Integrated understanding and targeting metabolic dysregulation in chronic liver disease

Abstract

The liver, vital for various metabolic functions in the body, is susceptible to genetic or environmental factors such as viral infections, diet, or alcohol consumption. These factors can trigger chronic liver disease (CLD), a condition that often progresses silently into more advanced stages, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). With increasing rates of alcohol consumption and metabolic disorders such as metabolic dysfunction-associated steatotic liver disease (MASLD), CLD has become a significant global health burden, contributing to high morbidity and mortality worldwide. This thesis employs systems biology approaches that integrate large-scale omics data to delve into the molecular mechanisms underpinning CLD and evaluate therapeutic interventions targeting metabolic dysfunctions associated with the disease.The first part of the thesis (Papers I and II) aims to enhance our understanding of the molecular basis of CLD using liver transcriptomics and proteomics data. To identify key pathogenic drivers of MASLD development, Paper I entails the deep characterization of transcriptomics data across large patient cohorts through integration analysis with biological networks, offering comprehensive insights into transcriptional dysregulation and its regulation in MASLD. Paper II extends this by combining transcriptomics and proteomics data to characterize both liver and plasma molecular pathophysiology associated with liver fibrosis in individuals with various causes of CLD, including those diagnosed with MASLD, chronic viral hepatitis, and alcohol-related liver disease.The studies in the second part of the thesis (Papers III to VI) aim to explore the systemic effects of potential therapeutic interventions—Combined Metabolic Activators (CMA) and JNK-IN-5A—in targeting metabolic dysfunction associated with MASLD in clinical and preclinical models. Papers III and IV present one-day double-blinded, placebo-controlled human clinical studies examining the acute effects of CMA administration with different formulations. Paper V investigates the effect of short-term CMA treatment on diet-induced liver steatosis in hamsters and characterizes liver transcriptomics changes in response to the treatment. Additionally, Paper VIinvestigates both hepatic and extrahepatic effects of JNK-IN-5A on metabolic dysfunction induced by sucrose overconsumption in rats.In summary, the work described here contributes to ongoing efforts in the molecular characterization of chronic liver diseases and the development of effective treatments for MASLD. The findings could help pave the way for new approaches in diagnosing and treating liver diseases, offering hope for better management strategies in the future.

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