Dietary sphingomyelin lowers hepatic lipid levels and inhibits intestinal cholesterol absorption in high-fat-fed mice

Abstract

Controlling intestinal lipid absorption is an important strategy for maintaining lipid homeostasis. Accumulation of lipids in the liver is a major risk factor for metabolic syndrome and nonalcoholic fatty liver disease. It is well-known that sphingomyelin (SM) can inhibit intestinal cholesterol absorption. It is, however, unclear if dietary SM also lowers liver lipid levels. In the present study (i) the effect of pure dietary egg SM on hepatic lipid metabolism and intestinal cholesterol absorption was measured with [(14)C]cholesterol and [(3)H]sitostanol in male C57BL/6 mice fed a high-fat (HF) diet with or without 0.6% wt/wt SM for 18 days; and (ii) hepatic lipid levels and gene expression were determined in mice given a HF diet with or without egg SM (0.3, 0.6 or 1.2% wt/wt) for 4 weeks. Mice supplemented with SM (0.6% wt/wt) had significantly increased fecal lipid and cholesterol output and reduced hepatic [(14)C]cholesterol levels after 18 days. Relative to HF-fed mice, SM-supplemented HF-fed mice had significantly lower intestinal cholesterol absorption (-30%). Liver weight was significantly lower in the 1.2% wt/wt SM-supplemented mice (-18%). Total liver lipid (mg/organ) was significantly reduced in the SM-supplemented mice (-33% and -40% in 0.6% wt/wt and 1.2% wt/wt SM, respectively), as were triglyceride and cholesterol levels. The reduction in liver triglycerides was due to inactivation of the LXR-SREBP-1c pathway. In conclusion, dietary egg SM has pronounced hepatic lipid-lowering properties in mice maintained on an obesogenic diet.

Figure 1. Relationship between liver cholesterol and A) percentage of intestinal cholesterol absorbed; B) liver [¹⁴C]cholesterol and C) liver triglyceride levels in mice fed a high-fat diet or a high-fat diet supplemented with 0.6% (wt/wt) sphingomyelin.

Each point represents data for an individual animal. Open circles represent high-fat-fed mice; filled circles represent high-fat fed animals supplemented with SM.

Figure 2. Total liver lipid (A), liver cholesterol (B), liver triglyceride (C) and liver phospholipid levels (D) in mice fed a high-fat diet or a high-fat diet supplemented with varying doses of egg sphingomyelin.

Bars represent means±SEM (n = 8–10 mice per group). Differences between groups were determined by one-way ANOVA: *P<0.05, **P<0.01, ***P<0.001.

Figure 3. Hierarchical clustering based on correlation coefficients derived from all significant changes in gene expression and lipid levels between high fat-fed mice and high fat-fed, SM-supplemented mice.

Figure 4. A relevance network of significantly different genes and lipids between high fat-fed mice and high fat-fed, SM-supplemented mice.