From cradle to grave: Familial hypercholesterolemia as a model for studying impact of lifelong cholesterol exposure
The goals of the present project is to identify markers of life-long cholesterol exposure important in the early progression of atherosclerosis, to identify markers in FH subjects with elevated risk [increased Lp(a)] and with lower risk (CVD Resistant FH subjects) and to investigate how modulation of cholesterol exposure may impact these markers. We will investigate the effect of life-long exposure to cholesterol in subjects with FH at young age (children), in older subjects (>75 years) with and without elevated Lp(a) levels with regard to inflammatory markers in circulation, gene expression levels in PBMCs and study PBMC epigenetic markers [DNA methylation pattern (methylated CpG genes)] and urine metabolome profiling. Hypercholesterolemia in adults is markedly influenced by lifestyle factors. These factors represent an important source of confounders for studies on the pure role of LDL in inflammation and atherosclerosis. Micro-inflammation in combination with hypercholesterolemia is a hallmark of atherosclerosis and monocyte activation play a key role. There is a large degree of monocyte heterogeneity and cell-surface expression of proteins defines functionally and phenotypically distinct subsets of monocytes. It has been suggested that some of these subsets, play a major role in the development of atherosclerosis because of the surface receptors they express and the panel of cytokines they release upon activation. It is well documented that saturated fat increased plasma cholesterol levels however the exact mechanisms remains to be elucidated. Postprandial hypertriglyceridemia has been shown to be an independent cardiovascular risk factor and may predict the incidence of coronary artery disease (CAD) , and is associated with a transient increase of pro-inflammatory mediators. Repeated exposure of the blood vessel wall of pro-inflammatory mediators may damage the vascular endothelium and promote atherosclerosis. Children and young adults with FH are characterized by an isolated and well defined genetic defect in a key player (LDL receptor) in the cholesterol metabolism. Subjects with FH (representing a human transgene model) represents thus a unique model system for exploring the effects on cholesterol homeostasis after intake of meals with different fatty acids composition. We will measure plasma lipids [e.g. total-, LDL and HDL-cholesterol, triglycerides, apoA1, apoB, Lp(a)] in addition to inflammatory markers. In addition, we will measure inflammatory markers at PBMC gene expression level. We will perform non-targeted metabolomics of serum and spot urine samples from the subjects before and after the meal in order to identify specific cholesterol-related metabolic signatures. In the last years nutrition research has undergone an important shift in focus from epidemiology and physiology to molecular biology and genetics. The effects of nutrition on health and disease cannot be elucidated without a profound understanding of how nutrients act at the molecular level. It is now well known that dietary changes also induce changes in gene expression. Nutrigenomics which comprise transcript, proteome and metabolome-profiling are applications by which responses to diet can be assessed in biological samples with high sensitivity. Use of a new high throughput genomics technology, (transcriptomics), allows quantification of genome-wide changes in gene expression of thousands of genes at the same time in one sample. Applying transcriptomics in relation to dietary information can be a powerful tool to understand how diet and dietary fat may influence numerous metabolic and inflammatory pathways, signaling routes and homeostatic control, elucidating the effects of nutrition on health and disease in humans. As project start was august 2016, the progress of the project in 2016 was mostly practical planning and sending invitations to patients.