated fat intake was twofold higher in the SAT group (33% [28][29][30][31][32][33][34][35][36]) than in the UNSAT group (14% [14][15][16][17][18], P , 0.001). Monounsaturated (28% [23][24][25][26][27][28][29][30] UNSAT vs. 13% [12][13][14][15] SAT, P , 0.001) and polyunsaturated (11% [10][11][12][13][14] UNSAT vs. 5% [4][5] SAT, P , 0.001) fat intakes were twofold higher in the UNSAT than in the SAT group.…”

“…TGs themselves are inert and do not confer IR (7). Ceramides are key mediators of saturated fat-induced IR (8)(9)(10)(30)(31)(32)(33) in mice and are the most upregulated lipid species in inflamed adipose tissue in human NAFLD (34). SFAs and ceramides originating from de novo ceramide synthesis cosegregate with IR in human NAFLD (7).…”