Research

The incidence of non-alcoholic or metabolic-associated fatty liver disease (NAFLD / MAFLD), which is characterized by hepatic lipid accumulation, is correlated with the body mass index. NAFLD is generally considered to be the hepatic manifestation of metabolic syndrome and is the most frequent cause of functional disorders of the liver. NAFLD comprises both the mild form of benign hepatic steatosis (fatty liver) as well as the progressive form of non-alcoholic steatohepatitis (NASH), in which hepatic steatosis is accompanied by inflammation and fibrosis. The development of NASH may result in hepatocellular carcinoma, liver cirrhosis and terminal organ failure. High fat diets and dietary cholesterol might impact the transition from fatty liver to NASH.

While saturated fatty acids and cholesterol as an animal lipid are generally considered harmful to health at elevated consumption levels, unsaturated fatty acids are regarded as potentially "good fats". The current general dietary recommendations of the German Nutrition Society specify that saturated fatty acids should be replaced by unsaturated fatty acids.

Our previous research demonstrated that the combination of soybean oil-based high fat diets, which are rich in omega-6-poly-unsaturated fatty acids, and dietary cholesterol initiated the pathogenesis of steatohepatitis (NASH) with excessive lipid accumulation, hepatocyte death and inflammation, whereas lard-based high fat diets, which consists mainly of saturated fatty acids, and dietary cholesterol lead to a fatty liver without severe inflammation in rodents.

Our current research investigates the role of dietary lipids in patho-biochemical and patho-physiological processes in the liver and other organs. We focus on the molecular mechanisms, how the fatty acid quality (saturated, mono-unsaturated, omega-3-poly-unsaturated and omega-6-poly-unsaturated) alone and in combination with cholesterol influence hepatocyte metabolism and lead to cellular damage.

A prolonged high-calorie diet with foods high in fat and sugar leads to fat accumulation and obesity. The diet-mediated expansion of white adipose tissue is associated with the development of insulin resistance and a low-grade inflammation.

Prostanoids are fatty acid-derived signal mediators with important regulatory functions, e.g. in adipose tissue formation, vascular homeostasis, renal function, bone remodeling as well as in the immune system, gastrointestinal tract, reproductive and neuroendocrine systems. Furthermore, they display a dominant role in the (patho-) physiology of the liver by modulating the sinusoidal blood flow and the transendothelial barrier function or influencing acute phase response and regenerative processes. Resident macrophages of the liver, the Kupffer cells, represent the largest pool of macrophages in the organism and, in parallel with other inflammatory mediators, produce mainly the prostanoid prostaglandin E₂ (PGE₂). This occurs primarily through increased induction of the prostaglandin E-generating enzymes cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1) by stimuli such as endotoxins or fatty acids.

In obesity-associated insulin resistance, inflammatory mediators from the adipose tissue in combination with dietary components from the intestine reach the liver and activate the resident macrophages there. As a consequence, macrophages initiate an inflammatory response that involves secretion of immune cell recruiting chemokines, pro-inflammatory cytokines and prostanoids such as prostaglandin E₂ (PGE₂).

The aim of the project is to elucidate the impact of the bioactive lipid PGE₂ in the development of obesity, insulin resistance, hepatic steatosis and inflammation in diet-induced fatty liver inflammation (NASH) and other metabolic diseases. This includes intervention studies in transgenic mice with tissue-specific deletion of prostaglandin E-generating enzymes as well as in vitro studies with cell lines and primary cells isolated from wild-type and transgenic mice.

Macrophages are phagocytosing cells of the immune system. Both in acute inflammatory reactions such as infections and in chronic inflammatory reactions, macrophage precursor cells (monocytes) migrate into affected tissues and influence their metabolism. Overweight or obese patients often suffer from such a low-grade chronic inflammation in addition to dyslipidemia, insulin resistance with an ensuing hyperinsulinemia and a mild endotoxinemia that results from an impaired intestinal barrier function. Macrophages play a central role in this setting and are exposed to a mixture of potential modulators of an inflammatory response. This includes fatty acids released from the insulin resistant adipocytes, elevated levels of insulin produced to compensate insulin resistance as well as bioactive lipids such as prostaglandin E₂ (PGE₂), which are released from activated macrophages.

In this project we investigate the interplay between these and other nutrition-related parameters on the differentiation and activation of macrophage as well as the extent of their inflammatory response using human cell lines and primary macrophages.

In addition to the macro- and micronutrients that are used for human nutrition, plants also produce other substances known as natural products, phytonutrients or secondary metabolites. These include phenolic, isoprenoid and alkaloid compounds, whose health-promoting effects are often discussed.

Essential oils are complex mixtures of volatile, lipophilic and odorous compounds from the secondary metabolism of plants and consist mainly of mono- and sesquiterpenes. They are often used as therapeutic agents due to their anti-inflammatory, anti-viral and anti-microbial properties. The monoterpene pinene, which has two active structural isomers, is mainly formed in lavender, rosemary and various conifers including pine trees, where it is largely responsible for the typical smell that we associate with a Christmas tree. Pinenes support the plant immune response within and between plants, but their effect on human cells has so far been insufficiently investigated.

This project investigates the effects of the isomers of pinene on metabolic processes in different cell models, e.g. the influence on the induced inflammatory response in macrophages or on the activation of stress kinase in hepatocytes.

The world population is expected to reach 9.7 billion people by 2050, necessitating a profound shift in food production and consumption strategies. Conventional food production systems such as livestock farming, which is mainly used to produce protein-rich products such as meat, eggs and milk, have to face ecological, ethical and economic challenges. Therefore, a transformation of the food system is necessary in the medium and long term, including the use of alternative protein sources such as edible insects and microalgae.

In the EU, some species of edible insects, e.g. mealworm (Tenebrio molitor) and buffalo worm (Alphitobius diaperinus) as well as migratory locust (Locusta migratoria) and house cricket (Acheta domesticus), are already approved as novel foods. They are proving to be a promising sustainable source of nutrients due to their low environmental impact, resource efficiency and competitive nutrient profile. Despite their potential, the widespread acceptance of insects as a food source is hindered by barriers in cultural acceptance and disgust, but also critical knowledge gaps. These include the assessment of the nutritional content, the microbial and toxic load or the allergenic potential of insects.

Microalgae such as spirulina (Arthrospira platensis) and Porphyridium purpureum are other promising alternative protein sources. To date, they have mainly been used in cosmetic products, as animal feed and for coloring food, but the comparatively high protein content in microalgae has not yet been used for human nutrition. In addition, some pigments of these colored microalgae, the so-called phycobiliproteins, are described as bioactive components that could have anti-oxidative, anti-inflammatory and even anti-carcinogenic effects on human cells.

Various edible insects and microalgae are being analyzed in subprojects with regard to their nutritional potential. In addition, the extent to which bioactive peptides from microalgae influence metabolic processes in various cellular models is being investigated.

Telomeres are repetitive structures found at the ends of chromosomes, which function to protect essential genetic material during DNA replication. DNA polymerases cannot fully replicate linear chromosomes, therefore the telomeres, instead of functional genes, are successively shortened at each cell division. When telomeres become critically short, cells stop dividing and become senescent. This process has been described as a molecular clock of aging and is also discussed as a protection against cancer. Stem cells are responsible for continuously renewing and regenerating our tissues by dividing and differentiating into various cell types. In order to slow the aging process, stem cells express Telomerase, an enzyme that can extend telomeres during cell division. Telomere shortening and the resulting stem cell exhaustion are considered major hallmarks of aging and can lead to age-related diseases, including inflammation and fibrosis. Furthermore, reduced Telomerase activity and/or telomere instability can lead to premature aging syndromes such as Telomere Biology Disorders (TBDs). Crucially, Telomerase activity and telomere length are influenced by nutrition, including factors such as body weight, alcohol consumption, caloric restriction and food choice, providing an important link between nutrition and healthy aging. The identification of Telomerase activating nutrients and compounds holds considerable promise in slowing the decay or even restoration of telomere length in age-related diseases.

In this project we are using different cell models to identify active nutrients and chemicals that modulate telomere length to better understand the pathways and genes affecting telomere stability. Furthermore, we are also interested in telomere dynamics in diet-induced fatty liver diseases.