Elsevier

Molecular Metabolism

Volume 6, Issue 5, May 2017, Pages 416-427
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2017.03.002Get rights and content
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open access

Highlights

  • Smpd1 knockout protects from dietary induced liver steaosis and abrogates hypertrophy of visceral adipocytes in mice.

  • Expression of genes related to browning is absent in human adipose tissue from obese individuals.

  • Protection from dietary-induced liver steatosis is associated with reduced Rictor/mTORC2 activity in Smpd1 knockout mice.

Abstract

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

Cited by (0)

7

Drs. Sydor and Sowa are equally contributing first authors.