Publications

The liver is frequently exposed to acute and chronic insults that disrupt its function, leading to inflammation, fibrosis, and serious conditions like cirrhosis and hepatocellular carcinoma. Fibrosis, driven by the activation of hepatic stellate cells is a key feature of chronic liver damage. Traditional 2D liver models face limitations in maintaining liver functions and accurately replicating chronic conditions like fibrosis. In response to these needs, 3D models have emerged as more physiologically relevant platforms for studying liver disease and drug testing. However, most existing 3D models still lack chronic injury features or immune elements. In this study, we developed a 3D human-liver model to investigate both acute and chronic drug-induced liver injury. The model consists of encapsulated human hepatocytes (HepaRG) and hepatic stellate cells (LX-2) within a gelatin methacryloyl (GelMA) and carboxymethyl cellulose methacrylate matrix. Over a 30-day culture period, the 3D liver constructs maintained physiologically relevant functions, including albumin secretion and cytochrome P450 activity, which are lost rapidly in conventional 2D models. The model enabled reliable simulation of low-level, long-term, and high-dose, short-term damage by administering lipopolysaccharide and Paracetamol. Chronic liver injury was characterized by progressive fibrosis, elevated expression of COL1A1, and persistent hyperammonemia. In contrast, acute models showed significant but transient injury. Moreover, dexamethasone treatment successfully reversed fibrotic markers and restored hepatocyte functionality, indicating the model's predictive power for evaluating potential therapies. Incorporating human monocytes (THP-1) allowed investigation of the immune response and macrophage activation, which are critical contributors to liver disease pathogenesis. Overall, this 3D liver model offers a physiologically relevant and versatile platform for studying complex multi-cellular interactions under acute and chronic injury. It has broad implications for drug safety screening, disease modeling, and personalized therapy. The tri-culture design extends the model's capacity to elucidate immune-driven hepatic pathology.

JTD Keywords: 3d liver model, Acute liver injury, Chronic liver injury, Culture, Drug-induced hepatotoxicity, Failure, Hepatic fibrosis, Hepatic stellate cells, Injury, Liver disease modeling

Prevalence and risk factors for hepatic steatosis (HS) in the human immunodeficiency virus (HIV)-positive population of western countries are controversially discussed and potentially confounded by coinfection with viral hepatitis. Significant HS (more than 10% of hepatocytes) can be accurately assessed using controlled attenuation parameter (CAP) determination. Aim of this study was to assess prevalence and factors associated with significant HS in HIV monoinfected patients. A total of 364 HIV-infected patients (289 monoinfected) were included in this prospective, cross-sectional study. All patients underwent CAP determination. Steatosis was classified as S1 (significant steatosis) with CAP > 238 dB/m, S2 with CAP > 260 dB/m, and S3 with CAP > 292 dB/m. Multivariable logistic regression analyses were performed to assess the factors associated with HS in this cohort. Significant HS was detected in 118 monoinfected patients (149 in the total cohort). In the total cohort as well as in the monoinfected patients alone, HS grade distribution showed a similar pattern (S1:29%, S2:34%, and S3:37%). Interestingly, patients with HS had a longer history of HIV infection and combined antiretroviral therapy (cART). Interalia, age, gender, ethnicity, and metabolic factors were strongly associated with HS, while body mass index (BMI), triglyceride, and glycated hemoglobin (HbA1c) levels were independently associated with significant HS. HS is highly prevalent among HIV monoinfected patients. Although metabolic risk factors, such as obesity and poorly controlled diabetes, are independently associated with HS in HIV monoinfected patients, cART and control of HIV seem to play an indirect role in the development of HS, probably through the return-to-health effect.

JTD Keywords: CAP, cART, HIV monoinfection, liver injury, NAFLD