Kai Simons

Max Planck Institute of Molecular Cell Biology and Genetics | MPI-CBG

Oxidation of polyunsaturated fatty acids (PUFA) in low-density lipoproteins (LDL) trapped in the arterial intima plays a critical role in atherosclerosis. Though there have been many studies on the atherogenicity of oxidized derivatives of unsaturated fatty acid esters of cholesterol, the effects of the oxidation end-products of these esters has be...

Human plasma lipidome captures risk for cardio-metabolic diseases. To discover new lipid-associated variants and understand link between lipid species and cardiometabolic disorders, we performed univariate and multivariate genome-wide analyses of 179 lipid species in 7,174 Finnish individuals. We further fine-mapped the associated loci, prioritized...

Background Despite well‐recognized differences in the atherosclerotic cardiovascular disease risk between men and women, sex differences in risk factors and sex‐specific mechanisms in the pathophysiology of atherosclerotic cardiovascular disease remain poorly understood. Lipid metabolism plays a central role in the development of atherosclerotic ca...

Type 2 diabetes is a complex, multifactorial disease with varying presentation and underlying pathophysiology. Recent studies using data-driven cluster analysis have led to a stratification of type 2 diabetes into novel subgroups based on six clinical measurements. Whether these subgroups truly correspond to the underlying phenotypic differences is...

Enzyme specificity in lipid metabolic pathways often remains unresolved at the lipid species level, which is needed to link lipidomic molecular phenotypes with their protein counterparts to construct functional pathway maps. We created lipidomic profiles of 23 gene knockouts in a proof-of-concept study based on a CRISPR/Cas9 knockout screen in mamm...

Despite well-recognized difference in the atherosclerotic cardiovascular disease (ASCVD) risk between men and women, sex differences in risk factors and sex specific mechanisms in the pathophysiology of ASCVD remain poorly understood. Lipid metabolism plays a central role in the development of ASCVD. Understanding sex differences in lipids and thei...

Type 2 diabetes (T2D) and cardiovascular disease (CVD) represent significant disease burdens for most societies and susceptibility to these diseases is strongly influenced by diet and lifestyle. Physiological changes associated with T2D or CVD, such has high blood pressure and cholesterol and glucose levels in the blood, are often apparent prior to...

Objectives: To find plasma biomarkers prognostic of type 2 diabetes, which could also inform on pancreatic ß-cell deregulations or defects in the function of insulin target tissues. Such biomarkers could help stratify patients according to the underlying patho-mechanisms and lead to more precise therapeutic approaches. Methods: We conducted a sy...

Aims/hypothesis Five clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes. In the current study we replicate and cross-validate these type 2 diabetes clusters in three large cohorts using variables readily measured in the clinic. Methods In three independent cohort...

Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity a previous study clustered people with diabetes into five diabetes subtypes. The aim of the current study is to investigate the aetiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15...

Background Localized stress and cell death in chronic inflammatory diseases may release tissue-specific lipids into the circulation causing the blood plasma lipidome to reflect the type of inflammation. However, deep lipid profiles of major chronic inflammatory diseases have not been compared. Methods Plasma lipidomes of patients suffering from tw...

Most research on human pancreatic islets is conducted on samples obtained from normoglycaemic or diseased brain-dead donors and thus cannot accurately describe the molecular changes of pancreatic islet beta cells as they progress towards a state of deficient insulin secretion in type 2 diabetes (T2D). Here, we conduct a comprehensive multi-omics an...

Lipidomics has become an indispensable method for the quantitative assessment of lipid metabolism in basic, clinical, and pharmaceutical research. It allows for the generation of information-dense datasets in a large variety of experimental setups and model organisms. Previous studies, mostly conducted in mice (Mus musculus), have shown a remarkabl...

We have deployed a multi-omics approach in large cohorts of patients with existing type 2 diabetes to identify biomarkers for disease progression across three molecular classes, metabolites, lipids and proteins. A Cox regression analysis for association with time to insulin requirement in 2,973 patients in the DCS, ANDIS and GoDARTS cohorts identif...

Background: Inflammation impacts several acute and chronic diseases causing localized stress and cell death, releasing tissue-specific lipids into the circulation from inflamed cells and tissues. The plasma lipidome may be expected to reflect the type of inflammation and the specific cells and tissues involved. However, deep lipid profiles of major...

Objective: Refeeding is the cornerstone of anorexia nervosa (AN) treatment, but little is known regarding the optimal pace and dietary composition or possible adverse effects of current clinical practices. Plasma lipids may be a moderating factor underlying unfavorable refeeding effects in AN, such as an abnormal central body fat distribution. The...

Background Dyslipidemia is a hallmark of cardiovascular disease but is characterized by crude measurements of triglycerides, HDL- and LDL cholesterol. Lipidomics enables more detailed measurements of plasma lipids, which may help improve risk stratification and understand the pathophysiology of cardiovascular disease. Methods Lipidomics was used t...

Objective: Type 2 diabetes mellitus (T2DM) is associated with dyslipidemia, but the detailed alterations in lipid species preceding the disease are largely unknown. We aimed to identify plasma lipids associated with development of T2DM and investigate their associations with lifestyle. Research design and methods: 178 lipids were measured at bas...

Context: Meal timing affects metabolic homeostasis and body weight, but how composition and timing of meals affect plasma lipidomics in humans is not well studied. Objective: We used high throughput shotgun plasma lipidomics to investigate effects of timing of carbohydrate and fat intake on lipid metabolism and its relation to glycaemic control....

Obesity is associated with changes in the plasma lipids. Although simple lipid quantification is routinely used, plasma lipids are rarely investigated at the level of individual molecules. We aimed at predicting different measures of obesity based on the plasma lipidome in a large population cohort using advanced machine learning modeling. A total...

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify...

Knust and Simons commemorate the life of the eminent developmental biologist, Suzanne Eaton.

Clinical risk factors explain only a fraction of the variability of estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes. Cross-omics technologies by virtue of a wide spectrum screening of plasma samples have the potential to identify biomarkers for the refinement of prognosis in addition to clinical variables. Here we...

Background We asked whether, after excluding familial hypercholesterolemia, individuals with high low‐density lipoprotein cholesterol ( LDL ‐C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population‐based hyperlipidemias. Methods...

Objective Shotgun lipidomics enables an extensive analysis of lipids from tissues and fluids. Each specimen requires appropriate extraction and processing procedures to ensure good coverage and reproducible quantification of the lipidome. Adipose tissue (AT) has become a research focus with regard to its involvement in obesity-related pathologies....

Shotgun lipidomics enables an extensive analysis of lipids from tissues and fluids. Each specimen requires appropriate extraction and processing procedures to ensure good coverage and reproducible quantification of the lipidome. Adipose tissue (AT) has become a research focus with regard to its involvement in obesity-related pathologies. However, t...

Aim: Genetic investigation of human plasma lipidome to get insights into lipid-related disorders beyond traditional lipid measures. Methods and Results: We performed a genome-wide association study (GWAS) of 141 lipid species (n=2,181 individuals), followed by phenome-wide scans (PheWAS) with 44 clinical end-points related to cardiometabolic, psych...

Omic sciences coupled with novel computational approaches such as machine intelligence offer completely new approaches to major depressive disorder (MDD) research. The complexity of MDD's pathophysiology is being integrated into studies examining MDD's biology within the omic fields. Lipidomics, as a late-comer among other omic fields, is increasin...

The envelope of Human Immunodeficiency Virus type 1 (HIV-1) consists of a liquid-ordered membrane enriched in raft lipids and containing the viral glycoproteins. Previous studies demonstrated that changes in viral membrane lipid composition affecting membrane structure or curvature can impair infectivity. Here, we describe novel antiviral compounds...

Aims: To characterize and compare coronary artery disease (CAD) risk and detailed lipidomic profiles of individuals with familial and population-ascertained hyperlipidemias. Methods and Results: We determined incident CAD risk for 760 members of 66 hyperlipidemic families (≥ 2 first degree relatives with the same hyperlipidemia) and 19,644 Finnish...

One of the promises of multiomic analysis was to transform the clinical diagnostics to deliver much more exact phenotyping of disease states. However, despite enormous investments, the transformation of clinical routine has not taken place. There are many reasons for this lack of success but one is the failure to deliver quantitative and reproducib...

Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of β-glucan (prototypical trained-immunity-inducing agonist) to mice...

Table S1. Results of GSEA on RNA-Seq Data from LT-HSCs from Mice on Day 7 after β-Glucan or PBS Administration Using MSigDB Hallmark Gene Set, Related to Figure 5 NAME is the gene set name; SIZE is the number of genes in the gene set after filtering out those genes not in the expression dataset; ES is the enrichment score for the gene set; NES is...

Table S2. Mice Treated with β-Glucan or PBS Were Injected 7 Days Later with a Single Dose of 5-FU, Related to Figure S6 Results of GSEA on RNA seq data from LT-HSC isolated on day 14 after 5-FU administration using MSigDB hallmark gene set. (NAME is the gene set name; SIZE is the number of genes in the gene set after filtering out those genes not...

The lipid raft concept of membrane sub-compartmentalization was introduced in 1997 and originated from studies on epithelial cell surface polarity. It was the first time that membrane lipid specificity was incorporated into the mechanisms that generate cell architecture. From its epithelial origins, the raft concept was generalized to explain how c...

While the cytosolic events of Wnt/β-catenin signaling (canonical Wnt signaling) pathway have been widely studied, only little is known about the molecular mechanisms involved in Wnt binding to its receptors at the plasma membrane. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt-receptor interaction. W...

Lipidomics have a great potential as clinical tool for monitoring metabolic changes in health and disease. Nevertheless hardly anything is known about the heritability of lipids. Therefore, it is necessary to clarify how and how much we can affect these progresses in individuals. In our interventional twin study (46 healthy, non-obese twin pairs) w...

The lipid composition of human skin is essential for its function; however the simultaneous quantification of a wide range of stratum corneum (SC) and sebaceous lipids is not trivial. We developed and validated a quantitative high-throughput shotgun mass spectrometry-based platform for lipid analysis of tape-stripped SC skin samples. It features co...

The pathogenesis and progression of many tumors, including hematologic malignancies is highly dependent on enhanced lipogenesis. De novo fatty-acid synthesis permits accelerated proliferation of tumor cells by providing membrane components but these may also alter physicochemical properties of lipid bilayers, which can impact signaling or even incr...

(A) Lipid features (fatty acid saturation and length) measured with shotgun MS for “membrane” (PC, PC-O, PE, PE-O, PS, PI, PG, PA, SM, Cer, HexCer, DiHexCer, GM3, Gb3, Gb4) and “storage” lipids (SE, TAG, DAG). (B) Lipid profile of sphingolipids measured in various AML samples. (PDF)

Lipidomic analysis of AML samples. Mol% values of individual lipid species determined with shotgun MS for particular patient samples. Each sample was measured in three independent runs. (XLSX)

Background Diabetes mellitus (DM) and cardiovascular disease are associated with dyslipidemia, but the detailed lipid molecular pattern in both diseases remains unknown. Methods and Results We used shotgun mass spectrometry to determine serum levels of 255 molecular lipids in 316 controls, 171 DM, and 99 myocardial infarction (MI) events from a co...

Table S1. Clinical Characteristics of the Study Samples Table S2. Clinical Characteristics of the MI Events Table S3. Clinical Characteristics of the DM Events Table S4. Model Quality Parameters Tables Table S5. Lipid Species With Significant VIP in the DM Model Table S6. Lipid Species With Significant VIP in the MI Model Table S7. All Lipid...

2-hydroxyoleic acid (OHOA, Minerval®) is an example of a substance used for membrane lipid therapy, where the cellular membranes rather than specific proteins constitute the therapeutical target. OHOA is thought to mediate its anti-tumor effect by affecting the biophysical properties of membranes, which leads to altered recruitment and activation o...

Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic β-amyloid (Aβ) peptides produced by β- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP). β-secretase inhibitors reduce Aβ levels, but mechanism-based side effects arise because they also inhibit...

This Transit Authority commentary is an account of how Ari Helenius started his research on membranes, viruses and detergents.

Glycosylation where glycans are enzymatically attached to proteins is a common post-translational modification among many membrane protein families. The glycans associated with glycosylation serve a variety of structural and functional roles in protein structures, such as recognition and cell-cell adhesion. Determination of glycosylation in membran...

Cell membranes have developed a tremendous complexity of lipids and proteins geared to perform the functions cells require. The lipids have for long remained in the background and are now regaining their role as important building blocks of cells. Their main function is to form the matrix of our cell membranes where they support a variety of functi...

Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are a class of membrane proteins containing a soluble protein attached by a conserved glycolipid anchor to the external leaflet of the plasma membrane. In polarized epithelial cells GPI-APs are predominantly sorted to the apical surface in the Trans Golgi Network (TGN) by clustering in...

Significance The function of the cell membrane as a barrier and a matrix for biochemical activity relies on the properties imparted by lipids. In eukaryotes, sterols are crucial for modulating the molecular order of membranes. Sterol ordering provides the basis for membrane lateral segregation and promotes a fluid, mechanically robust plasma membra...

Figure S1: Lipid extraction kinetics for different lipid classes.

Figure S4: Dynamic range determination per lipid class.

Figure S2: Sample amount titration.

Figure Caprion

Figure S3: Effect of sample amount on the normalized lipid species profile per lipid class.