Sphingomyelin Synthase 2 Activity and Liver Steatosis

Abstract

Objective Sphingomyelin Sphingolipid de novo biosynthesis is related with nonalcoholic fatty liver disease (NAFLD) or hepatic steatosis. However, the mechanism is still unclear. Sphingomyelin synthase (SMS), utilizing ceramide as one of the substrates to produce sphingomyelin, sits at the crossroads of sphingolipid biosynthesis. SMS has two isoforms: SMS1 and SMS2. SMS2 is the major isoform in the liver. Approach and Results To investigate the relationship between liver SMS2 activity-mediated sphingolipid changes and hepatic steatosis, we utilized two mouse models, SMS2 liver-specific transgenic (LTg) and SMS2 knockout (KO) mice. We found that SMS2LTg livers have lower ceramide and higher sphingomyelin, while SMS2 KO livers have higher ceramide and lower sphingomyelin. We also found that liver SMS2 overexpression promoted fatty acid uptaking and liver steatosis, while SMS2 deficiency had an opposite effect, in comparison with their respective controls. Importantly, the exogenous ceramide supplementation to Huh7 cells, a human hepatoma cell line, reduced the expression of PPAR γ2 and its target genes, CD36 and FSP27. PPAR γ reporter analysis confirmed this phenomenon. Moreover, PPARγ antagonist treatment significantly decreased triglyceride accumulation in SMS2LTg liver. Conclusions We attributed these effects to ceramide which can suppress of PPARγ2, thus reducing expression of CD36 and FSP27, and reducing liver steatosis. After all, SMS2 inhibition in the liver could diminish liver steatosis.

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…A regulatory interaction of GSLs with insulin signaling has been demonstrated (4,5,31). The insulin receptor is localized at the cell surface in a GSL-containing lipid microdomain (32,93,97). Cer, GC, ganglioside GM3, and other SLs are related to insulin resistance, pancreatic ␤-cell failure, and vascular dysfunction (33,75,79).…”

“…The cellular alterations in GD produce a proinflammatory milieu mediated by proresorptive cytokines, such as TNF-␣, leading to bone destruction through enhancement of monocyte differentiation to osteoclasts and osteoclast resorption activity (97,124,128). GC modulates endolysosomal pH in lymphocytes, suggesting that this mechanism is disrupted in GD (84,158,162).…”

“…Cer-mediated suppression of peroxisome proliferatoractivated receptor (PPAR) ␥2 reduces the expression of CD36 and Fsp27, and also reduces liver steatosis (97,151,101). SMS2 inhibition in the liver could diminish liver steatosis (97,151,101).…”

“…Cer-mediated suppression of peroxisome proliferatoractivated receptor (PPAR) ␥2 reduces the expression of CD36 and Fsp27, and also reduces liver steatosis (97,151,101). SMS2 inhibition in the liver could diminish liver steatosis (97,151,101). In a hyperinsulinemic-euglycemic clamp clinical trial in obese adults, a negative correlation was shown between insulin-mediated suppression of hepatic glucose production and intrahepatic diacylglycerol; however, it didn't occur with intrahepatic Cer or acylcarnitine (102,152,106).…”

“…Pharmacological inhibition of GSL synthesis improves insulin sensitivity in rodents with insulin resistance (32,93,97). Meanwhile partial GSL reduction is a therapeutic venue for obesity-induced insulin resistance and Type 2 diabetes.…”