eGastroenterology最新文献

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease, encompasses a broad range of hepatic metabolic disorders primarily characterised by the disruption of hepatic lipid metabolism, hepatic lipid accumulation and steatosis. Severe cases of MASLD might progress to metabolic dysfunction-associated steatohepatitis, characterised by hepatic inflammation, hepatocyte ballooning degeneration, activation of hepatic stellate cells (HSCs) and fibrogenesis. It may further progress to hepatocellular carcinoma. In the liver, long non-coding RNAs (lncRNAs) target multiple metabolic pathways in hepatocytes, HSCs, and Kupffer cells at different stages of MASLD and liver fibrosis. In this study, we overview recent findings on the potential role of lncRNAs in the pathogenesis of MASLD and liver fibrosis via modulation of de novo lipid synthesis, fatty acid β-oxidation, lipotoxicity, oxidative stress, metabolic inflammation, mammalian target of rapamycin signalling, apoptosis, ubiquitination and fibrogenesis. We critically assess the literature reports that investigate the complex interplay between lncRNA, microRNA and key mediators in liver injury, in both human participants and animal models of MASLD and liver fibrosis. We also highlight the therapeutic potential of lncRNAs in chronic liver diseases.

Background: Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by loss-of-function mutations in the CF transmembrane conductance regulator gene. CF-related pancreatic lesions are known to cause exocrine dysfunctions such as pancreatic insufficiency, and endocrine dysfunctions, including CF related diabetes. In a previous study, we generated CF rabbits using CRISPR/Cas9-mediated gene editing.

Methods: CF rabbits were subjected to histological analysis with a focus on CF associated pancreatic lesions. Endocrine function related assays were conducted to evaluate CF related pancreatic endocrine disorders in these animals.

Results: We report that CF rabbits develop spontaneous pancreatic lesions at a young age, characterised by pancreatic inflammation and fibrosis, vacuolar degeneration, epithelium mucus-secretory cell metaplasia, and pancreatic duct dilation. The size of the pancreatic islets in the CF rabbits is significantly smaller than that of the wild type animals. Consistent with these pathological findings, young CF rabbits exhibited signs of pancreatic endocrine related disorders such as lower insulin levels and impaired glucose metabolism.

Conclusions: Our results suggest that the CF rabbit could serve as a valuable model for translational research on CF related pancreatic endocrine dysfunction.

Endocrine and exocrine functions of the pancreas control nutritional absorption, utilisation and systemic metabolic homeostasis. Under basal conditions, the lysosome is pivotal in regulating intracellular organelles and metabolite turnover. In response to acute or chronic stress, the lysosome senses metabolic flux and inflammatory challenges, thereby initiating the adaptive programme to re-establish cellular homeostasis. A growing body of evidence has demonstrated the pathophysiological relevance of the lysosomal stress response in metabolic diseases in diverse sets of tissues/organs, such as the liver and the heart. In this review, we discuss the pathological relevance of pancreatic lysosome stress in diabetes mellitus. We begin by summarising lysosomal biology, followed by exploring the immune and metabolic functions of lysosomes and finally discussing the interplay between lysosomal stress and the pathogenesis of pancreatic diseases. Ultimately, our review aims to enhance our understanding of lysosomal stress in disease pathogenesis, which could potentially lead to the discovery of innovative treatment methods for these conditions.

Alcohol-associated liver disease (ALD) is a growing global health concern and its prevalence and severity are increasing steadily. While bacterial endotoxin translocation into the portal circulation is a well-established key factor, recent evidence highlights the critical role of sterile inflammation, triggered by diverse stimuli, in alcohol-induced liver injury. This review provides a comprehensive analysis of the complex interactions within the hepatic microenvironment in ALD. It examines the contributions of both parenchymal cells, like hepatocytes, and non-parenchymal cells, such as hepatic stellate cells, Kupffer cells, neutrophils, and liver sinusoidal endothelial cells, in driving the progression of the disease. Additionally, we explored the involvement of key mediators, including cytokines, chemokines and inflammasomes, which regulate inflammatory responses and promote liver injury and fibrosis. A particular focus has been placed on extracellular vesicles (EVs) as essential mediators of intercellular communication both within and beyond the liver. These vesicles facilitate the transfer of signalling molecules, such as microRNAs and proteins, which modulate immune responses, fibrogenesis and lipid metabolism, thereby influencing disease progression. Moreover, we underscore the importance of organ-to-organ crosstalk, particularly in the gut-liver axis, where dysbiosis and increased intestinal permeability lead to microbial translocation, exacerbating hepatic inflammation. The adipose-liver axis is also highlighted, particularly the impact of adipokines and free fatty acids from adipose tissue on hepatic steatosis and inflammation in the context of alcohol consumption.

Goblet cells (GCs) are specialised guardians lining the intestine. They play a critical role in gut defence and immune regulation. GCs continuously secrete mucus creating a physical barrier to protect from pathogens while harbouring symbiotic gut bacteria adapted to live within the mucus. GCs also form specialised GC-associated passages in a dynamic and regulated manner to deliver luminal antigens to immune cells, promoting gut tolerance and preventing inflammation. The composition of gut bacteria directly influences GC function, highlighting the intricate interplay between these components of a healthy gut. Indeed, imbalances in the gut microbiome can disrupt GC function, contributing to various gastrointestinal diseases like colorectal cancer, inflammatory bowel disease, cystic fibrosis, pathogen infections and liver diseases. This review explores the interplay between GCs and the immune system. We delve into the underlying mechanisms by which GC dysfunction contributes to the development and progression of gastrointestinal diseases. Finally, we examine current and potential treatments that target GCs and represent promising avenues for further investigation.

Bile acids are physiological detergents and signalling molecules that are critically implicated in liver health and diseases. Dysregulation of bile acid homeostasis alters cell function and causes cell injury in chronic liver diseases. Therapeutic agents targeting bile acid synthesis, transport and signalling hold great potential for treatment of chronic liver diseases. The broad cellular and physiological impacts of pharmacological manipulations of bile acid metabolism are still incompletely understood. Recent research has discovered new links of bile acid signalling to the regulation of autophagy and lysosome biology, redox homeostasis and endoplasmic reticulum stress. These are well-conserved mechanisms that allow cells to adapt to nutrient and organelle stresses and play critical roles in maintaining cellular integrity and promoting survival. However, dysregulation of these cellular pathways is often observed in chronic liver diseases, which exacerbates cellular dysfunction to contribute to disease pathogenesis. Therefore, identification of these novel links has significantly advanced our knowledge of bile acid biology and physiology, which is needed to understand the contributions of bile acid dysregulation in disease pathogenesis, establish bile acids as diagnostic markers and develop bile acid-based pharmacological interventions. In this review, we will first discuss the roles of bile acid dysregulation in the pathogenesis of chronic liver diseases, and then discuss the recent findings on the crosstalk of bile acid signalling and cellular stress responses. Future investigations are needed to better define the roles of these crosstalks in regulating cellular function and disease processes.