Investigating the role of growth hormone on hepatic lipids

Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity, insulin resistance and type 2 diabetes and develops on the background of chronic overnutrition and a lack of exercise due to our industrialized lifestyle. The accumulation of fat in the liver is mainly regulated by lipid synthesis (de novo lipogenesis), energy consumption (lipid oxidation / ATP turnover) and hepatic lipid export via VLDL secretion. Despite its high prevalence, up to now there is no established clinically effective medical therapy for NAFLD. Notably, recent data in patients suffering from acromegaly, a rare disease defined by long-term growth hormone (GH) excess, show that hepatic lipid content is extremely low compared to a control population of similar age, sex and body weight. On the other hand, patients suffering from GH deficiency show increased visceral and hepatic fat accumulation, which improves following the initiation of GH substitution therapy. This study thus aims to comprehensively elucidate the effects of GH on hepatic lipid accumulation in humans by combining tracer infusion experiments with state-of-the-art magnetic resonance (MR) imaging techniques. GH might exert antisteatotic action through multiple mechanisms, including increased hepatic lipid export via VLDL secretion, increased local energy consumption (lipid oxidation / ATP turnover) and decreased de novo lipogenesis (DNL). These will be investigated a group of healthy volunteers following short-term daily administration of GH or the GH antagonist pegvisomant. Identifying potential pathways by which GH exerts its antisteatotic effects might help to identify novel therapeutic targets for future liver specific GH agonists.

Growth hormone has profound effects on human hepatic fat metabolism. In our research project, we investigated the effects of short- and long-term modulation of growth hormone (GH) on various regulatory mechanisms of fat metabolism in the liver using advanced magnetic resonance imaging combined with tracer infusion techniques. In a study focusing on short-term GH excess, ten healthy male subjects received daily injections of GH or the GH receptor blocker Pegvisomant for one week each in a crossover study design. Before and after treatment, we assessed i) intrahepatic lipid content (IHL) using 1H-magnetic resonance spectroscopy (MRS), ii) hepatic triglyceride secretion via very-low-density lipoproteins (VLDL) using an Intralipid infusion protocol, iii) hepatic energy expenditure via 31P-MRS, and iv) de novo lipogenesis (DNL) using a novel method with stable isotope tracers. Additional methods included standardized laboratory analyses, clinical examination results, and body composition analysis. Measurements in this population have been completed, and the data were published in the Journal of Clinical Endocrinology and Metabolism (doi: 10.1210/clinem/dgaf155) and awarded two prizes at national congresses (ÖGES Science Award 2024, ÖDG Abstract Award 2024). The results showed a significant increase in VLDL triglyceride secretion after short-term GH excess, while DNL tended to increase after short-term blockade of GH action by Pegvisomant. Additionally, to develop new methods for assessing DNL, DO metabolism-including novel deuterium metabolic imaging techniques using 2H-MRS-was evaluated in ten healthy male subjects. The study experiments have been completed, samples have been collected, and data are currently being analyzed. Initial results from this research project are expected by mid-2026. The methodology established in healthy subjects was also applied to patients with acromegaly, a condition characterized by chronic GH excess, during the active disease state and after biochemical control following therapy. Data collection in this population is not yet complete, and results will be published following the successful conclusion of study-related activities. Preliminary analyses, however, suggest that-unlike short-term GH exposure-long-term exposure does not lead to a sustained increase in VLDL secretion. Instead, the effects on hepatic fat metabolism appear to be due to increased consumption or inhibited synthesis. In summary, our project provides new insights into GH-dependent modulation of hepatic fat metabolism. As a translational study, this work significantly contributes to understanding the role of GH in anti-steatotic mechanisms in humans and could lead to the development of new, GH signaling-based therapeutic strategies for metabolically associated steatotic liver disease. Follow-up projects using GH as a therapy for patients with fatty liver disease are in planning.