IntroductionWestern diet containing both saturated fat and cholesterol impairs cardio-metabolic health partly by modulating diversity and function of the microbiota. While diet containing only high fat has comparable effects, it is unclear how diets only enriched in cholesterol impact the microbiota. Therefore, we aimed to characterize the response of host and microbiota to a high cholesterol (HC) diet in mice susceptible to cardio-metabolic disease.MethodsLDLR knockout mice received either 1.25% HC or no cholesterol containing control diet (NC) for 12 weeks before characterizing host cholesterol metabolism and intestinal microbiota composition (next generation sequencing).ResultsHC diet substantially increased plasma (1.6-fold) and liver cholesterol levels (21-fold), biliary cholesterol secretion (4.5-fold) and fecal neutral sterol excretion (68-fold, each p < 0.001) but not fecal bile acid excretion. Interestingly, despite the profound changes in intestinal cholesterol homeostasis no differences in microbial composition between control and HC-fed mice were detected. In both groups the main phyla were Bacteroidetes (55%), Firmicutes (27%) and Verrucomicrobia (14%).ConclusionOur results demonstrate that in mice HC diet alone does not alter the microbiota composition despite inducing substantial adaptive changes in whole body cholesterol homeostasis. The impact of Western diet on intestinal microbiota thus appears to be mediated exclusively by its high fat content.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-017-0170-x) contains supplementary material, which is available to authorized users.
This study demonstrates that the antioxidative function of HDL (i) does not predict cardiovascular or all-cause mortality in RTR, but (ii) conceivably contributes to the development of graft failure, however, not independent of baseline kidney function and inflammatory load.
Pregnancy complications such as preeclampsia cause increased fetal oxidative stress and fetal growth restriction, and associate with a higher incidence of adult metabolic syndrome. However, the pathophysiological contribution of oxidative stress per se is experimentally difficult to discern and has not been investigated. This study determined, if increased intrauterine oxidative stress (IUOx) affects adiposity, glucose and cholesterol metabolism in adult Ldlr−/−xSod2+/+ offspring from crossing male Ldlr−/−xSod2+/+ mice with Ldlr−/−xSod2 +/- dams (IUOx) or Ldlr−/−xSod2 +/- males with Ldlr−/−xSod2+/+ dams (control). At 12 weeks of age mice received Western diet for an additional 12 weeks. Adult male IUOx offspring displayed lower body weight and reduced adiposity associated with improved glucose tolerance compared to controls. Reduced weight gain in IUOx was conceivably due to increased energy dissipation in white adipose tissue conveyed by higher expression of Ucp1 and an accompanying decrease in DNA methylation in the Ucp1 enhancer region. Female offspring did not show comparable phenotypes. These results demonstrate that fetal oxidative stress protects against the obesogenic effects of Western diet in adulthood by programming energy dissipation in white adipose tissue at the level of Ucp1.
The acute phase protein group IIA secretory phospholipase A2 (sPLA2-IIA) has intrinsic proatherosclerotic properties. The present prospective cohort study investigated whether plasma sPLA2-IIA associates with graft failure, cardiovascular, and all-cause mortality in renal transplant recipients (RTRs), patients with accelerated atherosclerosis formation both systemically and within the graft. In 511 RTRs from a single academic center with stable graft function >1 year, baseline plasma sPLA2-IIA was determined by ELISA. Primary end points were death-censored graft failure and mortality (median follow-up, 7.0 years). Baseline sPLA2-IIA was higher in RTRs than in healthy controls (median 384 ng/dL (range 86–6951) vs. 185 ng/dL (range 104–271), p < 0.001). Kaplan–Meier analysis demonstrated increased risk for graft failure (p = 0.002), as well as cardiovascular (p < 0.001) and all-cause mortality (p < 0.001), with increasing sPLA2-IIA quartiles. Cox regression showed strong associations of sPLA2-IIA with increased risks of graft failure (hazard ratio (HR) = 1.42 (1.11–1.83), p = 0.006), as well as cardiovascular (HR = 1.48 (1.18−1.85), p = 0.001) and all-cause mortality (HR = 1.39 (1.17−1.64), p < 0.001), dependent on parameters of kidney function. Renal function during follow-up declined faster in RTRs with higher baseline sPLA2-IIA levels. In RTRs, sPLA2-IIA is a significant predictive biomarker for chronic graft failure, as well as overall and cardiovascular disease mortality dependent on kidney function. This dependency is conceivably explained by sPLA2-IIA impacting negatively on kidney function.
Breast milk cholesterol content may imply to affect short- and long-term cholesterol homeostasis in the offspring. However, mechanisms of regulating milk cholesterol concentration are only partly understood. We used different mouse models to assess the impact of high cholesterol diet (HC)- or genetically-induced hypercholesterolaemia on milk cholesterol content. At day 14 postpartum we determined milk, plasma and tissue lipids in wild type (WT), LDL receptor knockout (Ldlr−/−), and ATP-binding cassette transporter G8 knockout (Abcg8−/−) mice fed either low- or 0.5% HC diet. In chow-fed mice, plasma cholesterol was higher in Ldlr−/− dams compared to WT. HC-feeding increased plasma cholesterol in all three models compared to chow diet. Despite the up to 5-fold change in plasma cholesterol concentration, the genetic and dietary conditions did not affect milk cholesterol levels. To detect possible compensatory changes, we quantified de novo cholesterol synthesis in mammary gland and liver, which was strongly reduced in the various hypercholesterolaemic conditions. Together, these data suggest that milk cholesterol concentration in mice is not affected by conditions of maternal hypercholesterolaemia and is maintained at stable levels via ABCG8- and LDLR-independent mechanisms. The robustness of milk cholesterol levels might indicate an important physiological function of cholesterol supply to the offspring.
Epidemiological research showed that feeding breast milk, which is rich in cholesterol, translates into reduced cardiovascular risk in adulthood compared to feeding formula, which is cholesterol free. The mechanisms underlying these observations are unclear. Therefore, the present study aimed to investigate the impact of reduced dietary cholesterol availability during the suckling period on cholesterol metabolism in adult life in mice. To achieve reduced dietary cholesterol exposure from breast milk LDLR knockout offspring were given the cholesterol absorption inhibitor ezetimibe for 3 weeks during the suckling period. Ezetimibe was added to the food of nursing dams and reached the offspring’s intestine via excretion into breast milk. Low cholesterol exposure (LC) mice were compared to normal cholesterol (NC) controls with respect to all relevant parameters of cholesterol metabolism including biliary and fecal cholesterol excretion, intestinal absorption and endogenous synthesis using stable isotope kinetics. At 24 weeks intestinal cholesterol absorption was decreased in LC mice (-30%, p<0.001) due to decreased Npc1l1 expression, the main intestinal cholesterol uptake transporter (-50%, p<0.05). Methylation analysis of the NPC1L1 promoter revealed substantial differences between jejunum and colon (p<0.001), but not between LC and NC. Plasma cholesterol levels were not different between NC and LC due to increased endogenous synthesis in the LC group (p<0.05). Food intake, biliary and fecal cholesterol excretion did not differ between groups. In summary, our results demonstrate that early life reduction of dietary cholesterol exposure programs the murine intestine in adulthood towards decreased cholesterol absorption via reduced Npc1l1 expression. These results support a key role of the intestine as sensor and integrator of cholesterol metabolism with high relevance for cardio-metabolic disease.
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