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

Abstract

ObjectiveAlterations 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.MethodsSmpd1−/− 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.ResultsAlthough 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.ConclusionThese 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.

Sphingolipids in metabolic disease: The good, the bad, and the unknown

“…However, a relic of this mindset is that catabolic pathways of sphingolipid metabolism have been largely unexplored. Although deficiency of acid sphingomyelinase that generates ceramide from sphingomyelin hydrolysis protects mice against adipocyte hypertrophy and diet-induced steatosis (Sydor et al, 2017), the mechanism of the protection has not been elucidated. Furthermore, while the major human neutral sphingomyelinase, SMPD3, was shown to be elevated in inflamed versus healthy adipose tissue in obese women (Kolak et al, 2012), the link to metabolic disease is still unclear.…”

Adipose Morphology: a Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction

“…In addition, Acid sphingomyelinase (Asm), a member of phospholipids, plays a critical role in regulating membrane composition via transformation of membrane lipid sphingomyelin to ceramide. Knockout of Asm mice displayed the absence of adipocyte hypertrophy and increased expression of genes related to brown adipocyte differentiation [165]. In the field of free fatty acid, when C57BL/6J mice were fed with high-fat (HF) diet supplemented with eicosapentaenoic acid (EPA) (45% of energy from fat; 36 g/kg EPA; HF + EPA) for 11 weeks, their body weight, total fat mass, and adipocyte size were remarkably reduced [166].…”

Ceramide and sphingosine 1-phosphate in adipose dysfunction

“…These effects are recapitulated by the aSMase inhibitor, amitriptyline, which reduces plasma ceramide and attenuates adiposity, insulin resistance and glomerular injury in HFD C57BL/6J mice [140]. Finally, the genetic loss of Smpd1 prevents adipocyte hypertrophy and promotes brown adipose tissue differentiation via a mechanism involving alterations in gene expression of adipocytes in Western diet-fed mice [141]. The improvement in adipose tissue function contributes to diminished liver steatosis [141].…”

“…Finally, the genetic loss of Smpd1 prevents adipocyte hypertrophy and promotes brown adipose tissue differentiation via a mechanism involving alterations in gene expression of adipocytes in Western diet-fed mice [141]. The improvement in adipose tissue function contributes to diminished liver steatosis [141].…”