Acid sphingomyelinase deficiency in Western diet-fed mice protects against adipocyte hypertrophy and diet-induced liver steatosis

Mol Metab. 2017 Mar 12;6(5):416-427. doi: 10.1016/j.molmet.2017.03.002. eCollection 2017 May.


Objective: Alterations in sphingolipid and ceramide metabolism have been associated with various diseases, including nonalcoholic fatty liver disease (NAFLD). Acid sphingomyelinase (ASM) converts the membrane lipid sphingomyelin to ceramide, thereby affecting membrane composition and domain formation. We investigated the ways in which the Asm knockout (Smpd1-/-) genotype affects diet-induced NAFLD.

Methods: Smpd1-/- mice and wild type controls were fed either a standard or Western diet (WD) for 6 weeks. Liver and adipose tissue morphology and mRNA expression were assessed. Quantitative proteome analysis of liver tissue was performed. Expression of selected genes was quantified in adipose and liver tissue of obese NAFLD patients.

Results: Although Smpd1-/- mice exhibited basal steatosis with normal chow, no aggravation of NAFLD-type injury was observed with a Western diet. This protective effect was associated with the absence of adipocyte hypertrophy and the increased expression of genes associated with brown adipocyte differentiation. In white adipose tissue from obese patients with NAFLD, no expression of these genes was detectable. To further elucidate which pathways in liver tissue may be affected by Smpd1-/-, we performed an unbiased proteome analysis. Protein expression in WD-fed Smpd1-/- mice indicated a reduction in Rictor (mTORC2) activity; this reduction was confirmed by diminished Akt phosphorylation and altered mRNA expression of Rictor target genes.

Conclusion: These findings indicate that the protective effect of Asm deficiency on diet-induced steatosis is conferred by alterations in adipocyte morphology and lipid metabolism and by reductions in Rictor activation.

Keywords: Ceramide; NAFLD; Rictor; Western diet.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipocytes / pathology*
  • Animals
  • Diet, Western / adverse effects
  • Mechanistic Target of Rapamycin Complex 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sphingomyelin Phosphodiesterase / deficiency
  • Sphingomyelin Phosphodiesterase / genetics*
  • Sphingomyelin Phosphodiesterase / metabolism


  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • ASMase, mouse
  • Sphingomyelin Phosphodiesterase