Research

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common metabolic disorders, affecting more than one-third of the world’s population. This metabolic disorder is defined by the presence of fatty liver and at least one cardiometabolic risk factor (e.g., obesity, hyperglycemia, prediabetes/diabetes, hypertension, dyslipidemia). The spectrum of MASLD encompasses both simple steatosis and the severe form of metabolic dysfunction-associated steatohepatitis (MASH), in which steatosis is accompanied by hepatic inflammation and, in some cases, fibrosis. The presence of MASH significantly increases the risk of liver cirrhosis and the development of hepatocellular carcinoma. Several risk factors for MASLD and its progression have been identified, including an unhealthy lifestyle characterized by a high-calorie diet rich in sugar and fat.

However, the consumption of dietary lipids must be viewed in a more nuanced way. While the consumption of high amounts of saturated fatty acids and cholesterol from animal sources is generally considered harmful to health and may promote the progression to MASH, polyunsaturated fatty acids in particular are predominantly attributed with health-promoting properties. The recommendations of the German Nutrition Society (DGE) call for replacing saturated fatty acids with unsaturated ones.

However, our previous animal studies showed that the combination of a soybean oil-based high-fat diet, which contains large amounts of omega-6 fatty acids, and dietary cholesterol led to the development of steatohepatitis (NASH/MASH) with excessive lipid accumulation, inflammation, and incipient fibrosis. In contrast, animals fed a similar high-fat diet and cholesterol, but with lard as the fat source – which contains primarily saturated fatty acids – also became obese and insulin-resistant, yet they developed only simple fatty liver without significant signs of inflammation.

In current research projects, we are investigating the influence of dietary lipids in the context of pathobiochemical and pathophysiological processes in the liver and other organs such as muscle and adipose tissue. We focus on the molecular mechanisms by which fatty acid quality (saturated, monounsaturated, omega-3, and omega-6 polyunsaturated fatty acids) and the combination of different fatty acids and cholesterol impair metabolism in hepatocytes and lead to cellular damage.

Metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) have become a major global health problem. Risk factors for MASLD and its progression to severe MASH with fibrosis include high-calorie diets rich in sugar and fat, but also low physical activity, overweight and obesity, as well as comorbidities such as metabolic syndrome. Furthermore, it is suspected that other relatively common conditions, such as small intestinal bacterial overgrowth (SIBO), occur more frequently in patients with liver disease compared to the general population. The clinical symptoms of SIBO vary and often include abdominal pain, bloating, diarrhea, or constipation, and in more severe cases, malabsorption syndrome. SIBO can lead to inflammatory reactions, which are thought to be a cause of impaired intestinal barrier integrity. It is hypothesized that the resulting endotoxemia and the translocation of bacteria via the portal vein to the liver could influence the incidence and progression of MASLD.

A deeper understanding of the potential role of SIBO as a triggering factor is important for developing further effective measures that can delay or even halt the progression of the disease to the severe form known as MASH and to liver cirrhosis.

As part of a pilot study, we are collaborating with Kulmbach Hospital and two industry partners to investigate whether the pattern and intensity of inflammation- and fibrosis-associated factors differ in patients with MASLD when small intestinal bacterial overgrowth is also present. The study uses data and biomaterials collected during routine clinical care. The results of the pilot study are intended to serve as the basis for subsequent studies.

The world population is projected to reach 9.7 billion by 2050, requiring a profound transformation in food production and consumption strategies. Conventional food production systems, such as livestock farming – which is primarily used to produce protein-rich products like meat, eggs, and milk – face ecological, ethical, and economic challenges. Therefore, a transformation of the food system is necessary in the medium and long term, one that includes the use of alternative protein sources such as edible insects and microalgae.

In the European Union, several species of edible insects – such as the mealworm (Tenebrio molitor) and the buffalo worm (Alphitobius diaperinus), as well as the migratory locust (Locusta migratoria) and the house cricket (Acheta domesticus) – have already been approved as novel foods. Due to their low environmental impact, resource efficiency, and competitive nutritional profile, they are proving to be a promising sustainable source of nutrients. Despite their potential, the widespread acceptance of insects as a food source is hindered by barriers related to cultural acceptance and disgust, as well as critical knowledge gaps. These include the assessment of nutrient content, microbial and toxic contamination, and allergenic potential.

In subprojects, various edible insects and microalgae are being comparatively analyzed for their nutritional potential. In addition, initial products are being produced and characterized biochemically and sensorily, in which a portion of the meat has been replaced by insect meal.

In addition to the experimental studies, nutrition workshops and tastings featuring alternative products already available on the market are being conducted to raise awareness among children and adults about sustainable and healthy nutrition.

A long-term high-calorie diet rich in fatty and sugary foods leads to obesity and adiposity. Diet-induced expansion of white adipose tissue is associated with the development of insulin resistance and low-grade inflammation. Prostanoids are signaling molecules derived from fatty acids that perform important regulatory functions, e.g., in adipose tissue formation, vascular homeostasis, renal function, bone remodeling, as well as in the gastrointestinal tract, the reproductive system, the neuroendocrine system, and the immune system. They also play an important role in the (patho)physiology of the liver, as they modulate, among other things, sinusoidal blood flow and the transendothelial barrier function, and influence the acute-phase response and regenerative processes. The macrophages resident in the liver, known as Kupffer cells, constitute the largest macrophage pool in the body and, in addition to other inflammatory mediators, primarily produce 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 adipose tissue, in addition to dietary components from the gut, reach the liver and activate the resident macrophages there. These immune cells then initiate an inflammatory response that involves the release of immune cell-recruiting chemokines, pro-inflammatory cytokines, and prostanoids such as prostaglandin E₂ (PGE₂).

A subproject of the research group aims to further elucidate the influence of the bioactive lipid PGE₂ on the development of obesity, insulin resistance, hepatic steatosis, and inflammation in diet-induced metabolic dysfunction-associated steatohepatitis (MASH) and other metabolic diseases. This also includes intervention studies in transgenic mice with tissue-specific deletion of prostaglandin E-generating enzymes, as well as in vitro studies using cell lines and primary cells isolated from wild-type and transgenic mice.

Macrophages are phagocytic cells of the immune system that play a key role in inflammatory responses. In both acute inflammatory reactions, such as infections, and chronic inflammatory reactions, macrophage precursor cells (monocytes) migrate into affected tissues and can modulate their metabolism. Overweight or obese patients often suffer from such low-grade chronic inflammation in white adipose tissue. This is compounded by dyslipidemia, insulin resistance with resulting hyperinsulinemia, and mild endotoxemia resulting from impaired intestinal barrier function. Macrophages play a central role in this metabolic environment and are exposed to a combination of potential stimulators and modulators. These include fatty acids released from insulin-resistant adipocytes, elevated insulin levels produced to compensate for insulin resistance, and bioactive lipids such as prostaglandin E₂ (PGE₂), which are released by activated macrophages. On the other hand, ketone bodies, whose plasma concentrations rise significantly during fasting or on ketogenic diets, can also influence the differentiation and activation of macrophages.

This project focuses on the interaction between these and other diet-related parameters and their influence on the differentiation and activation of macrophages, as well as the extent of the resulting inflammatory response.

In addition to the macro- and micronutrients used in the human diet, plants also produce other substances known as natural compounds, phytonutrients, or secondary metabolites. These include, among others, phenolic, isoprenoid, and alkaloid compounds, whose health-promoting effects are frequently discussed.

Monoterpenes such as pinene, which exist in two structural isomers and are primarily produced in lavender, rosemary, and various coniferous trees, support the plant immune response within and between plants; however, their effects on human cells have not yet been sufficiently investigated. Prenylflavonoids such as xanthohumol and their degradation products are primarily found in hops but undergo changes during processing steps such as beer brewing. Microalgae such as Porphyridium purpureum form protein-pigment complexes (phycobilisomes) as colored structures for energy production through photosynthesis, which can be broken down by digestive processes into potentially bioactive peptides and other secondary structures.

Various subprojects are investigating the effects of these metabolites on inflammatory and metabolic processes in different cell models, such as their influence on the induced inflammatory response in macrophages or on the regulation of insulin-mediated glucose metabolism in hepatocytes.

Telomeres are repetitive structures at the ends of chromosomes that protect essential genetic information during DNA replication. DNA polymerases cannot fully replicate linear chromosomes. Therefore, telomeres – rather than functional genes – are successively shortened with each cell division. When telomeres fall below a critical length, cells stop dividing and become senescent. This process has been described as the molecular clock of aging, but it is also thought to protect against the spread of cancer. Stem cells renew and regenerate our tissues through cell division and differentiation into various cell types. To slow down the aging process, stem cells produce telomerases – enzymes that can lengthen telomeres during cell division. The shortening of telomeres and the resulting senescence of stem cells are key features of the aging process and can lead to age-related diseases involving inflammation and fibrosis.

Furthermore, reduced telomerase activity and/or telomere instability can lead to premature aging disorders, such as telomere biology disorders (TBDs). Our lifestyle – including dietary habits and factors such as body weight, alcohol consumption, calorie restriction, and food choices – can influence telomerase activity and telomere length. This represents an important link between nutrition and health in old age. Identifying nutrients and compounds that increase telomerase activity offers an opportunity to slow the rate of telomere shortening in age-related diseases or even to extend telomere length.

In this project, various cell models are used to identify nutrients and other nutritional substances that may influence telomere length. This allows us to better understand the signaling pathways and genes that influence telomere stability. Additionally, we are also interested in telomere length dynamics in the liver in diet-induced steatotic liver disease.