Novel computational biology modeling system can accurately forecast response to neoadjuvant therapy in early breast cancer.

BACKGROUND: Generalizable population-based studies are unable to account for individual tumor heterogeneity that contributes to variability in a patient's response to physician-chosen therapy. Although molecular characterization of tumors has advanced precision medicine, in early-stage and locally advanced breast cancer patients, predicting a patient's response to neoadjuvant therapy (NAT) remains a gap in current clinical practice. Here, we perform a study in an independent cohort of early-stage and locally advanced breast cancer patients to forecast tumor response to NAT and assess the stability of a previously validated biophysical simulation platform. METHODS: A single-blinded study was performed using a retrospective database from a single institution (9/2014-12/2020). Patients included: ≥ 18 years with breast cancer who completed NAT, with pre-treatment dynamic contrast enhanced magnetic resonance imaging. Demographics, chemotherapy, baseline (pre-treatment) MRI and pathologic data were input into the TumorScope Predict (TS) biophysical simulation platform to generate predictions. Primary outcomes included predictions of pathological complete response (pCR) versus residual disease (RD) and final volume for each tumor. For validation, post-NAT predicted pCR and tumor volumes were compared to actual pathological assessment and MRI-assessed volumes. Predicted pCR was pre-defined as residual tumor volume ≤ 0.01 cm3 (≥ 99.9% reduction). RESULTS: The cohort consisted of eighty patients; 36 Caucasian and 40 African American. Most tumors were high-grade (54.4% grade 3) invasive ductal carcinomas (90.0%). Receptor subtypes included hormone receptor positive (HR+)/human epidermal growth factor receptor 2 positive (HER2+, 30%), HR+/HER2- (35%), HR-/HER2+ (12.5%) and triple negative breast cancer (TNBC, 22.5%). Simulated tumor volume was significantly correlated with post-treatment radiographic MRI calculated volumes (r = 0.53, p = 1.3 × 10-7, mean absolute error of 6.57%). TS prediction of pCR compared favorably to pathological assessment (pCR: TS n = 28; Path n = 27; RD: TS n = 52; Path n = 53), for an overall accuracy of 91.2% (95% CI: 82.8% - 96.4%; Clopper-Pearson interval). Five-year risk of recurrence demonstrated similar prognostic performance between TS predictions (Hazard ratio (HR): - 1.99; 95% CI [- 3.96, - 0.02]; p = 0.043) and clinically assessed pCR (HR: - 1.76; 95% CI [- 3.75, 0.23]; p = 0.054). CONCLUSION: We demonstrated TS ability to simulate and model tumor in vivo conditions in silico and forecast volume response to NAT across breast tumor subtypes.

Compared to an Oatmeal Breakfast, Two Eggs/Day Increased Plasma Carotenoids and Choline without Increasing Trimethyl Amine N-Oxide Concentrations.

BACKGROUND: Habitual consumption of eggs has been hypothesized to positively modify biomarkers of cardiovascular disease risk through proposed antioxidant properties. OBJECTIVES: To examine this relationship, 50 young, healthy men and women were enrolled into a randomized crossover clinical intervention. METHODS: Participants consumed either 2 eggs per day or one packet of oatmeal a day for 4 weeks, followed by a 3-week wash-out and crossed over to the alternate breakfast. Fasting blood samples and peripheral blood mononuclear cells (PBMCs) were collected at the end of each intervention period. RESULTS: Increases in plasma large high-density lipoprotein (HDL) and large low-density lipoprotein (LDL) particle concentrations as measured by nuclear magnetic resonance were found following egg consumption (p < 0.001, p < 0.05), respectively, with increases in apolipoprotein concentration as well (p < 0.05). Though there was no difference in the intake of antioxidants lutein and zeaxanthin, a significant increase in plasma concentrations of these carotenoids was observed (p < 0.001) after egg consumption. There was no change in lecithin-cholesterol acyl transferase, cholesteryl ester transfer protein, or paroxanase-1 arylesterase activities between breakfast interventions. Dietary and plasma choline were both higher following egg consumption compared to oatmeal consumption (p < 0.001); however, there was no change in plasma trimethylamine N-oxide (TMAO) concentrations. Two eggs per day had no impact on PBMC gene expression related to cholesterol metabolism, oxidation, or TMAO production. CONCLUSIONS: These results suggest that compared to oatmeal, consumption of 2 eggs for breakfast provided increased plasma carotenoids and improved biomarkers of cardiovascular disease (CVD) risk while not affecting TMAO levels in this population.

Intake of up to 3 Eggs per Day Is Associated with Changes in HDL Function and Increased Plasma Antioxidants in Healthy, Young Adults.

Background: HDL function may be more important than HDL concentration in determining risk for cardiovascular disease. In addition, HDL is a carrier of carotenoids and antioxidant enzymes, which protect HDL and LDL particles against oxidation.Objective: The goal of this study was to determine the impact of consuming 0-3 eggs/d on LDL and HDL particle size, HDL function, and plasma antioxidants in a young, healthy population.Methods: Thirty-eight healthy men and women [age 18-30 y, body mass index (in kg/m2) 18.5-29.9] participated in this 14-wk crossover intervention. Subjects underwent a 2-wk washout (0 eggs/d) followed by sequentially increasing intake of 1, 2, and 3 eggs/d for 4 wk each. After each period, fasting blood was collected for analysis of lipoprotein subfractions, plasma apolipoprotein (apo) concentration, lutein and zeaxanthin concentration, and activities of lecithin-cholesterol acyltransferase, cholesteryl ester transfer protein, and paraoxonase-1.Results: Compared with intake of 0 eggs/d, consuming 1-3 eggs/d resulted in increased large-LDL (21-37%) and large-HDL (6-13%) particle concentrations, plasma apoAI (9-15%), and lecithin-cholesterol acyltransferase activity (5-15%) (P < 0.05 for all biomarkers). Intake of 2-3 eggs/d also promoted an 11% increase in apoAII (P < 0.05) and a 20-31% increase in plasma lutein and zeaxanthin (P < 0.05), whereas intake of 3 eggs/d resulted in a 9-16% increase in serum paraoxonase-1 activity compared with intake of 1-2 eggs/d (P < 0.05). Egg intake did not affect cholesteryl ester transfer protein activity.Conclusions: Intake of 1 egg/d was sufficient to increase HDL function and large-LDL particle concentration; however, intake of 2-3 eggs/d supported greater improvements in HDL function as well as increased plasma carotenoids. Overall, intake of ≤3 eggs/d favored a less atherogenic LDL particle profile, improved HDL function, and increased plasma antioxidants in young, healthy adults. This trial was registered at clinicaltrials.gov as NCT02531958.

Moringa Leaves Prevent Hepatic Lipid Accumulation and Inflammation in Guinea Pigs by Reducing the Expression of Genes Involved in Lipid Metabolism.

To investigate the mechanisms by which Moringa oleifera leaves (ML) modulate hepatic lipids, guinea pigs were allocated to either control (0% ML), 10% Low Moringa (LM) or 15% High Moringa (HM) diets with 0.25% dietary cholesterol to induce hepatic steatosis. After 6 weeks, guinea pigs were sacrificed and liver and plasma were collected to determine plasma lipids, hepatic lipids, cytokines and the expression of genes involved in hepatic cholesterol (CH) and triglyceride (TG) metabolism. There were no differences in plasma lipids among groups. A dose-response effect of ML was observed in hepatic lipids (CH and TG) with the lowest concentrations in the HM group (p < 0.001), consistent with histological evaluation of lipid droplets. Hepatic gene expression of diglyceride acyltransferase-2 and peroxisome proliferator activated receptor-γ, as well as protein concentrations interleukin (IL)-1ß and interferon-γ, were lowest in the HM group (p < 0.005). Hepatic gene expression of cluster of differentiation-68 and sterol regulatory element binding protein-1c were 60% lower in both the LM and HM groups compared to controls (p < 0.01). This study demonstrates that ML may prevent hepatic steatosis by affecting gene expression related to hepatic lipids synthesis resulting in lower concentrations of cholesterol and triglycerides and reduced inflammation in the liver.

Compared with Powdered Lutein, a Lutein Nanoemulsion Increases Plasma and Liver Lutein, Protects against Hepatic Steatosis, and Affects Lipoprotein Metabolism in Guinea Pigs.

BACKGROUND: It is not clear how oil-in-water nanoemulsions of lutein may affect bioavailability and consequently alter lipoprotein metabolism, oxidative stress, and inflammation. OBJECTIVE: The bioavailability as well as effects of a powdered lutein (PL) and an oil-in-water lutein nanoemulsion (NANO; particle size: 254.2 nm; polydispersity index: 0.29; and ζ-potential: -65 mV) on metabolic variables in liver, plasma, and adipose tissue in a guinea pig model of hepatic steatosis were evaluated. METHODS: Twenty-four 2-mo-old male Hartley guinea pigs, weighing 200-300 g (n = 8/group), were fed diets containing 0.25 g cholesterol/100 g to induce liver injury for the duration of the study. They were allocated to control (0 mg lutein), PL (3.5 mg/d), or NANO (3.5 mg/d) groups. After 6 wk, plasma, liver, and adipose tissue were collected for determination of lutein, plasma lipids, tissue cholesterol, and inflammatory cytokines. RESULTS: The NANO group had 2-fold higher concentrations of lutein in plasma (P < 0.001) and 1.6-fold higher concentrations in liver (P < 0.001) than did the PL group, indicating greater bioavailability of this carotenoid. The NANO group also had 24% lower hepatic steatosis scores (P < 0.05), 31% lower hepatic cholesterol accumulation (P < 0.05), and 64% lower plasma alanine aminotransferase (P < 0.05) than did the control group. Hepatic oxidized LDL was 55% lower in both the PL and NANO groups than in the control group (P < 0.05). In plasma, the NANO group had 2-fold higher concentrations of LDL and HDL cholesterol as well as a 2-fold higher number of VLDL, LDL, and HDL particles than did the other 2 groups as evaluated by nuclear magnetic resonance. Furthermore, the NANO group had 15% higher concentrations of free cholesterol in adipose tissue, resulting in higher concentrations of inflammatory markers, than did the other 2 groups. CONCLUSIONS: These results indicate that, although this lutein nanoemulsion exerted protective effects against hepatic steatosis, plasma lipoproteins and adipose tissue cholesterol were increased. These data suggest that the metabolic effects of this particular nanoemulsion might not be protective in all tissues in guinea pigs.

Black elderberry extract attenuates inflammation and metabolic dysfunction in diet-induced obese mice.

Dietary anthocyanins have been shown to reduce inflammation in animal models and may ameliorate obesity-related complications. Black elderberry is one of the richest sources of anthocyanins. We investigated the metabolic effects of anthocyanin-rich black elderberry extract (BEE) in a diet-induced obese C57BL/6J mouse model. Mice were fed either a low-fat diet (n 8), high-fat lard-based diet (HFD; n 16), HFD+0·25 % (w/w) BEE (0·25 %-BEE; n 16) or HFD+1·25 % BEE (1·25 %-BEE; n 16) for 16 weeks. The 0·25 % BEE (0·034 % anthocyanin, w/w) and 1·25 % BEE (0·17 % anthocyanin, w/w) diets corresponded to estimated anthocyanin doses of 20-40 mg and 100-200 mg per kg of body weight, respectively. After 16 weeks, both BEE groups had significantly lower liver weights, serum TAG, homoeostasis model assessment and serum monocyte chemoattractant protein-1 compared with HFD. The 0·25 %-BEE also had lower serum insulin and TNFα compared with HFD. Hepatic fatty acid synthase mRNA was lower in both BEE groups, whereas PPARγ2 mRNA and liver cholesterol were lower in 1·25 %-BEE, suggesting decreased hepatic lipid synthesis. Higher adipose PPARγ mRNA, transforming growth factor ß mRNA and adipose tissue histology suggested a pro-fibrogenic phenotype that was less inflammatory in 1·25 %-BEE. Skeletal muscle mRNA expression of the myokine IL-6 was higher in 0·25 %-BEE relative to HFD. These results suggest that BEE may have improved some metabolic disturbances present in this mouse model of obesity by lowering serum TAG, inflammatory markers and insulin resistance.

Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and alanine aminotransferase, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma (PPARγ) in hepatocytes and promote steatosis. Therefore, we assessed the role that hepatocyte-specific PPARγ plays in the development of NASH, and how it alters the therapeutic effects of TZD on the liver of mice with diet-induced NASH. METHODS: Hepatocyte-specific PPARγ expression was knocked out in adult mice before and after the development of NASH induced with a high fat, cholesterol, and fructose (HFCF) diet. RESULTS: HFCF diet increased PPARγ expression in hepatocytes, and rosiglitazone further activated PPARγ in hepatocytes of HFCF-fed mice in vivo and in vitro. Hepatocyte-specific loss of PPARγ reduced the progression of HFCF-induced NASH in male mice and increased the benefits derived from the effects of TZD on extrahepatic tissues and non-parenchymal cells. RNAseq and metabolomics indicated that HFCF diet promoted inflammation and fibrogenesis in a hepatocyte PPARγ-dependent manner and was associated with dysregulation of hepatic metabolism. Specifically, hepatocyte-specific loss of PPARγ plays a positive role in the regulation of methionine metabolism, and that could reduce the progression of NASH. CONCLUSIONS: Because of the negative effect of hepatocyte PPARγ in NASH, inhibition of mechanisms promoted by endogenous PPARγ in hepatocytes may represent a novel strategy that increases the efficiency of therapies for NAFLD.

Cow's milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet.

Milk sphingomyelin (SM), a polar lipid (PL) component of milk fat globule membranes, is protective against dyslipidemia. However, it is unclear whether ingestion of milk PLs protect against atherosclerosis. To determine this, male LDLr-/- mice (age 6 weeks) were fed ad libitum either a high-fat, added-cholesterol diet (CTL; 45% kcal from fat, 0.2% cholesterol by weight; n=15) or the same diet supplemented with 1% milk PL (1% MPL; n=15) or 2% milk PL (2% MPL; n=15) added by weight from butter serum. After 14 weeks on diets, mice fed 2% MPL had significantly lower serum cholesterol (-51%) compared to CTL (P<.01), with dose-dependent effects in lowering VLDL- and LDL-cholesterol. Mice fed 2% MPL displayed lower inflammatory markers in the serum, liver, adipose and aorta. Notably, milk PLs reduced atherosclerosis development in both the thoracic aorta and the aortic root, with 2% MPL-fed mice having significantly lower neutral lipid plaque size by 59% (P<.01) and 71% (P<.02) compared to CTL, respectively. Additionally, the 2% MPL-fed mice had greater relative abundance of Bacteroidetes, Actinobacteria and Bifidobacterium, and lower Firmicutes in cecal feces compared to CTL. Milk PL feeding resulted in significantly different microbial communities as demonstrated by altered beta diversity indices. In summary, 2% MPL strongly reduced atherogenic lipoprotein cholesterol, modulated gut microbiota, lowered inflammation and attenuated atherosclerosis development. Thus, milk PL content may be important to consider when choosing dairy products as foods for cardiovascular disease prevention.

Protective properties of milk sphingomyelin against dysfunctional lipid metabolism, gut dysbiosis, and inflammation.

The identification of natural bioactive compounds aimed at promoting optimal gut health and improving lipid metabolism is paramount in the prevention of chronic disease. In this review, we summarize basic science and clinical research examining the protective properties of milk sphingomyelin (SM) against dysfunctional lipid metabolism, gut dysbiosis, and inflammation. Dietary SM dose-dependently reduces the intestinal absorption of cholesterol, triglycerides, and fatty acids in cell culture and rodent studies. Overall, rodent feeding studies show dietary milk SM, milk polar lipid mixtures, and milk fat globule membrane reduce serum and hepatic lipid concentrations. Furthermore, these hypolipidemic effects are observed in some supplementation studies in humans, although the extent of reductions in serum cholesterol is typically smaller and only one trial was conducted with purified SM. Dietary milk SM has been reported to affect the gut microbiota in rodent studies and its hydrolytic product, sphingosine, displays bactericidal activity in vitro. Milk SM may also improve gut barrier function to prevent the translocation of inflammatory gut bacteria-derived molecules. Current evidence from pre-clinical studies indicates that dietary milk SM has protective properties against dysfunctional lipid metabolism, gut dysbiosis, and inflammation. The hypolipidemic effects of milk SM observed in animal studies have been reported in some human studies, although the magnitude of such effects is typically smaller. More research is warranted to clearly define how dietary milk SM influences lipid metabolism, gut microbiota, and inflammation in humans.

Dietary Egg Sphingomyelin Prevents Aortic Root Plaque Accumulation in Apolipoprotein-E Knockout Mice.

Western-style diets have been linked with dyslipidemia and inflammation, two well-known risk factors associated with cardiovascular disease (CVD). Dietary sphingomyelin (SM) has been reported to modulate gut microbiota, and lower serum lipids and inflammation in mice on Western-style diets. However, few studies have examined if nutritionally-relevant intake of dietary SM can impact atherosclerosis progression. Thus, the aim of this study was to determine if incorporating 0.1% (w/w) egg SM (ESM) (equivalent to ~750 mg/day in humans) into a high-fat (45% kcal), cholesterol-enriched diet (HFD) could prevent atheroprogression in apoE-/- mice (n = 15/group). We found that mice fed with the ESM-rich diet had significantly lower epididymal fat mass (-46%) and tended to have higher spleen weights (+15%). There were no significant differences in serum lipids between groups. However, ESM-fed mice had significantly lower alanine aminotransferase (ALT) activity. Additionally, ESM-fed mice displayed significantly less aortic root lipid accumulation (-31%) compared to controls. This improvement in atherosclerosis was paired with over a two-fold reduction in circulating serum amyloid A (SAA) in ESM-fed mice. Finally, there was also a modulation of the gut microbiota with ESM supplementation. ESM may have the potential to prevent atherosclerosis, however further research in the clinical setting is warranted.

Effects of Freeze-Dried Grape Powder on High-Density Lipoprotein Function in Adults with Metabolic Syndrome: A Randomized Controlled Pilot Study.

BACKGROUND: High-density lipoprotein (HDL) particles are protective against atherosclerosis. However, HDL function is impaired in metabolic syndrome (MetS) due to low-grade inflammation and dyslipidemia. Foods containing polyphenols, such as grapes, may prevent HDL dysfunction via antioxidant or anti-inflammatory effects. We evaluated the effects of grape powder ingestion on measures of HDL function in adults with MetS. METHODS: Twenty adults (age: 32-70 years; body mass index: 25.3-45.4 kg/m2) consumed either 60 grams/day of freeze-dried grape powder (GRAPE) or a placebo for 4 weeks, separated by a 3-week washout period, in a randomized, double-blind crossover study. The primary outcome was serum paraoxonase-1 (PON1) arylesterase activity, a measure of HDL antioxidant function. Secondary outcomes included PON1 lactonase activity, plasma lipids, metabolic markers, cholesterol efflux capacity, and other HDL functional markers. RESULTS: After 4 weeks, GRAPE did not alter the serum PON1 activity or other markers of HDL function compared with placebo. Measures of HDL function were positively correlated with each other and inversely with measures of insulin resistance and inflammation. GRAPE intake led to a significant reduction in fasting plasma triglycerides compared with placebo (P = 0.032). No other significant effects of GRAPE were observed for other plasma lipids, anthropometrics, or metabolic measures. CONCLUSIONS: Grape powder consumption did not impact HDL function in this cohort of adults with MetS. However, it was shown to improve fasting triglycerides, a risk factor for cardiovascular disease.

Long-Term Supplementation of Black Elderberries Promotes Hyperlipidemia, but Reduces Liver Inflammation and Improves HDL Function and Atherosclerotic Plaque Stability in Apolipoprotein E-Knockout Mice.

SCOPE: HDL particles are protective against atherosclerosis, but may become dysfunctional during inflammation and chronic disease progression. Anthocyanin-rich foods, such as the black elderberry, may improve HDL function and prevent disease development via antioxidant and/or anti-inflammatory effects. This study investigates the long-term consumption of black elderberry extract (BEE) on HDL function and atherosclerosis in apolipoprotein (apo) E-/- mice. METHODS AND RESULTS: ApoE-/- mice (n = 12/group) are fed a low-fat diet, supplemented with 0, 0.25%, or 1% (by weight) BEE (≈37.5-150 mg anthocyanins per kg body weight) for 24 weeks. Feeding 1% BEE increases total serum cholesterol (+31%) and non-HDL cholesterol (+32%) compared with the control diet. PON1 arylesterase (+32%) and lactonase (+45%) activities also increase with the 1% BEE diet. Both 0.25% BEE and 1% BEE diets strongly increase HDL cholesterol efflux capacity (CEC) by 64% and 85%, respectively. Further, BEE dose-dependently lowers serum liver enzymes and hepatic inflammatory gene expression. Although there is no change in neutral lipid accumulation in atherosclerotic lesions, BEE promotes connective tissue deposition in the aortic root. CONCLUSIONS: Chronic BEE supplementation in apoE-/- mice dose-dependently improves HDL function. Despite BEE promoting hyperlipidemia, which likely offsets HDL effects, BEE increases connective tissue content, suggesting improved atherosclerotic plaque stability.

Dietary sphingolipids: potential for management of dyslipidemia and nonalcoholic fatty liver disease.

The development of therapeutic approaches aimed at reducing inflammation, improving lipid metabolism, and preventing nonalcoholic fatty liver disease holds significant potential in the management of obesity-associated disease. In this review, the recent basic science and clinical research examining dietary sphingolipid intake and the prevention of dyslipidemia and nonalcoholic fatty liver disease is summarized. Dietary sphingolipids have been shown to dose-dependently reduce the acute intestinal absorption of cholesterol, triglycerides, and fatty acids in rodents. Overall, studies feeding dietary sphingolipids to rodents typically show reductions in serum lipids. Furthermore, these hypolipidemic effects are also observed in most human studies, although the magnitude of such effects is typically smaller. Dietary sphingolipids also appear useful in preventing hepatic lipid uptake and accumulation and have shown benefits in preventing hepatic steatosis in rodent models. Dietary sphingolipids may affect the gut-liver axis by preventing the translocation of gut bacteria-derived lipopolysaccharide and/or inhibiting its proinflammatory effects. Current evidence from preclinical studies indicates that dietary sphingolipids have lipid-lowering and anti-inflammatory properties, although their potential to prevent human chronic disease has not been fully explored. It will be important to determine if such effects seen in cell and animal models translate to humans. More research is warranted to define how dietary sphingolipids influence lipid metabolism and inflammation.

Dietary and Endogenous Sphingolipid Metabolism in Chronic Inflammation.

Chronic inflammation is a common underlying factor in many major metabolic diseases afflicting Western societies. Sphingolipid metabolism is pivotal in the regulation of inflammatory signaling pathways. The regulation of sphingolipid metabolism is in turn influenced by inflammatory pathways. In this review, we provide an overview of sphingolipid metabolism in mammalian cells, including a description of sphingolipid structure, biosynthesis, turnover, and role in inflammatory signaling. Sphingolipid metabolites play distinct and complex roles in inflammatory signaling and will be discussed. We also review studies examining dietary sphingolipids and inflammation, derived from in vitro and rodent models, as well as human clinical trials. Dietary sphingolipids appear to influence inflammation-related chronic diseases through inhibiting intestinal lipid absorption, altering gut microbiota, activation of anti-inflammatory nuclear receptors, and neutralizing responses to inflammatory stimuli. The anti-inflammatory effects observed with consuming dietary sphingolipids are in contrast to the observation that most cellular sphingolipids play roles in augmenting inflammatory signaling. The relationship between dietary sphingolipids and low-grade chronic inflammation in metabolic disorders is complex and appears to depend on sphingolipid structure, digestion, and metabolic state of the organism. Further research is necessary to confirm the reported anti-inflammatory effects of dietary sphingolipids and delineate their impacts on endogenous sphingolipid metabolism.

Dietary sphingomyelin attenuates hepatic steatosis and adipose tissue inflammation in high-fat-diet-induced obese mice.

Western-type diets can induce obesity and related conditions such as dyslipidemia, insulin resistance and hepatic steatosis. We evaluated the effects of milk sphingomyelin (SM) and egg SM on diet-induced obesity, the development of hepatic steatosis and adipose inflammation in C57BL/6J mice fed a high-fat, cholesterol-enriched diet for 10 weeks. Mice were fed a low-fat diet (10% kcal from fat) (n=10), a high-fat diet (60% kcal from fat) (HFD, n=14) or a high-fat diet modified to contain either 0.1% (w/w) milk SM (n=14) or 0.1% (w/w) egg SM (n=14). After 10 weeks, egg SM ameliorated weight gain, hypercholesterolemia and hyperglycemia induced by HFD. Both egg SM and milk SM attenuated hepatic steatosis development, with significantly lower hepatic triglycerides (TGs) and cholesterol relative to HFD. This reduction in hepatic steatosis was stronger with egg SM supplementation relative to milk SM. Reductions in hepatic TGs observed with dietary SM were associated with lower hepatic mRNA expression of PPARγ-related genes: Scd1 and Pparg2 in both SM groups, and Cd36 and Fabp4 with egg SM. Egg SM and, to a lesser extent, milk SM reduced inflammation and markers of macrophage infiltration in adipose tissue. Egg SM also reduced skeletal muscle TG content compared to HFD. Overall, the current study provides evidence of dietary SM improving metabolic complications associated with diet-induced obesity in mice. Further research is warranted to understand the differences in bioactivity observed between egg and milk SM.

Milk sphingomyelin improves lipid metabolism and alters gut microbiota in high fat diet-fed mice.

High dietary fat intake can cause elevated serum and hepatic lipids, as well as contribute to gut dysbiosis, intestinal barrier dysfunction and increased circulating lipopolysaccharide (LPS). Dietary milk sphingomyelin (SM) has been shown to inhibit lipid absorption in rodents. We evaluated the effects of milk SM on lipid metabolism and LPS levels in C57BL/6J mice fed a high-fat diet for 4weeks and compared it with egg SM. Mice were fed a high-fat diet (45%kcal from fat) (CTL, n=10) or the same diet modified to contain 0.25% (wt/wt) milk SM (MSM, n=10) or 0.25% (wt/wt) egg SM (ESM, n=10). After 4weeks, MSM had gained significantly less weight and had reduced serum cholesterol compared to CTL. ESM had increases in serum cholesterol, triglycerides, phospholipids and SM compared to CTL. MSM significantly decreased, while ESM increased, hepatic triglycerides. This may have been related to induction of hepatic stearoyl-CoA desaturase-1 mRNA observed in ESM. MSM displayed intestinal and hepatic gene expression changes consistent with cholesterol depletion. MSM had significantly lower serum LPS compared to CTL, which may have been due to altered distal gut microbiota. Fecal Gram-negative bacteria were significantly lower, while fecal Bifidobacterium were higher, in MSM. These results suggest that milk SM is more effective than egg SM at combating the detrimental effects of a high-fat diet in mice. Additionally, distal gut microbiota is altered with milk SM and this may have contributed to the lower serum LPS observed.